Pseudogout

I. What every physician needs to know.

Calcium pyrophosphate dihydrate (CPPD) deposition can be asymptomatic or, alternatively, may present in a number of ways. Pseudogout, which affects approximately 25% of people with CPPD deposition disease, is one such manifestation of CPPD. This chapter will not discuss CPPD in its entirety but rather will focus on the management of pseudogout (also known as calcic gout).

Gout and pseudogout are the two most common types of crystalline arthritis. The term pseudogout was coined by McCarty and colleagues in 1962 to denote acute gout like attacks precipitated by nonurate crystals in patients initially believed to be having gouty attacks. Pseudogout refers to the acute inflammatory presentation of CPPD deposition.

An increase in inorganic pyrophophatase production and decreased levels of pyrophosphatases in cartilage is seen in patients with CPPD deposition disease. The pyrophosphate can combine with calcium to form CPPD crystals. CPPD crystals released into the joint space undergo phagocytosis by monocyte-macrophages and neutrophils, which release chemotactic and inflammatory substances resulting in an acute attack of pseudogout.

II. Diagnostic Confirmation: Are you sure your patient has Pseudogout?

Radiographic evidence of chondrocalcinosis increases the likelihood of CPPD deposition disease. Definitive diagnosis, however, requires visualization of characteristic crystals on aspirated synovial fluid or articular tissue. Unfortunately, the sensitivity for CPPD crystal deposition on synovial fluid examination may be as low as 12%.

The classic CPPD crystal description is one of weakly positively birefringent rhomboid-shaped crystals using compensated polarized light microscopy. These crystals, which can be intra- or extracellular, appear blue when parallel to the long axis of the compensator and yellow when perpendicular. However, CPPD crystals are commonly not birefringent. Synovial fluid during an acute attack is usually inflammatory with 5,000 to 25,000 white blood cells/microliter (cells/µl), predominantly neutrophils. However, white blood cell counts greater than 100,000 cells/µl (numbers typically seen with septic arthritis) have been reported in patients with pseudogout.

A. History Part I: Pattern Recognition:

Pseudogout presents as acute arthritis (manifesting as pain) in one (monoarticular) or several (oligoarticular) joints which can last for several days to 2 weeks. Attacks are typically self-limited and can be associated with fever and a peripheral leukocytosis with a left shift.

Pseudogout occurs predominantly in patients above the age of 55 years and typically affects large and small joints. The knee is the most commonly affected joint (accounting for almost 50% of attacks) followed by the wrist. However, any joint (including the first metatarsal joint, which is most commonly affected in acute gouty arthritis) can be affected.

B. History Part 2: Prevalence:

CPPD deposition disease can be categorized as either sporadic, familial, or secondary due to metabolic causes.

Certain metabolic conditions associated with CPPD deposition include:

Primary hyperparathyroidism (Nucleation of CPPD crystals is enhanced by high concentrations of calcium).
Hemochromatosis (Nucleation of CPPD crystals is enhanced by high concentrations of iron).
Hypophosphatemia.
Hypomagnesemia:

CPPD deposition has been reported in a several conditions associated with low magnesium including Gitelman’s syndrome, short bowel syndrome, and familial forms of renal magnesium wasting.

Magnesium increases the solubility of CPPD crystals and acts as a cofactor for alkaline phosphatase and other pyrophosphatases which hydrolyze pyrophosphate. As a result, hypomagnesemia can decrease the solubility of CPPD crystals and suppress the activity of pyrophosphatases leading to increases in pyrophosphate concentrations with resultant CPPD crystal formation.

Thiazide diuretics, which can cause magnesium depletion, may also predispose to the development of CPPD deposition.
Chronic gout.

Other conditions less commonly associated with CPPD deposition include: Wilson disease, ochronosis, familial hypocalciuric hypercalcemia, X-linked hypophosphatemic rickets, and acromegaly. In contrast to early observational studies, subsequent controlled studies have failed to support an association between CPPD deposition disease and diabetes mellitus or hypothyroidism.

Increasing age is the most important risk factor for pseudogout. In fact, pseudogout is uncommon in patients below the age of 55 years.

Reported precipitants of pseudogout attacks include:

Trauma – prior trauma to an affected joint, especially meniscal injuries to the knee.
Arthroscopic lavage for knee osteoarthritis – 26% of patients with preexisting chondrocalcinosis will develop an acute attack of pseudogout following arthroscopic knee lavage.
Rapid decrease in serum calcium concentration – as can be seen in severe medical illness, after parathyroidectomy, or after other surgery.
Hypomagnesemia.
Drugs (case reports):

Etanercept.

Bisphosphonates including pamidronate, alendronate (at the weekly dose), and etidronate. The mechanism is believed to be due a rapid drop in calcium concentration which can result in shedding of preformed cartilaginous and synovial CPPD crystal deposits into the joint space.

Intra-articular injection of hyaluronic acid in the treatment of osteoarthritis. It is hypothesized that injection of hyaluronic acid containing preparations, which contain high concentrations of phosphate, may decrease the intraarticular calcium concentrations, thereby precipitating an acute attack of pseudogout.

Granulocyte colony stimulating factor (G-CSF).

Polyethylene glycol (PEG).

C. History Part 3: Competing diagnoses that can mimic Pseudogout.

Pseudogout can mimic certain diseases:

Gout:

Gout is estimated to occur in 5% of patients who have pseudogout. Although rare, acute and pseudogout affecting different joints has been reported to occur simultaneously in the same patient.

Synovial fluids analysis can be useful in distinguishing these two entities. In pseudogout, rhomboid-shaped weakly positively birefringent (or nonbirefringent) CPPD crystals are found. In gout, needle-shaped, strongly negatively birefringent monosodium urate crystals are seen.

Tophi occur more commonly in gout than in pseudogout but the presence of tophi is not diagnostic of gout as tophi resulting from deposition of CPPD crystals have been reported.
Septic arthritis:

Synovial fluid in both septic arthritis and pseudogout may be inflammatory and purulent appearing due to a marked increase in total cell count (usually greater than 90% neutrophils).

Both conditions can manifest with fever, peripheral leukocytosis, and an elevated erythrocyte sedimentation rate (ESR).

However, blood staining of synovial fluid, while rare in septic arthritis, is common in pseudogout.

An acute attack of pseudogout may by the first clinical evidence of CPPD deposition disease; however, spontaneous joint sepsis is rare in individuals with no prior joint disease, systemic predisposition, or risk factor for infection.

The presence of crystals in the synovial fluid does not rule out the possibility of septic arthritis as pseudogout and sepsis may occasionally coexist in the same joint. Thus, synovial fluid Gram stain and culture should be routinely obtained. If CPPD crystals are identified and the Gram stain is negative, antibiotics can be withheld if clinical suspicion for septic arthritis is low. If CPPD crystals are identified but there remains a high clinical suspicion for septic arthritis despite a negative Gram stain, then empiric antibiotics should be initiated pending synovial fluid culture. If synovial culture is negative at 48 hours, antibiotics can likely be discontinued.
Rheumatoid arthritis:

Symmetric arthritis in multiple joints mimicking rheumatoid arthritis occurs in almost 5% of patients with CPPD deposition. A small percent of these patients have low rheumatoid factor titers further confounding the picture.

D. Physical Examination Findings.

Pseudogout presents as acute synovitis in one or more joints with tenderness, swelling, and erythema of the affected joint(s) noted on physical examination.

E. What diagnostic tests should be performed?

Aspiration of synovial fluid of the affected joint should be performed to make a definitive diagnosis as noted in section II.

Complete blood count (CBC) and ESR may be useful in helping to distinguish pseudogout from septic arthritis; however, as both white blood cell count and ESR may be elevated in pseudogout and septic arthritis, elevated values may not help to distinguish between these two entities.

Once the diagnosis of pseudogout is made, a creatinine level should be obtained if therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine is being considered.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Given the associated metabolic conditions, the following laboratory testing should be performed in patients diagnosed with pseudogout: serum calcium, phosphorus, magnesium, and alkaline phosphatase. Some authors suggest obtaining thyroid stimulating levels as well, but others suggest that the association between hypothyroidism and pseudogout is not clear.

The presence of pseudogout in persons below the age of 55 years should raise suspicion for a familial form of the disease or one of the associate metabolic conditions including hyperparathyroidism, hypomagnesemia, and hemachromatosis. In these patients, genetic studies, including testing for the Progressive ankyloses protein homolog (ANKH) gene, and measurement of serum calcium, phosphorus, alkaline phosphatase, magnesium, serum iron, and transferrin should be undertaken. Serum ceruloplasmin levels should also be considered if Wilson disease is suspected.

In patients older than 55 years of age, evaluation for hyperparathyroidism should be undertaken because both pseudogout and hyperparathyroidism are more common in this age group.

Abnormal values should prompt additional evaluation for possible associated metabolic conditions.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Findings of CPPD deposition on imaging can support the diagnosis of pseudogout.

Plain radiographs – Plain radiographs can support the diagnosis of pseudogout by demonstrating chondrocalcinosis, linear densities found in hyaline articular cartilage or fibrocartilage in joints. Chondrocalcinosis is most easily visualized on plain films of the knees, wrist (triangular cartilage of the radiocarpal joint), and the symphysis pubis. Screening for chondrocalcinosis can be performed with four plain films: anteroposterior view of the knee, anteroposterior view of the pelvis, and posteroanterior view of both hands to include the wrists. Chondrocalcinosis is, however, not a sensitive finding as 60% of patients with CPPD deposition will not have evidence of chondrocalcinosis.

Pseudogout may also result in destructive radiographic changes including subchondral collapse, bone fragmentation, and intra-articular radiodense bodies.

Ultrasound – Ultrasound criteria have been proposed for the diagnosis of CPPD deposition; however, the utility of ultrasound is operator dependent and, therefore, it is variably employed.

Computed tomography (CT) scan – CT scan can be used to identify patients with CPPD deposition, particularly of the spine. However, CT scan is not typically used to diagnose CPPD deposition in practice.

Magnetic resonance imaging (MRI) – MRI is relatively insensitive for the visualization of articular calcium crystals and has no role in the diagnosis of pseudogout.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Early observational studies suggested an associated between hypothyroidism and CPPD deposition disease, and many reviews continue to recommend screening with a TSH in patients with pseudogout. However, this association has not been replicated in subsequent controlled studies. In fact, a study using the Framingham data found a modest decreased risk of chondrocalcinosis in patients with hypothyroidism.

III. Default Management.

Treatment of acute attacks of pseudogout typically result in symptom resolution within 10 days. Nonpharmacologic treatment includes aspiration of synovial fluid; some patients with pseudogout will have immediate relief after arthrocentesis. Unfortunately, no current treatments have been shown to prevent or slow CPPD deposition or to stop the gradual joint damage resulting from chondrocalcinosis.

Pharmacologic treatment options are the same as the treatment options for acute gouty attacks and include:

NSAIDs:

Those drugs with a short half-life are most effective and typically include: indomethacin 25-50 milligrams (mg) three times a day (tid), ibuprofen 800mg tid, or diclofenac 50mg tid.
Oral colchicine:

One to two 0.6 mg tablets given every 6-8 hours over several days with subsequent tapering can be considered. Colchicine should be discontinued promptly if loose stools develop.
Intra-articular steroid injection:

For mono- or oligoarthritis intraarticular triamcinolone acetonide 20-40mg or methylprednisolone 25-50mg can be considered.
Systemic corticosteroids:

Often reserved for patients in whom other treatment options are limited, in patients with severe disease, or for attacks in joints not amenable to intra-articular steroid injection.

Prednisone 30-50mg/day followed by a gradual taper can be considered.
Adrenocorticotrophic hormone (ACTH):

Can be considered in lieu of systemic corticosteroids.

If a secondary cause of pseudogout (e.g., hyperparathyroidism, hypomagnesemia, etc) is found, treatment should also be directed at the underlying disease process. In fact, correction of hypomagnesemia has been reported to decrease the recurrence of pseudogout in affected individuals.

Based on earlier case series, methotrexate has been suggested as an option for treating CPPD arthropathy refractory to standard therapy. However, another case series subsequently yielded contradictory results. A more recent randomized controlled trial found that methotrexate provided no benefit when used for the treatment of chronic or recurrent CPPD arthropathy.

A. Immediate management.

As above.

B. Physical Examination Tips to Guide Management.

The physician should perform daily joint examination to assess improvement in synovitis/inflammation as well as to monitor for development of new synovitis.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

If the white blood cell count is elevated at the time of diagnosis, periodic monitoring (daily or every other day) to trend improvement may be of value. For a patient being treated with NSAID’s or colchicine, daily or every other day basic metabolic panels may be useful to detect changes in renal function. Baseline CBC should be obtained in patients in whom treatment with NSAIDs or prolonged treatment with colchicine is anticipated.

In patient where electrolyte abnormalities are believed to be the precipitant factor (e.g., hypomagnesemia, hypocalcemia, etc.), daily monitoring of these levels with supplementation as indicated would be prudent.

D. Long-term management.

Daily prophylactic doses of low dose oral colchicine may be helpful in decreasing the frequency of attacks but is typically less helpful than in preventing recurrence of acute gouty arthritis.

If the pseudogout results from a metabolic process, treatment of the underlying condition often prevents recurrence. For example, treatment of Gitelman syndrome with magnesium supplementation often prevents recurrence of pseudogout attacks and also leads to regression of articular chondrocalcinosis.

E. Common Pitfalls and Side-Effects of Management.

The presence of crystals in the synovial fluid does not eliminate the possibility of septic arthritis. Thus, Gram stain and culture of synovial fluid should be routinely obtained with empiric treatment based on the clinical picture.

Corticosteroid treatment should not be initiated until septic arthritis has been ruled out.

CPPD crystals can coexist with urate crystals making it difficult in certain patients to identify the primary etiology of the acute arthritis. However, in the immediate setting, treatment for gout and pseudogout are similar.

Intravenous colchicine should generally be avoided as a treatment option given the significant potential associated risks of the intravenous administration of colchicine and available alternative options.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Avoid the use of NSAID’s in patients with renal insufficiency.

Renally dose colchicine in patients with renal insufficiency.

B. Liver Insufficiency.

Adjust the dose of colchicine in patients with severe liver disease. Use caution with NSAID use in patients with severe liver disease.

C. Systolic and Diastolic Heart Failure.

Use caution when prescribing NSAIDs to patients with congestive heart failure.

D. Coronary Artery Disease or Peripheral Vascular Disease.

NSAIDs may increase the risk of serious and potentially fatal cardiovascular thrombotic events, myocardial infarction, and stroke.

E. Diabetes or other Endocrine issues.

Monitor for development of hyperglycemia in patients treated with corticosteroids.

Use corticosteroids cautiously in patients with osteoporosis.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.)

Weigh the risks/benefits of corticosteroid treatment in this patient population.

H. Primary Lung Disease (COPD, Asthma, ILD).

Weigh the risks/benefits of systemic corticosteroid treatment in this patient population.

I. Gastrointestinal or Nutrition Issues.

Avoid use of NSAIDs or systemic corticosteroids in patients with peptic ulcer disease.

Prescribe NSAIDs with food. Use NSAIDs for the shortest effective duration to minimize risks, especially in elderly patients.

J. Hematologic or Coagulation Issues.

Avoid use of NSAIDs in patients at increased risk for bleeding.

Obtain a baseline CBC in patients in whom prolonged treatment with colchicine is anticipated given the potential risk of myelosuppression.

K. Dementia or Psychiatric Illness/Treatment.

Monitor for steroid-induced psychosis in patients treated with high doses of systemic corticosteroids.

V. Transitions of Care.

A. Sign-out Considerations While Hospitalized.

For a patient with pseudogout in whom coexisting septic arthritis remains a possibility, hemodynamic instability should raise concern for sepsis. In the setting of hemodynamic instability, blood cultures should be obtained and empiric antibiotics should be considered pending synovial culture results.

B. Anticipated Length of Stay.

2-3 days.

C. When is the Patient Ready for Discharge?

The patient is typically ready for discharge when joint pain no longer limits mobility. In patients who also present with fever and leukocytosis, typically improvement in fever curve and leukocytosis should be demonstrated prior to discharge.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom?

The patient should follow-up with the primary care physician approximately one week after discharge. For patients with a severe attack of pseudogout or recurrent episodes of pseudogout, follow-up with a rheumatologist may also be appropriate.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

N/A

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

Consider obtaining a basic metabolic panel after discharge in patients treated with NSAIDs.

E. Placement Considerations.

In patients presenting with severe attacks of pseudogout who have marked limitations in mobility due to synovitis and whose symptoms are slow to resolve with pharmacologic therapy, placement in a skilled nursing facility for physical therapy may need to be considered.

F. Prognosis and Patient Counseling.

N/A

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients treated with NSAIDs or systemic corticosteroids should receive gastrointestinal prophylaxis against peptic ulcer disease.

Patients who are not ambulatory due to joint pains should receive treatment for DVT prophylaxis.

VII. What’s the evidence?

Alderman, JS, Wortmann, RL, Imboden, JB, Hellman, DB, Stone, JH. “Chapter 46. Pseudogout: Calcium Pyrophosphate Dihydrate Crystal Deposition Disease”. CURRENT Rheumatology Diagnosis, & Treatment.

Dalbeth, N, McQueen, FM. “Use of Imaging to Evaluate Gout and Other Crystal Deposition Disorders”. Curr Opin Rheumatol. vol. 21. 2009. pp. 124-131.

Fam, AG. “Calcium Pyrophosphate Crystal Deposition Disease and Other Crystal Deposition Diseases”. Curr Opin Rheumatol. vol. 4. 1992. pp. 574-582.

Fam, AG. “What is New About Crystals Other Than Monosodium Urate?”. Curr Opin Rheumatol. vol. 12. 2000. pp. 228-234.

Finckh, A, McCarthy, GM, Madigan. “Methotrexate in Chronic-Recurrent Calcium Pyrophosphate Deposition Disease: No Significant Effect in a Randomized Crossover Trial”. Arthritis Research & Therapy. vol. 16. 2014. pp. 458

Josefina, MJ, Ana, CJ, Ariel, V, Silvio, AA. “Development of Pseudogout During Etanercept Treatment”. J Clin Rheumatol. vol. 13. 2007. pp. 177

Mehta, BP, Shmerling, RH, Moss, AC. “Pseudogout After Polyetheylene Glycol Bowel Cleansing”. J Clin Gastroenterol. vol. 43. 2009. pp. 95-96.

Perez-Ruiz, F, Testillano, M, Gastaca, MA, Herrero-Beites, AM. “"Pseudoseptic" Pseudogout Associated with Hypomagnesemia in Liver Transplant Patients”. Transplantation. vol. 71. 2001. pp. 696-698.

Richette, P, Bardin, T, Doherty, M. “An Update on the Epidemiology of Calcium Pyrophosphate Dihydrate Crystal Deposition Disease”. Rheumatology. vol. 48. 2009. pp. 711-715.

Rosenthal, AK. “Calcium Crystals and Arthritis: What is New Under Polarizing Light?”. J Clin Rheumatol. vol. 15. 2009. pp. 42-45.

Rosenthal, AK. “Calcium Crystal-Associated Arthritides”. Curr Opin Rheumatol. vol. 10. 1998. pp. 273-277.

Rosenthal, AK. “Update in Calcium Deposition Diseases”. Curr Opin Rheumatol. vol. 19. 2007. pp. 158-162.

Schumacher, H. R, Chen Lan, X, Kasper, D, Fauci, A, Hauser, S, Longo, D, Jameson, JL, Loscalzo, J. “"Chapter 395. Gout and Other Crystal Arthropathies" (Chapter)”. Harrison’s Principles of Internal Medicine.

Young-Min, SA, Herbert, L, Dick, M, Fordham, J. “Weekly Aledronate-Induced Acute Pseudogout”. Rheumatology. vol. 44. 2005. pp. 131-132.

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