> Table of Contents > Pseudogout (Calcium Pyrophosphate Dihydrate)
Pseudogout (Calcium Pyrophosphate Dihydrate)
Caitlyn M. Rerucha, MD
image BASICS
  • Autoinflammatory disease triggered by calcium pyrophosphate dihydrate (CPPD) crystal deposition in the joints
  • One of many diseases associated with pathologic deposition of crystal, mineralization, and ossification
    • CPPD crystal deposition = chondrocalcinosis, pseudogout
    • Monosodium urate crystal deposition = gout
    • Hydroxyapatite deposition associated with ankylosing spondylitis, osteoarthritis, and vascular calcification
  • Suspect pseudogout in arthritis cases with a pattern of joint involvement not usually affected by degenerative joint disease (e.g., metacarpophalangeal joints, wrists)
  • Clinical presentation is broad:
    • Asymptomatic CPPD (incidentally identified on radiograph by chondrocalcinosis with or without additional findings of osteoarthritis)
    • Acute CPPD arthritis (acute onset, self-limiting, synovitis)
    • Chronic CPPD crystal inflammatory arthritis (1)[C]
  • Chronic CPPD crystal deposition may cause a progressive degenerative arthritis in numerous joints:
    • Primarily affects the elderly
    • Usually involves large joints
  • Symptom onset is usually insidious.
  • Definitive diagnosis requires the identification of CPPD crystals in synovial fluid.
  • System(s) affected: endocrine/metabolic; musculoskeletal
  • Synonyms: pseudogout; CPPD; pyrophosphate arthropathy; chondrocalcinosis—when calcification visibly seen within tissues on imaging
  • Predominant age: 80% of patients >60 years
  • Predominant sex: male > female 1.4:1
  • Prevalence varies on method of identification (chondrocalcinosis on radiograph vs. CPPD crystals in synovial fluid)
  • Chondrocalcinosis is present in 1:10 adults age 60 to 75 years and 1:3 by >80 years; however, only a small percentage develop arthropathy.
  • 20-43% prevalence of CPPD cyrstals in synovial fluid of osteoarthritic joints at time of joint replacement
  • Arthropathy results from an acute autoinflammatory reaction to CPPD crystals in the synovial cavity.
  • CPPD crystal deposition occurs in three general stages:
    • CPPD crystals first develop in the pericellular matrix of the articular cartilage via overproduction of anionic pyrophosphate (PPi).
    • PPi binds calcium to form CPPD crystals that are released from cartilage surface and elicit an inflammatory response. Neutrophils engulf CPPD crystals, inducing the formation of extracellular traps.
    • Increased deposition of CPPD crystals in and around cartilage causes inflammation and damage. Cartilage degeneration is accelerated through mechanical wear and tear of the joint (2)[C].
Uncommonly seen in familial pattern with autosomal dominant inheritance (<1% of patients); most cases are sporadic. Mutation in ANKH gene increased risk for calcium crystal formation.
  • Advanced age
  • Traumatic injury
  • CPPD often may occur as a complication in patients hospitalized for other medical and surgical illnesses.
Colchicine 0.6 mg BID may be used prophylactically to reduce frequency of episodes in recurrent CPPD.
  • Hyperparathyroidism
  • Hemochromatosis
  • Gout
  • Hypophosphatasia
  • Hypothyroidism
  • Ochronosis
  • Wilson disease
  • Amyloidosis
  • Hypomagnesemia
  • Familial hypocalciuric hypercalcaemia
  • X-linked hypophosphatemic rickets
  • Acromegaly
  • Inflammation (erythema, warmth, tender to touch), joint effusion, decreased range of motion of joint
  • 50% associated with fever
  • Any synovial joint may be involved.
  • Illnesses that may cause acute inflammatory arthritis in a single or multiple joint(s):
    • Gout
    • Septic arthritis
    • Trauma
  • Other illnesses that may present with an acute inflammatory arthritis:
    • Reiter syndrome
    • Lyme disease
    • Acute RA
Initial Tests (lab, imaging)
Synovial fluid analysis shows an inflammatory effusion:
  • Cell count 2,000 to 100,000 WBCs/mL
  • Differential predominantly neutrophils (80-90%)
  • >50,000 WBC count increases likelihood of septic arthritis, 11% prevalence; number needed to treat (NNT) = 9; >100,000 WBCs/mL, 22% prevalence
  • Wet prep with polarized microscopy may demonstrate small numbers of crystals. False-negative rate is high.
  • Obtain the following metabolic studies in patients <50 years of age and consider in the elderly to exclude underlying disease:
    • Serum calcium, phosphorus, and magnesium
    • Serum alkaline phosphatase
    • Serum parathormone (i-PTH)
    • Serum iron, total iron-binding capacity, and serum ferritin
    • Serum thyroid-stimulating hormone (TSH) level
  • Plain radiograph
    • Radiographic findings in pseudogout are neither sensitive nor specific.
    • Punctate and linear calcifications may be visualized in articular hyaline or fibrocartilage (e.g., menisci).
    • Knees, hips, symphysis pubis, and wrists are most commonly affected.
    • Patients with chronic CPPD may demonstrate subchondral cysts and loose bodies (osseous fragmentation with formation of intra-articular radiodense bodies) in joints not typically affected by degenerative joint disease.
  • Ultrasound (US)
    • US may be more useful than plain radiography for the diagnosis of pseudogout in peripheral joints, with a positive predictive value of 92% and negative predictive value of 93% (3)[C].
    • US imaging characteristics include joint effusion, synovial thickening, and hyperechoic deposits.
  • MRI
    • Chondrocalcinosis may be evident as hypointense lesions on MRI, particularly in association with the menisci of the knee.
Diagnostic Procedures/Other
Test Interpretation
CPPD crystal deposition in articular cartilage, synovium, ligaments, and tendons

Target symptom relief (reduce inflammation):
  • Rest and elevate affected joint(s).
  • Apply ice/cool compresses to affected joints.
  • Nonweight bearing on affected joint while painful; use crutches or a walker.
First Line
  • A combination of pharmacologic and nonpharmacologic measures is recommended.
  • Acute attacks should be treated with cool packs, rest, and joint aspiration with or without steroid injection.
  • Chronic inflammatory CPPD arthropathy should be managed prophylactically with oral NSAIDs and/or colchicine (3)[C].
  • Oral NSAIDs
    • Ibuprofen 600 to 800 mg PO TID-QID with food; maximum 3.2 g/day
    • Naproxen 500 mg PO BID with food
    • Other NSAIDs at anti-inflammatory doses are effective, although indomethacin has higher complication rates (relative risk [RR] = 2.2) compared with ibuprofen (RR = 1.2).
  • Contraindications:
    • History of hypersensitivity to NSAIDs or aspirin
    • Active peptic ulcer disease or history of recurrent upper GI lesions
    • Avoid in renal insufficiency.
    • Serious GI bleeding can occur without warning; patient should be instructed on signs/symptoms. Administer proton pump inhibitor (PPI) or misoprostol 200 &mgr;g PO QID in patients at risk for NSAID-induced gastric ulcers.
  • Oral colchicine
    • 0.6 mg QID or 0.6 mg hourly until symptoms relieved or vomiting/diarrhea develops; maximum dose per attack 4 to 6 mg; alternatively 0.5 to 1 mg/day may be used; avoid cholchicine with significant renal insufficiency.
  • Intra-articular steroid injection
    • Prednisolone-sodium phosphate 4 to 20 mg or triamcinolone diacetate 2 to 40 mg with local anesthetic
Second Line
  • Oral prednisone: 30 to 50 mg/day for 7 to 10 days
  • IM triamcinolone acetonide 40 mg; may repeat in 1 to 4 days
  • Consider referring patients with large spaceoccupying tophaceous lesions for surgical removal.
  • Alternative therapies for chronic CPPD
    • ACTH, Anakinra (anti-IL1), hydroxychloroquine, infliximab, probenecid, magnesium, ethyldiamine tetracetic acid (EDTA) have all been suggested. Large scale studies are needed to evaluate effectiveness (4)[C].
Consider consultation with orthopedist or rheumatologist if septic joint or patient is not responding.
Physical therapy
  • Isometric exercises to maintain muscle strength during the acute stage (e.g., quadriceps isometric contractions, leg lifts if knee affected)
  • Begin joint range-of-motion (ROM) exercises as inflammation and pain subside.
  • Resume weight bearing when pain subsides.
Perform arthrocentesis and joint fluid analysis.
Admission Criteria/Initial Stabilization
Consider admission for septic arthritis if:
  • Synovial fluid WBC count >50,000/mL
  • Treat with appropriate antibiotics pending culture results.
Patient Monitoring
Reevaluate response to therapy 48 to 72 hours after beginning treatment; reexamine in 1 week then as needed.
No known relationship to diet
  • Rest affected joint.
  • Symptoms usually resolve in 7 to 10 days.
  • Acute attack usually resolves in 10 days; prognosis for resolution of acute attack is excellent.
  • Patients may experience progressive joint damage and functional limitation.
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.
2. Rosenthal AK, Ryan LM. Nonpharmacologic and pharmacologic management of CPP crystal arthritis and BCP arthropathy and periarticular syndromes. Rheum Dis Clin North Am. 2014;40(2):343-356.
3. 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.
4. Pascart T, Richette P, Flipo RM. Treatment of nongout joint deposition diseases: an update. Arthritis. 2014; 2014:375202.
5. Finckh A, Mc Carthy GM, Madigan A, et al. Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial. Arthritis Res Ther. 2014;16(5):458.
Additional Reading
  • Bruges-Armas J, Bettencourt BF, Couto AR, et al. Effectiveness and safety of infliximab in two cases of severe chondrocalcinosis: nine years of follow-up. Case Rep Rheumatol. 2014;2014:536856.
  • Daoussis D, Antonopoulos I, Andonopoulos AP. ACTH as a treatment for acute crystal-induced arthritis: update on clinical evidence and mechanisms of action. Semin Arthritis Rheum. 2014;43(5):648-653.
  • Demertzis JL, Rubin DA. MR imaging assessment of inflammatory, crystalline-induced, and infectious arthritides. Magn Reson Imaging Clin N Am. 2011;19(2):339-363.
  • Macmullan P, McCarthy G. Treatment and management of pseudogout: insights for the clinician. Ther Adv Musculoskelet Dis. 2012;4(2):121-131.
  • Richette P, Bardin T, Doherty M. An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease. Rheumatology (Oxford). 2009;48(7):711-715.
  • Sattui SE, Singh JA, Gaffo AL. Comorbidities in patients with crystal diseases and hyperuricemia. Rheum Dis Clin North Am. 2014;40(2):251-278.
  • M11.20 Other chondrocalcinosis, unspecified site
  • M11.269 Other chondrocalcinosis, unspecified knee
  • M11.29 Other chondrocalcinosis, multiple sites
Clinical Pearls
  • Suspect CPPD if arthritis case doesn't follow a pattern typical of degenerative joint disease (e.g., metacarpophalangeal joints, wrists).
  • Perform arthrocentesis to confirm diagnosis.
  • If septic arthritis is considered, treat presumptively with antibiotics until culture results are available.
  • NSAID therapy is the preferred treatment for acute flare.
  • Oral steroids are useful if NSAIDs are contraindicated.
  • Intra-articular steroids can be used if septic arthritis has been excluded.