Pseudogout (Calcium Pyrophosphate Dihydrate)

Caitlyn M. Rerucha, MD Reviewed 06/2017
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Subject: Pseudogout (Calcium Pyrophosphate Dihydrate)

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BASICS

DESCRIPTION

  • 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

EPIDEMIOLOGY

Prevalence

  • 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

ETIOLOGY AND PATHOPHYSIOLOGY

  • 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].

Genetics

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. 

RISK FACTORS

  • Advanced age

  • Traumatic injury

  • CPPD often may occur as a complication in patients hospitalized for other medical and surgical illnesses.

GENERAL PREVENTION

Colchicine 0.6 mg BID may be used prophylactically to reduce frequency of episodes in recurrent CPPD. 

COMMONLY ASSOCIATED CONDITIONS

  • Hyperparathyroidism

  • Hemochromatosis

  • Gout

  • Hypophosphatasia

  • Hypothyroidism

  • Ochronosis

  • Wilson disease

  • Amyloidosis

  • Hypomagnesemia

  • Familial hypocalciuric hypercalcaemia

  • X-linked hypophosphatemic rickets

  • Acromegaly

DIAGNOSIS

HISTORY

  • Presentation often mimicks gout (“pseudogout”).

  • Acute CPPD: pain and swelling of ≥1 or more joints; knee involved in 50% of cases; ankle, wrist, toe, and shoulder are also common.

  • Can present in proximal joints (mimicking polymyalgia rheumatica), often accompanied by tibiofemoral and ankle arthritis and tendinous calcifications

  • Multiple symmetric joint involvement (mimicking RA) in ≪5% of cases

  • May develop after intra-articular injection of hyaluronic acid (Hyalgan, Synvisc)

  • Chronic CPPD: progressive degenerative arthritis with superimposed acute inflammatory attacks

PHYSICAL EXAM

  • Inflammation (erythema, warmth, tender to touch), joint effusion, decreased range of motion of joint

  • 50% associated with fever

  • Any synovial joint may be involved.

DIFFERENTIAL DIAGNOSIS

  • 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

DIAGNOSTIC TESTS & INTERPRETATION

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.

ALERT

Rhomboid-shaped weakly positively birefringent crystals in the fluid and within neutrophils is pathognomonic. In contrast, gout crystals are needle-shaped and negatively birefringent.

 
  • 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

ALERT

Aspiration of joint fluid with synovial fluid analysis and demonstration of CPPD crystals is required for diagnosis; aspiration may relieve symptoms and speed resolution of the inflammatory process.

 

Test Interpretation

CPPD crystal deposition in articular cartilage, synovium, ligaments, and tendons 

TREATMENT

GENERAL MEASURES

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.

MEDICATION

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 μg 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
ALERT

Significant adverse effects of NSAIDs:

  • May elevate BP in patients on antihypertensive therapy

  • May blunt antihypertensive effects of ACE inhibitors

  • May prolong prothrombin time (PT) in patients taking oral anticoagulants

  • Avoid concomitant aspirin use.

  • May blunt diuretic effect of furosemide and hydrochlorothiazide

  • May increase plasma lithium level in patients taking lithium carbonate

 

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 space-occupying tophaceous lesions for surgical removal.

  • Alternative therapies for chronic CPPD

ALERT

Recent randomized trial showed no significant effect of methotrexate in chronic-recurrent CPPD 5[B].

 

ISSUES FOR REFERRAL

Consider consultation with orthopedist or rheumatologist if septic joint or patient is not responding. 

ADDITIONAL THERAPIES

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.

SURGERY/OTHER PROCEDURES

Perform arthrocentesis and joint fluid analysis. 

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

Consider admission for septic arthritis if: 
  • Synovial fluid WBC count >50,000/mL

  • Treat with appropriate antibiotics pending culture results.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

Reevaluate response to therapy 48 to 72 hours after beginning treatment; reexamine in 1 week then as needed. 

DIET

No known relationship to diet 

PATIENT EDUCATION

  • Rest affected joint.

  • Symptoms usually resolve in 7 to 10 days.

PROGNOSIS

  • Acute attack usually resolves in 10 days; prognosis for resolution of acute attack is excellent.

  • Patients may experience progressive joint damage and functional limitation.

COMPLICATIONS

  • Recurrent acute attacks

  • Osteoarthritis

Geriatric Considerations

Elderly patients treated with NSAIDs require careful monitoring and are at higher risk for GI bleeding and acute renal insufficiency. No loading dose for colchicine due to high rates of renal insufficiency in elderly patients. 

REFERENCES

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.  [View Abstract]
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.  [View Abstract]
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.  [View Abstract]
Pascart  T, Richette  P, Flipo  RM. Treatment of nongout joint deposition diseases: an update. Arthritis.  2014; 2014:375202.  [View Abstract]
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.  [View Abstract]

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.

CODES

ICD10

  • M11.20 Other chondrocalcinosis, unspecified site

  • M11.269 Other chondrocalcinosis, unspecified knee

  • M11.29 Other chondrocalcinosis, multiple sites

ICD9

  • 275.49 Other disorders of calcium metabolism

  • 712.30 Chondrocalcinosis, unspecified, site unspecified

  • 712.26 Chondrocalcinosis, due to pyrophosphate crystals, lower leg

  • 712.29 Chondrocalcinosis, due to pyrophosphate crystals, multiple sites

SNOMED

  • 201637001 Chondrocalcinosis due to pyrophosphate crystals

  • 239834007 Pyrophosphate arthritis (disorder)

  • 239838005 Chondrocalcinosis (disorder)

  • 239833001 Chondrocalcinosis due to pyrophosphate crystals of the knee (disorder)

  • 201646007 Chondrocalcinosis due to pyrophosphate crystals, of multiple sites (disorder)

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.

 
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