Clinical Features, Diagnosis, and Treatment of Calcium Pyrophosphate Disease (CPPD)
Clinical Features
CPPD presents in four distinct clinical phenotypes that determine management approach: asymptomatic chondrocalcinosis, acute CPP crystal arthritis (pseudogout), chronic CPP inflammatory arthritis, and osteoarthritis with CPPD. 1
Acute CPP Crystal Arthritis (Pseudogout)
- Sudden onset of severe pain, swelling, and tenderness with overlying erythema, typically affecting large joints 2
- Most commonly involves the knee, wrist, shoulder, and hip 2
- Can affect ligaments, tendons, bursae, bone, and spine 2
- Crowned dens syndrome (atlanto-occipital joint involvement) presents with acute cervico-occipital pain, fever, neck stiffness, and elevated inflammatory markers 2
Chronic CPP Inflammatory Arthritis
- Joint swelling, morning stiffness, persistent pain 2
- Elevated ESR and CRP 2
- May mimic rheumatoid arthritis (pseudorheumatoid presentation) 3
Osteoarthritis with CPPD
- Standard OA features with concurrent CPP crystal deposition 1
- May have increased inflammatory component compared to OA alone 1
- Relationship between OA and CPPD remains unclear regarding causality 2
Risk Factors to Evaluate
- Age >60 years (prevalence 10-15% in ages 65-75, >40% in those over 80) 3
- Prior joint injury 4
- Metabolic conditions: hyperparathyroidism, hemochromatosis, hypomagnesemia, hypophosphatasia 4
- Genetic variants (ANKH and osteoprotegerin genes) 4
- Early-onset disease (before age 60) mandates screening for metabolic disorders, particularly hemochromatosis 3
Diagnosis
Synovial Fluid Analysis (Gold Standard)
- Non-polarized light microscopy initially screens for characteristic crystal morphology 2
- Compensated polarized light microscopy shows weakly positive birefringent crystals (definitive identification), though this pattern only occurs in ~20% of samples 2
Imaging
- Conventional radiography: Punctate and linear radiodense areas in fibrocartilage and hyaline cartilage 3
- Ultrasonography: Increasingly used for detecting CPP crystal deposition 4
- CT: Particularly useful for axial joint calcification, including crowned dens syndrome 4
Treatment
Asymptomatic CPPD
No treatment is required for asymptomatic chondrocalcinosis, as no disease-modifying therapies exist to reduce articular calcification. 1, 5
Acute CPP Crystal Arthritis
First-Line Treatment (Monoarticular/Oligoarticular)
Joint aspiration combined with intra-articular long-acting glucocorticosteroid injection is the optimal first-line treatment, often sufficient alone. 1
- Apply ice or cool packs and temporary rest 1
- Intra-articular GCS is particularly useful and safe for monoarticular or oligoarticular attacks 1
Systemic Treatment Options
When intra-articular injection is not feasible, use oral NSAIDs with gastroprotection OR low-dose colchicine (1.2 mg initially, then 0.6 mg one hour later, then 0.5 mg 2-3 times daily). 1, 6
- NSAIDs: Always combine with proton pump inhibitors, especially in older patients or those requiring long-term use 1
- Colchicine: Low-dose regimen (0.5 mg up to 3-4 times daily) is as effective as high-dose with fewer side effects 1, 6
- Avoid intravenous colchicine due to high risk of serious toxicity 7
Alternative for Polyarticular Attacks or Contraindications
Short tapering course of oral glucocorticosteroids, parenteral GCS, or ACTH is effective when NSAIDs/colchicine are contraindicated. 1
- Intramuscular betamethasone 7 mg or intravenous methylprednisolone 125 mg provides rapid pain control (NNT=3 on day 1) 1
- Prednisone may provide the best benefit-risk ratio 4
- ACTH 40-80 units (IV, IM, or subcutaneous) is effective 1
Prophylaxis Against Recurrent Acute Attacks
Low-dose oral colchicine (0.5-1.0 mg daily) OR low-dose oral NSAIDs with gastroprotection prevent recurrent flares. 1, 7
Chronic CPP Inflammatory Arthritis
First-Line Treatment
Oral NSAIDs with gastroprotection and/or low-dose colchicine (0.5-1.0 mg daily) are first-line for chronic inflammatory arthritis. 1
- Low-dose colchicine (0.5 mg twice daily) demonstrated NNT of 2 (95% CI 1-4) at 4 months for >30% pain reduction 1, 8
Second-Line Treatment for Refractory Cases
Hydroxychloroquine is the preferred second-line agent, with NNT of 2 (95% CI 1-7) for clinical response. 1, 8
- Hydroxychloroquine: Demonstrated efficacy in 6-month RCT with >30% reduction in swollen/tender joint count 1, 8
- Low-dose glucocorticoids: May be used when other treatments fail 1, 8
Third-Line Treatment
Methotrexate (5-10 mg/week) should be used for severe CPPD resistant to conventional treatments. 1, 8
- Uncontrolled trial showed excellent clinical response in all patients with significant decrease in pain intensity and joint counts 1, 8
- Mean response time was 7.4 weeks 1
Refractory Disease
- Anakinra (IL-1 inhibitor): Can alleviate acute flares when other treatments fail 5
- Tocilizumab (IL-6 inhibitor): May be used in refractory chronic cases 5, 9
Osteoarthritis with CPPD
Management objectives and treatment options are identical to OA without CPPD, following standard evidence-based OA guidelines. 1
- Critical caveat: Avoid intra-articular high molecular weight hyaluronan as it may induce acute attacks 1, 7
Treatment of Associated Metabolic Conditions
If detected, treat hyperparathyroidism, hemochromatosis, or hypomagnesemia according to their respective guidelines. 1, 7
- Magnesium supplementation may have theoretical benefit but lacks strong evidence for reducing radiographic chondrocalcinosis 1
Critical Pitfalls to Avoid
- Never use traditional high-dose colchicine regimens due to marked side effects 7
- Never use intravenous colchicine due to serious toxicity risk 7
- Avoid intra-articular hyaluronan in CPPD patients 1, 7
- Always provide gastroprotection with NSAIDs in older patients (the typical CPPD population) 1
- Screen for drug interactions with colchicine (macrolides, antifungals, cyclosporine, HIV medications) 6
- Reduce colchicine dose in renal or hepatic impairment 6
- Early treatment initiation is critical for effectiveness 7