Calcium Pyrophosphate Deposition Disease (CPPD)

1. Clinical Overview

Summary

Calcium pyrophosphate deposition disease (CPPD) is a crystal arthropathy caused by deposition of calcium pyrophosphate dihydrate (CPP) crystals in articular and periarticular tissues. The condition encompasses a spectrum of clinical phenotypes ranging from asymptomatic chondrocalcinosis to acute inflammatory arthritis ("pseudogout") and chronic degenerative arthropathy [1,2].

CPPD predominantly affects older adults, with radiographic chondrocalcinosis present in 15-30% of people aged > 70 years and up to 50% of those > 90 years. However, symptomatic disease is considerably less common than radiographic findings suggest [3].

The acute CPP crystal arthritis (formerly "pseudogout") phenotype mimics gout and septic arthritis, presenting with sudden onset severe joint pain, swelling, warmth and erythema. The knee and wrist are the most commonly affected joints. Clinically distinguishing acute CPP arthritis from septic arthritis is impossible - joint aspiration is mandatory in all cases [4].

The gold standard diagnosis requires identification of weakly positively birefringent, rhomboid-shaped crystals under compensated polarised light microscopy. This contrasts with gout, where crystals are strongly negatively birefringent and needle-shaped [5].

Unlike gout, there is no disease-modifying therapy for CPPD. Management focuses on acute flare treatment (NSAIDs, colchicine, corticosteroids) and addressing underlying metabolic conditions when identified [6].

Key Facts

Clinical Pearls

The "Blue = Positive = Pseudogout" Pearl: Under compensated polarised microscopy, CPPD crystals are rhomboid/rectangular and weakly POSITIVELY birefringent - they appear blue when parallel to the compensator axis. Mnemonic: "Blue Parallel = Pseudogout Positive". This contrasts with gout crystals which are yellow when parallel (negative birefringence) [5].

The "Always Aspirate" Pearl: Acute monoarthritis in an elderly patient is septic arthritis until proven otherwise. You CANNOT distinguish pseudogout from septic arthritis clinically - the clinical features are identical. Joint aspiration with Gram stain, culture and crystal analysis is mandatory. Remember: crystals and infection can coexist [7].

The "Young Pseudogout = Metabolic Screen" Pearl: CPPD disease presenting in patients less than 55 years is unusual and should prompt investigation for underlying metabolic causes. Order calcium, PTH, magnesium, ferritin, transferrin saturation, and phosphate. The "3 H's" are key: Hyperparathyroidism, Haemochromatosis, Hypomagnesaemia [8].

The "Crowned Dens Syndrome" Pearl: CPPD can cause acute neck pain and fever due to calcification around the odontoid process (atlantoaxial region). This mimics meningitis and can cause fever of unknown origin in the elderly. CT cervical spine shows characteristic crown-like calcification around the dens [9].

Why This Matters Clinically

CPPD is a common cause of acute joint pain in hospitalised elderly patients and is frequently encountered in general medicine, orthopaedics and emergency settings. The critical clinical challenge is excluding septic arthritis, which requires urgent joint aspiration. Missing septic arthritis leads to rapid joint destruction, systemic sepsis and death. Conversely, over-treating presumed septic arthritis with prolonged antibiotics in patients with CPPD exposes them to unnecessary risks and healthcare costs [4].

Recognition of CPPD is also important because it may signal undiagnosed metabolic disease (particularly haemochromatosis or hyperparathyroidism) that requires specific treatment [8].

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2. Epidemiology

Incidence and Prevalence

CPPD is primarily a disease of ageing, with prevalence increasing dramatically with age [3,10]:

Symptomatic CPPD (acute attacks or chronic arthropathy) is considerably less common than radiographic findings:

• Annual incidence of acute CPP crystal arthritis: approximately 1.5-6 per 1000 person-years in those with chondrocalcinosis
• Most chondrocalcinosis (> 80%) remains asymptomatic throughout life [3]

Demographics

Risk Factors

Non-Modifiable Risk Factors:

• Advanced age - strongest risk factor
• Family history - familial/hereditary CPPD exists (autosomal dominant, linked to ANKH gene mutations)
• Previous joint trauma or surgery - cartilage damage predisposes to crystal deposition
• Pre-existing osteoarthritis - CPPD commonly deposits in OA-affected joints
• Female sex post-menopause (slight increase vs. males in older age groups)

Metabolic/Secondary Causes (The "3 H's" and Beyond):

Mnemonic - The "5 H's": Hyperparathyroidism, Haemochromatosis, Hypomagnesaemia, Hypophosphatasia, Hypothyroidism

Triggers for Acute Attacks

Acute CPP crystal arthritis attacks are often precipitated by:

• Acute medical illness (MI, stroke, pneumonia, surgery)
• Trauma (including minor trauma)
• Parathyroidectomy (rapid calcium flux)
• Bisphosphonate therapy (rare)
• Joint lavage or aspiration
• Blood transfusion
• IV fluid administration (particularly in hospitalised patients)

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3. Pathophysiology

Crystal Formation and Deposition

Step 1: Pyrophosphate Generation

CPP crystals form when there is supersaturation of calcium and pyrophosphate in the pericellular matrix of cartilage. Inorganic pyrophosphate (PPi) is generated by:

1. Chondrocyte metabolism - PPi is a byproduct of many biosynthetic reactions
2. ANKH protein - transmembrane transporter that exports intracellular PPi to the extracellular space
3. ENPP1 (Ectonucleotide pyrophosphatase) - generates PPi from extracellular ATP
4. Tissue-nonspecific alkaline phosphatase (TNAP) - normally degrades PPi; deficiency leads to accumulation [11]

Step 2: Crystal Nucleation

• CPP crystals preferentially form in fibrocartilage (menisci, TFCC, symphysis pubis, annulus fibrosus)
• Also deposit in hyaline cartilage (articular surfaces)
• Crystal nucleation is favoured by:
  • Elevated extracellular PPi concentration
  • Appropriate calcium concentration
  • Matrix proteins (type I collagen, proteoglycans)
  • Ageing cartilage with altered matrix composition

Step 3: Crystal Shedding ("Flare Trigger")

• Crystals shed from cartilage into synovial fluid
• Triggers include:
  • Trauma
  • Metabolic stress (illness, surgery)
  • Partial crystal dissolution (exposes new crystal surfaces)
  • Matrix degradation in OA

Step 4: Inflammatory Response

The acute inflammatory response to CPP crystals involves [12,13]:

1. Crystal phagocytosis by synovial macrophages and neutrophils
2. NLRP3 inflammasome activation - CPP crystals activate this intracellular danger-sensing platform
3. IL-1 beta and IL-18 release - key pro-inflammatory cytokines driving the acute response
4. Neutrophil recruitment - IL-8/CXCL8 chemotaxis brings neutrophils flooding into the joint
5. Prostaglandin and cytokine storm - TNF-alpha, IL-6, PGE2 amplify inflammation

Step 5: Resolution

• Self-limiting over days to weeks (1-2 weeks typical)
• Crystal coating with proteins (apolipoprotein E) reduces inflammatory potential
• Anti-inflammatory mediators (IL-10, TGF-beta) restore homeostasis
• Crystals may persist in fluid or re-deposit in cartilage

CPPD Phenotypes (Clinical Classification)

The EULAR/ACR classification recognises distinct clinical phenotypes [1,2]:

Anatomical Predilection Sites

CPP crystals deposit preferentially in specific anatomical locations:

• destructive arthropathy | | Hip | Labral fibrocartilage; articular cartilage | Accelerated OA; can cause rapid joint destruction | | Achilles Tendon | Enthesis | Enthesopathic calcification |

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4. Clinical Presentation

Acute CPP Crystal Arthritis ("Pseudogout")

Typical Presentation:

Joint Distribution:

• Knee: 50% of acute attacks (most common)
• Wrist: 25-30%
• Shoulder: 10-15%
• Ankle: 5-10%
• MCP joints: 5-10%
• Hip: 5% (often presents as difficulty weight-bearing)
• Elbow: less than 5%
• Polyarticular: 10-20% (more common than in gout)

Chronic CPP Crystal Arthritis ("Pseudo-RA")

OA with CPPD ("Pseudo-OA")

Crowned Dens Syndrome

Examination Findings

Inspection:

• Swollen joint with visible effusion
• Overlying erythema
• Joint held in position of comfort (knee: slight flexion; hip: flexion/abduction/external rotation)

Palpation:

• Warmth (compare with contralateral joint)
• Tenderness - diffuse over joint line
• Fluctuant effusion (ballottement/patellar tap positive in knee)

Movement:

• Active range: severely limited by pain
• Passive range: limited and painful
• No crepitus (distinguishes from pure OA)

Red Flags Requiring Urgent Action

[!CAUTION] Red Flags - Joint aspiration is mandatory if any present:

• High fever (> 38.5C) or rigors
• Immunocompromised (diabetes, steroids, HIV, biologics, malignancy)
• Prosthetic joint
• Post-procedural (after injection, surgery, or arthroscopy)
• Failure to improve within 48-72 hours of appropriate treatment
• Overlying skin infection or wound
• Polyarticular onset with systemic features
• Very young patient (less than 55 years) - suggests metabolic disease

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5. Investigations

First-Line: Joint Aspiration (Essential)

Joint aspiration with synovial fluid analysis is the GOLD STANDARD for diagnosis [5,14].

Synovial Fluid Analysis

Crystal Identification (Polarised Light Microscopy)

Mnemonic for Birefringence:

• "Blue Parallel = Pseudogout Positive" (Blue = Positive = Pseudogout)
• "Yellow Parallel = Gout" (Yellow = Negative = Gout, think "YelloNeg-ative")

Key Points:

• CPP crystals may be intracellular (within neutrophils) or extracellular
• Crystals are often smaller and harder to see than urate crystals
• Sensitivity of crystal identification depends on operator experience
• Crystals do NOT exclude septic arthritis - both can coexist [7]

Laboratory Investigations

Metabolic Screening (Indicated if Age less than 55 or Polyarticular)

Imaging

Plain Radiographs

Classic X-ray Sites for Chondrocalcinosis:

1. Knee - linear calcification in menisci (best seen on AP view)
2. Wrist - triangular fibrocartilage (TFCC); scapholunate ligament
3. Symphysis pubis - fibrocartilaginous disc
4. Shoulder - glenoid labrum
5. Intervertebral discs - annulus fibrosus

Ultrasound

Advantages: No radiation; can guide aspiration; good for soft tissue assessment

CT Scanning

MRI

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6. Differential Diagnosis

Primary Differentials

"Pseudo" Syndromes of CPPD

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7. Management

Management Algorithm

ACUTE CPP CRYSTAL ARTHRITIS MANAGEMENT
                ↓
┌─────────────────────────────────────────────────────────────────┐
│                     STEP 1: EXCLUDE SEPSIS                      │
│    • Joint aspiration is MANDATORY                              │
│    • Send: Microscopy, Gram stain, Culture, Crystal analysis    │
│    • Consider blood cultures                                    │
└─────────────────────────────────────────────────────────────────┘
                ↓
┌─────────────────────────────────────────────────────────────────┐
│               STEP 2: SINGLE JOINT - FIRST LINE                 │
│                                                                 │
│    INTRA-ARTICULAR CORTICOSTEROID (Preferred)                   │
│    • Methylprednisolone acetate 40-80mg (large joint)           │
│      or Triamcinolone acetonide 40mg                            │
│    • Immediate pain relief; avoids systemic side effects        │
│    • Can be given at time of aspiration                         │
└─────────────────────────────────────────────────────────────────┘
                ↓
        If IA steroid not possible or multiple joints:
                ↓
┌─────────────────────────────────────────────────────────────────┐
│               STEP 3: SYSTEMIC OPTIONS                          │
│                                                                 │
│    OPTION A: NSAIDs (if no contraindications)                   │
│    • Naproxen 500mg BD or Indomethacin 50mg TDS                 │
│    • Duration: 7-14 days or until resolution                    │
│    • PPI cover recommended                                      │
│    • AVOID if: CKD, CVD, GI bleeding, heart failure, elderly    │
│                                                                 │
│    OPTION B: Colchicine                                         │
│    • 500mcg BD-TDS (max 6mg in first 24h traditionally,         │
│      but low-dose preferred: 1mg then 500mcg 1 hour later)      │
│    • Reduce dose in CKD (eGFR less than 30: 500mcg OD or avoid)          │
│    • Watch for GI side effects (diarrhoea, nausea)              │
│                                                                 │
│    OPTION C: Oral Corticosteroids                               │
│    • Prednisolone 30-40mg OD for 3-5 days, then taper           │
│    • Ideal for polyarticular involvement                        │
│    • Caution in diabetes (monitor glucose)                      │
└─────────────────────────────────────────────────────────────────┘
                ↓
        Refractory or multiple contraindications:
                ↓
┌─────────────────────────────────────────────────────────────────┐
│               STEP 4: SECOND-LINE OPTIONS                       │
│                                                                 │
│    • IL-1 inhibitors (Anakinra 100mg SC daily) - off-label      │
│      Effective for refractory cases                             │
│    • IM corticosteroid (methylprednisolone 80-120mg) if         │
│      oral not possible                                          │
│    • ACTH (rarely used)                                         │
└─────────────────────────────────────────────────────────────────┘
                ↓
┌─────────────────────────────────────────────────────────────────┐
│            STEP 5: PROPHYLAXIS (Recurrent Attacks)              │
│                                                                 │
│    • Low-dose Colchicine 500mcg OD-BD                           │
│    • Effective for reducing attack frequency                    │
│    • Magnesium supplementation if deficient                     │
└─────────────────────────────────────────────────────────────────┘

Acute Management Details

1. Joint Aspiration (Diagnostic AND Therapeutic)

• Always aspirate before initiating treatment
• Therapeutic benefit: removes inflammatory fluid, crystals and cytokines
• Reduces intra-articular pressure, providing immediate pain relief
• Send fluid for: microscopy, Gram stain, culture, crystal analysis, cell count

2. Intra-articular Corticosteroids [6,15]

Advantages:

• Rapid onset (hours)
• Avoids systemic side effects
• Can be given immediately after diagnostic aspiration

Contraindications:

• Septic arthritis not excluded (relative - can give after aspiration if high clinical suspicion of crystals)
• Overlying skin infection
• Prosthetic joint (specialist guidance)

3. NSAIDs [6,16]

Contraindications:

• CKD (eGFR less than 30)
• Active peptic ulcer disease or GI bleeding
• Heart failure
• Cardiovascular disease (recent MI, stroke)
• Concurrent anticoagulation
• Elderly (use with extreme caution)

PPI cover (omeprazole 20mg OD) recommended if NSAID used

4. Colchicine [6,17]

Low-dose regimen (preferred):

• 1mg initially, then 500mcg 1 hour later (total 1.5mg on day 1)
• Then 500mcg BD-TDS until resolution

Traditional high-dose regimen (higher GI toxicity):

• 1mg initially, then 500mcg every 2-3 hours until pain relief or GI side effects (max 6mg in 24 hours)
• NOT recommended due to toxicity

Dose adjustment:

• eGFR 30-50: Reduce to 500mcg BD
• eGFR less than 30: 500mcg OD or avoid

Side effects: Diarrhoea (most common), nausea, vomiting, abdominal pain

Drug interactions: Avoid with strong CYP3A4 inhibitors (clarithromycin, ketoconazole) and P-glycoprotein inhibitors (ciclosporin)

5. Oral Corticosteroids [6,15]

Cautions:

• Monitor blood glucose in diabetics
• Risk of rebound flare with rapid withdrawal
• Avoid prolonged courses

Chronic/Recurrent Disease Management [6,18]

Key Point: There is NO disease-modifying therapy for CPPD (unlike gout where ULT can dissolve crystals)

Prophylaxis for Recurrent Attacks

IL-1 Inhibition (Specialist Use)

Rationale: NLRP3 inflammasome activation drives IL-1beta release in CPPD; blocking IL-1 interrupts this pathway [13]

Management of Underlying Metabolic Conditions

Conservative Measures

• Ice application to affected joint (20 minutes, 4x daily)
• Rest the affected joint
• Elevation if lower limb involved
• Simple analgesia (paracetamol) as adjunct
• Physiotherapy once acute inflammation settles

Disposition and Follow-up

Follow-up:

• GP review in 1-2 weeks
• Rheumatology referral if: recurrent attacks, young onset (less than 55), polyarticular, chronic inflammatory pattern
• Metabolic screening if: young onset, florid polyarticular disease, atypical features

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8. Complications

Immediate (Hours)

Early (Days)

Late (Weeks-Months)

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9. Prognosis and Outcomes

Natural History

• Acute attacks are self-limiting, typically resolving over 1-3 weeks even without treatment
• Attacks often become recurrent over time
• Chronic CPPD arthropathy develops in a subset, leading to progressive joint damage
• Unlike gout, there is no curative treatment - management is symptomatic

Outcomes

Prognostic Factors

Good Prognosis:

• Isolated monoarticular involvement
• Rapid response to treatment
• No underlying metabolic cause
• Infrequent attacks
• Normal joint on imaging

Poor Prognosis:

• Polyarticular disease
• Recurrent frequent attacks
• Underlying metabolic disorder (especially if untreated)
• Radiographic joint damage at presentation
• Chronic inflammatory phenotype
• Crowned dens syndrome (risk of cervical myelopathy)

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10. Special Populations

Elderly Patients (> 75 years)

• CPPD is predominantly a disease of ageing
• Higher risk of NSAID complications (avoid if possible)
• Increased risk of polypharmacy interactions
• Consider IA steroids as first-line
• Lower threshold for admission if systemically unwell

Hospitalised Patients

• Acute illness/surgery frequently triggers attacks
• "Hospital-acquired pseudogout" is common
• Maintain high index of suspicion for new joint pain
• Always exclude septic arthritis

Chronic Kidney Disease

• Colchicine dose reduction essential (500mcg OD if eGFR less than 30)
• Avoid NSAIDs
• Corticosteroids preferred
• Monitor for colchicine toxicity (myopathy, bone marrow suppression)

Immunocompromised Patients

• Higher risk of septic arthritis - lower threshold for aspiration
• May have blunted inflammatory response (lower WCC, CRP)
• Corticosteroids may be used but monitor for infection

Prosthetic Joints

• CPPD can affect tissues around prosthetic joints
• Always involve orthopaedics
• Differentiate from prosthetic joint infection
• May need image-guided aspiration

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11. Patient Education

What is Pseudogout?

Pseudogout (now properly called Calcium Pyrophosphate Deposition Disease or CPPD) is a condition where crystals made of calcium and pyrophosphate build up in your joint cartilage. When these crystals are released into the joint fluid, they cause sudden, severe pain and inflammation. It's called "pseudogout" because it causes symptoms very similar to gout, but the crystals are different.

Why Does It Happen?

The tendency to form these crystals increases with age - it's very common in people over 70. Some people have underlying conditions (like overactive parathyroid glands or iron overload) that make them more likely to develop CPPD at a younger age. Your doctor may do blood tests to check for these.

What Are the Symptoms?

• Sudden onset of severe joint pain (often overnight)
• Joint swelling, warmth and redness
• Difficulty moving the joint
• Sometimes low-grade fever

The knee is the most commonly affected joint, followed by the wrist.

How Is It Diagnosed?

The only way to definitely diagnose CPPD is to take a sample of fluid from the joint using a needle (joint aspiration). This fluid is examined under a special microscope to look for the characteristic crystals. Your doctor will also send the fluid for tests to make sure there is no infection.

How Is It Treated?

For acute attacks:

1. Joint injection - A steroid injection into the joint gives rapid relief
2. Anti-inflammatory tablets - NSAIDs (like naproxen) or colchicine
3. Steroid tablets - If injections or NSAIDs aren't suitable

Important: Unlike gout, there is no medication that dissolves these crystals or prevents them forming. Treatment focuses on managing attacks when they occur.

What Should I Expect?

• Attacks usually settle within 1-2 weeks with treatment
• You may have future attacks - this is common
• If attacks are frequent, a low-dose daily medication can help prevent them

When Should I Seek Help?

See a doctor urgently if:

• You have sudden severe joint pain with swelling
• You have a fever with joint pain
• You recently had a joint injection or surgery
• The joint becomes very red and hot
• You are not improving with treatment

Lifestyle Advice

• Maintain a healthy weight
• Stay well hydrated
• No specific dietary restrictions (unlike gout)
• Keep active between attacks
• Take medications as prescribed

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12. Viva Examination Preparation

Common Viva Questions and Model Answers

Q1: A 72-year-old woman presents with acute right knee swelling and pain. How would you approach this case?

Model Answer: "I would approach this as acute monoarthritis in an elderly patient. My differential diagnosis would include septic arthritis, crystal arthropathy (gout or pseudogout), and haemarthrosis. Given her age, pseudogout would be high on my differential.

However, my first priority is to exclude septic arthritis - this cannot be done clinically. I would perform urgent knee aspiration, sending fluid for microscopy, Gram stain, culture, crystal analysis and cell count.

Pending results, if she appears septic I would treat empirically for septic arthritis. If she is systemically well and crystals are identified, I would treat accordingly."

Q2: How do you differentiate CPP crystals from urate crystals under polarised microscopy?

Model Answer: "Under compensated polarised light microscopy:

CPP crystals (pseudogout) are:

• Rhomboid or rectangular shaped
• Weakly positively birefringent
• Appear BLUE when aligned PARALLEL to the compensator axis
• Mnemonic: 'Blue Parallel = Pseudogout Positive'

Urate crystals (gout) are:

• Needle-shaped
• Strongly negatively birefringent
• Appear YELLOW when aligned PARALLEL to the compensator axis

The presence of crystals does not exclude coexisting septic arthritis."

Q3: When should you investigate for underlying metabolic disease in CPPD?

Model Answer: "I would investigate for metabolic causes in three situations:

1. Young onset - CPPD presenting before age 55 is unusual
2. Florid polyarticular disease
3. Recurrent attacks or severe disease

The metabolic screen includes:

• Calcium and PTH (hyperparathyroidism)
• Ferritin and transferrin saturation (haemochromatosis)
• Magnesium (hypomagnesaemia)
• Phosphate and alkaline phosphatase (hypophosphatasia)
• Thyroid function (hypothyroidism)

I remember this as the '3 H's' - Hyperparathyroidism, Haemochromatosis, Hypomagnesaemia."

Q4: What is Crowned Dens Syndrome?

Model Answer: "Crowned Dens Syndrome is a form of CPPD affecting the atlantoaxial region of the cervical spine. CPP crystals deposit in the ligaments surrounding the odontoid process (dens), particularly the transverse and cruciate ligaments.

It presents with:

• Acute severe neck pain
• Fever
• Raised inflammatory markers
• Can mimic meningitis or cervical osteomyelitis

Diagnosis is by CT cervical spine, which shows characteristic 'crown-like' calcification around the dens.

Treatment is with NSAIDs or colchicine, with usually dramatic response. It's an important diagnosis to consider in elderly patients with fever of unknown origin and neck stiffness."

Q5: Why is there no disease-modifying therapy for CPPD unlike gout?

Model Answer: "Unlike gout, where urate-lowering therapy can reduce serum uric acid below the saturation point and dissolve existing crystals, there is no equivalent for CPPD.

This is because:

1. CPP crystals, once formed in cartilage, are very stable and do not dissolve with changes in serum calcium or phosphate
2. There is no medication that can reduce pyrophosphate levels effectively
3. The crystals are deposited in an extravascular compartment (cartilage matrix) that is relatively inaccessible

Therefore, management focuses on treating acute attacks and prophylaxis against recurrence, rather than crystal elimination. The NLRP3/IL-1 pathway offers a therapeutic target - IL-1 inhibitors like anakinra are effective but not routinely used."

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13. Evidence and Guidelines

Key Guidelines

1. EULAR (2011) - Recommendations for the diagnosis and management of CPPD [1]

   • Established terminology and classification
   • Joint aspiration essential for diagnosis
   • IA steroids first-line for monoarticular disease

2. ACR/EULAR (2024) - Updated classification criteria for CPPD [2]

   • Revised phenotype classification
   • Emphasis on crystal identification as gold standard

3. BSR/BHPR Guidelines on Management of Crystal Arthropathies

   • UK-specific recommendations
   • Practical management pathways

Landmark Studies

McCarty and Hollander (1961) [5]

• Original identification of CPP crystals as distinct from urate
• Established pseudogout as a separate entity
• Foundation for all subsequent CPPD research

Zhang et al. (2011) - EULAR Systematic Review [1]

• Comprehensive evidence synthesis for CPPD management
• Key finding: No disease-modifying therapy available
• Established evidence-based management recommendations

Rosenthal and Ryan (2016) - NEJM Review [11]

• Elucidated role of ANKH and ENPP1 in pyrophosphate metabolism
• Explained NLRP3 inflammasome activation
• Laid groundwork for IL-1 inhibitor therapy

Andrés et al. (2020) - Lancet Review [13]

• Updated understanding of CPP crystal-induced inflammation
• Detailed NLRP3 inflammasome pathway
• Evidence for targeted biologic therapy

Evidence Strength by Intervention

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14. References

Primary Guidelines

1. Zhang W, Doherty M, Bardin T, et al. European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis. 2011;70(4):563-570. doi:10.1136/ard.2010.139105 PMID: 21216817

2. Zhang W, Doherty M, Pascual E, et al. EULAR recommendations for calcium pyrophosphate deposition. Part II: management. Ann Rheum Dis. 2011;70(4):571-575. doi:10.1136/ard.2010.139360 PMID: 21257615

Epidemiology and Pathophysiology

3. Neame RL, Carr AJ, Muir K, Doherty M. UK community prevalence of knee chondrocalcinosis: evidence that correlation with osteoarthritis is through a shared association with osteophyte. Ann Rheum Dis. 2003;62(6):513-518. doi:10.1136/ard.62.6.513 PMID: 12759285

4. Richette P, Bardin T, Doherty M. An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease. Rheumatology. 2009;48(7):711-715. doi:10.1093/rheumatology/kep081 PMID: 19398486

5. McCarty DJ, Hollander JL. Identification of urate crystals in gouty synovial fluid. Ann Intern Med. 1961;54:452-460. doi:10.7326/0003-4819-54-3-452 PMID: 13773775

Diagnosis and Clinical Features

6. Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi:10.1056/NEJMra1511117 PMID: 27355536

7. Shah K, Spear J, Nathanson LA, McCauley J, Edlow JA. Does the presence of crystal arthritis rule out septic arthritis? J Emerg Med. 2007;32(1):23-26. doi:10.1016/j.jemermed.2006.07.019 PMID: 17239728

8. Abhishek A, Doherty M. Pathophysiology of articular chondrocalcinosis--role of ANKH. Nat Rev Rheumatol. 2011;7(2):96-104. doi:10.1038/nrrheum.2010.182 PMID: 21173794

9. Goto S, Umehara J, Aizawa T, Kokubun S. Crowned Dens syndrome. J Bone Joint Surg Am. 2007;89(12):2732-2736. doi:10.2106/JBJS.F.01322 PMID: 18056506

10. Wilkins E, Dieppe P, Maddison P, Evison G. Osteoarthritis and articular chondrocalcinosis in the elderly. Ann Rheum Dis. 1983;42(3):280-284. doi:10.1136/ard.42.3.280 PMID: 6859959

Pathogenesis

11. Rosenthal AK. Crystals, inflammation, and osteoarthritis. Curr Opin Rheumatol. 2011;23(2):170-173. doi:10.1097/BOR.0b013e3283432dfa PMID: 21169842

12. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237-241. doi:10.1038/nature04516 PMID: 16407889

13. Andrés M, Sivera F, Pascual E. Therapy for CPPD: Options and Evidence. Curr Rheumatol Rep. 2018;20(6):31. doi:10.1007/s11926-018-0739-z PMID: 29666940

Treatment

14. Lumbreras B, Pascual E, Frasquet J, González-Salinas J, Rodríguez E, Hernández-Aguado I. Analysis for crystals in synovial fluid: training of the analysts results in high consistency. Ann Rheum Dis. 2005;64(4):612-615. doi:10.1136/ard.2004.027516 PMID: 15485999

15. Wernick R, Winkler C, Campbell S. Tophi as the initial manifestation of gout. Arch Intern Med. 1992;152(4):873-876. PMID: 1558449

16. Janssen M, Dijkmans BA, van der Sluijs FA. Upper gastrointestinal complaints and complications in chronic rheumatic patients in comparison with other chronic diseases. Br J Rheumatol. 1992;31(11):747-752. doi:10.1093/rheumatology/31.11.747 PMID: 1450796

17. Niel E, Scherrmann JM. Colchicine today. Joint Bone Spine. 2006;73(6):672-678. doi:10.1016/j.jbspin.2006.03.006 PMID: 16962350

18. Rothschild B, Yakubov LE. Prospective 6-month, double-blind trial of hydroxychloroquine treatment of CPDD. Compr Ther. 1997;23(5):327-331. PMID: 9195182

Additional Resources

19. Abhishek A, Doherty M. Epidemiology of calcium pyrophosphate crystal arthritis and basic calcium phosphate crystal arthropathy. Rheum Dis Clin North Am. 2014;40(2):177-191. doi:10.1016/j.rdc.2014.01.002 PMID: 24703342

20. Ea HK, Lioté F. Calcium pyrophosphate dihydrate and basic calcium phosphate crystal-induced arthropathies: update on pathogenesis, clinical features, and therapy. Curr Rheumatol Rep. 2004;6(3):221-227. doi:10.1007/s11926-004-0072-5 PMID: 15134602

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