PSEUDOGOUT [CALCIUM PYROPHOSPHATE DEHYDRATE DEPOSITION (CPPD)]

Calcium pyrophosphate dehydrate (CPPD) deposition, also known as acute CPP crystal arthritis, chondrocalcinosis, pyrophosphate arthropathy, or pseudogout, is a metabolic, inflammatory joint disease. It is characterized by the periarticular deposition of CPP crystals, typically occurring in the triangular fibrocartilage (TFCC) and hyaline cartilage and most commonly affecting the knees, wrists, and/or shoulders. Pseudogout demonstrates various clinical manifestations, ranging from an asymptomatic state to destructive arthropathy, in which arthritic attacks can last up to several weeks and cause a variety of painful symptoms in the wrist (eg, swelling, tenderness, stiffness, or joint effusion). Treatment is typically conservative and used to reduce the severity of symptoms during attacks, primarily consisting of non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroid injections, joint aspiration, and/or splinting. Surgical intervention may be recommended if conservative efforts fail, and options depend on the specific location of the disease and degree ogf joint destruction.^1-4,9,10

Pathophysiology

• Pseudogout may occur sporadically or be inherited in an autosomal dominant fashion with a variable penetrance⁵
• Patients with pseudogout have an increased production of inorganic pyrophosphate and decreased levels of pyrophosphatases in the cartilage, and crystals form as pyrophosphate combines with calcium.^3. Crystals first appear in the synovial fluid, and are then deposited in the synovial membrane, the wrist ligaments and fibrocartilaginous structures, and then in the articular cartilage.  Calcium pyrophosphate crystals localize in and around joints, and crystal deposition at the wrist can cause pseudotumours that bulge into the carpal canal
• The classic feature that is most specific for pseudogout is calcification of the triangular fibrocartilage complex (TFCC) with calcification in 73% of the wrist X-rays in one study.⁹
• Isolated scapho-trapezio-trapezoidal (STT) joint disease is also specific to pseudogout, and the scapholunate (SL) joint is the next most frequently involved joint, followed by the distal radioulnar joint (DRUJ), then the lunotriquetral (LT), isolated midcarpal, radiolunate, and pisotriquetral joints⁵
• Pseudogout has also been found to affect the metacarpophalangeal and interphalangeal joints¹
• When pseudogout spontaneously causes pain and swelling of the wrist or thumb, it is often due to an acute inflammatory episode that may be mistaken for a joint infection or an attack of gout; these attacks may be precipitated by recent trauma, surgery, or a rapid decrease in serum calcium, which can cause CPPD deposits to infiltrate and weaken ligaments and cartilage^3,5
• Risk factors for pseudogout include advanced age, osteoarthritis, rheumatoid arthritis, previous joint injury, metabolic disease, hyperparathyroidism, and familial predisposition^1,4
• Tumoral pseudogout appears to contain CPPD crystals that form a tumor-like mass in an extra-articular location, and the mechanism of this development is not well known¹

Related Anatomy

• TFCC
• STT joint
• SL joint
• DRUJ
• LT joint
• Midcarpal joint
• Radiocarpal joint
• Radiolunate joint
• Pisotriquetral joint
• Carpal tunnel

Incidence 

• The incidence of pseudogout in the US is 275 cases per 100,000 people, which is roughly half the incidence of gout^6,7
• Pseudogout most commonly develops between ages 50-70, and its male-to-female ratio is 1.5:1^7,8
• Carpal tunnel syndrome (CTS) is the initial presentation in 14% of pseudogout cases, and both wrists are affected in 66% of patients⁵

Related Conditions

• Symmetric synovitis
• Carpal tunnel syndrome
• Hyperparathyroidism
• Gout
• Rheumatoid arthritis
• Osteoarthritis
• Hemochromatosis
• Systemic lupus erythematosus
• Wilson's disease
• Hemophilia

Differential Diagnosis

• Gout
• Rheumatoid arthritis
• Osteoarthritis
• Osteoarthritis with pseudogout (pseudo-osteoarthritis)
• Cellulitis nephrolithiasis
• Septic arthritis
• Hungry bone disease
• Charcot neuroarthropathy
• Seronegative arthritis
• Cellulitis
• Hyperparathyroidism
• Hypothyroidism
• Hydroxyapatite deposition disease
• Ochronosis
• Acromegaly
• Paget's disease
• Hypomagnesemia

The typical patient is a 67-year-old man with rheumatoid arthritis and hyperparathyroidism. He had been dealing with arthritic symptoms throughout his body for several years, but suffered a fall within the past year that resulted in damage to his wrists. Since the injury, he noticed that symptoms of pain, swelling, stiffness, and tenderness within the wrists had become more frequent and severe, which led him to seek out treatment.

• Permanent joint damage
• Renal disease
• Infection after surgical treatment

• A conservative treatment course of splinting, corticosteroid injections, and NSAIDs has been identified as efficient in two-thirds of pseudogout patients⁵ 
• Joint aspiration, NSAIDs, and corticosteroid injections have also been found to reduce symptoms in less than 10 days³
• Colchicine use is relatively inconsistent in relieving symptoms, and NSAIDs are generally considered to be more helpful⁴
• Daily injections of anakinra have been shown effective in patients whose pseudogout does not respond to other therapies.^3. Anakinra is an interleukin (IL&IL1) antagonidt.

• The definitive diagnosis for pseudogout is made by noting the presence of rhomboid or rod-like crystals in synovial fluid or articular tissue: under polarized light microscopy, the crystals show positive birefringence
• There is a poor correlation between X-ray calcifications and symptom severity.
• Diagnosis can be made when characteristic CPPD crystals are demonstrated or the typical calcifications are present on radiographs.  Deposits can occur as heavy punctate or linear calcifications in the fibrocartilage, but they may also occur in articular hyaline cartilage and joint capsule.  When pseudogout involves the wrist, calcifications of the TFCC and DRUJ are typical.  The TFCC is the most frequent and earlist area to show calcifications.⁹
• Some patients display elevated blood counts and raised erythrocyte sedimentation rate (ESR)
• The combined presence of CTS and dorsal wrist synovitis should raise suspicions of pseudogout and lead to a wrist X-ray⁵
• The pseudogout pattern is marked by acute or sub-acute arthritic attacks lasting from one day up to four weeks. 
• Pseudogout is one of the most frequently found wrist pathologies, but it has not attracted much attention, mainly because it affects elderly people and is often asymptomatic; however, the disease can be quite disabling to the wrist, and many patients who have it are not correctly diagnosed⁵
• Diagnosing pseudogout may be challenging, especially in post-surgical patients in whom fever, leukocytosis, and pain may be attributed to other causes⁴
• One study found that ultrasound had high sensitivity and specificity for diagnosing pseudogout, and declared that it should be considered the most relevant imaging procedure—over X-rays—for detecting the disease, especially for locations in which synovial fluid analysis is challenging²  This can also help in the differential diagnosis for other crystal-related diseases like gout and rheumatoid arthritis²
• Unlike pseudogout, gout results from monosodium urate crystals in the joints, it rarely affects the wrist, and is typically unilateral rather than bilateral; gout is also far more common than pseudogout, affecting more than eight million Americans^3,5

Cited

1. Park HJ, Chung HW, Oh TS, et al. Tumoral pseudogout of the proximal interphalangeal joint of a finger: a case report and literature review. Skeletal Radiol 2016;45(7):1007-12. PMID: 27048476
2. Forien M, Combier A, Gardette A, et al. Comparison of ultrasonography and radiography of the wrist for diagnosis of calcium pyrophosphate deposition. Joint Bone Spine 2017.S1297-319X(17)30165-3. PMID: 28965942
3. Higgins PA. Gout and pseudogout. JAAPA 2016 Mar;29(3):50-2. PMID: 26914781
4. Priesand S, Wyckoff J, Wrobel J, Schmidt B. Acute pseudogout of the foot following Parathyroidectomy: a case report. Clin Diabetes Endocrinol 2017;3:10. PMID: 29177077
5. Saffar P. Chondrocalcinosis of the wrist. J Hand Surg Br 2004;29(5):486-93. PMID: 15336755
6. Shurnas PA, Coughlin M. Surgery of the Foot and Ankle: Chapter 16 Arthritic Conditions of the Foot. 8th ed. 2007.
7. Beutler A, Schumacher HR Jr. Gout and 'pseudogout'. When are arthritic symptoms caused by crystal deposition? Postgrad Med 1994;95(2):103-6, 109, 113-6. PMID: 8309855
8. Albin RK, Weil LS. Flexible implant arthroplasty of the great toe: An evaluation. J Am Podiatry Assoc 1974;64(12):967-75. PMID: 4443543
9. Resnick CS, Miller BW, Gelberman RH, Resnick D. Hand and wrist involvement in calcium pyrophosate hydrate crystal deposition disease. J Hand Surg Am. 1983; 8:856-863
10. Lans J, Machol JA, Deml C, Chen NC, Jupiter JB.  Nonrheumatoid arthritis of the hand.  J hand Surg Am. 2018; 43(1): 61-67.

New Articles

1. Muangchan C, Bhurihirun T. An investigation of the independent risk factors that differentiate gout from pseudogout in patients with crystal-induced acute arthritis: a cross-sectional study. Rheumatol Int 2017. PMID: 29214345
2. Forien M, Combier A, Gardette A, et al. Comparison of ultrasonography and radiography of the wrist for diagnosis of calcium pyrophosphate deposition. Joint Bone Spine 2017.S1297-319X(17)30165-3. PMID: 28965942

Reviews

1. Saffar P. Chondrocalcinosis of the wrist. J Hand Surg Br 2004;29(5):486-93. PMID: 15336755
2. Park HJ, Chung HW, Oh TS, et al. Tumoral pseudogout of the proximal interphalangeal joint of a finger: a case report and literature review. Skeletal Radiol 2016;45(7):1007-12. PMID: 27048476

Classics

1. Hamilton EJ, Jessamine AG, Eidus L. Pseudogout. Can Med Assoc J 1964;90:698-9. PMID: 14127387
2. Twigg HL, Zvaifler NJ, Nelson CW. Chondrocalcinosis. Radiology 1964;82:655-9. PMID: 14131670