Pseudogout - Causes, Symptoms, Diagnosis, and Treatment

What Is Pseudogout?

Pseudogout, also known as calcium pyrophosphate deposition disease (CPPD) or pyrophosphate arthropathy, is a rheumatologic disorder causing joint redness, stiffness, and tenderness due to crystal depositions. Pseudogout usually affects the larger weight-bearing joints, usually just one at a time, while the chronic stage may also include multiple smaller joints.

Who Is More Susceptible to Pseudogout?

Acute pseudogout affects mostly populations over the age of 60 years, with an average onset age of 68 years and a prevalence rate of 5.2 in 1000 individuals. Males are 90 percent more prone to Pseudogout than females. About 30 to 50 percent of the cases are above the age of 85 years.

A larger study reveals the presence of joint calcification in about four to seven percent of the general population.

What Causes Pseudogout?

Pseudogout is caused due to an imbalance between the pyrophosphatases (enzymes responsible for breaking pyrophosphate) in diseased cartilage and the production of pyrophosphate in the body.

The pyrophosphates accumulate in the joints due to inadequate removal by the ectoenzyme nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1), leading to its combination with calcium within the joins to form the calcium pyrophosphate (CPP) crystals.

The formation of CPP crystals induces the immune system, which further damages the soft tissues.

The risk population for pseudogout includes patients with a prior diagnosis of:

• A thyroid condition.

• Kidney failure.

• Parathyroid disease.

• Low magnesium.

• Calcium, phosphate, or iron metabolism metabolic disorders.

• Osteoarthritis or degenerative joint disease.

• Rheumatoid arthritis.

• Osteoporosis.

What Is the Pathophysiology of Pseudogout?

• The formation of CPP crystals is very rare in non-cartilaginous tissues as the chondrocytes are the only cells that produce articular cartilage vesicles which are the primary sites of CPP crystal formation-the first stage of pseudogout.

• The formation of CPP requires the presence of inorganic pyrophosphate (PPi) from ATP molecules (energy-providing cells of mammals). PPi in pseudogout is analogous to the rate of gout disorder.

• The efflux of ATP into extracellular space is regulated by a membrane protein (ANKH) present on the plasma membrane of the chondrocytes. Some drugs like Probenecid are antagonists to ANKH functioning.

• Extracellular ATPs are metabolized in the presence of enzymes with nucleoside triphosphate pyrophosphohydrolase activity to give PPi. The metabolism is modulated by growth factors, cytokines, and certain pharmacological agents. The resultant PPi combines with free calcium in the extracellular space to form CPP crystals.

• CCP deposition over the cartilage introduces mechanical dysfunction of the tissue that either initiates or hastens joint destruction.

• Apart from deposition, CPP induces pseudogout by activating NLRP3 inflammasome and by inducing catabolic effects on chondrocytes and synoviocytes, which results in the production and recruitment of destructive matrix metalloproteinases and prostaglandins, further destroying the joint cartilage.

What Are the Signs and Symptoms of Pseudogout?

Pseudogout is characterized by a sudden acute onset of redness, hotness, swelling, and pain in one of the large joints. Other symptoms include edema (swelling), erythema (redness), and low-grade fever. There might be waxing and waning episodes of non-synchronous inflammatory arthritis affecting multiple non-weight-bearing joints.

The knee is the most affected joint, but other weight-bearing joints like hips and shoulders might also get involved.

CPPD can also occur in the upper and lower segments of the spine, putting pressure on spinal nerves, which may cause pain in the arms or legs.

What Is a Familial Pseudogout?

Although the occurrence of pseudogout is spontaneous and random, a premature and extensive onset before the age of 60 persuades an investigation of family members’ medical history for similar symptoms/disorders.

Mutations in the CCAL2 locus on chromosome 5p lead to hyperactivity of ANKH protein and show an autosomal dominant pattern of inheritance. Evidence of mutations in the CCAL1 locus on chromosome 8 resulting in CPPD is also observed. Recent studies have also detected a gain-of-function mutation in the TNFRSF11B gene that results in premature osteoarthritis and chondrocalcinosis.

How to Diagnose Pseudogout?

On presentation of acute symptoms associated with any of the joints, the patient must undergo arthrocentesis for synovial fluid analysis (aspirating and analyzing synovial fluid from the affected joint) and radiography of the involved joints.

Synovial fluid presents with white blood cell infiltration and rhomboid CPP crystals, which gives positive birefringence under polarized microscopic analysis.

Radiographs show the presence of joint cartilage calcification-chondrocalcinosis. An early diagnosis can also be made with the help of an ultrasound and MRI (magnetic resonance imaging) of the joints.

X-rays might reveal joint effusion, soft-tissue swelling, and fractures in the surrounding bones. The use of ultrasound can detect the presence of urea or pyrophosphate crystals in the joint with high accuracy. MRIs are often not beneficial in the diagnosis and are useful only when used adjunct to ultrasound and standard radiographs. The detection of crystals in the joint with MRI is highly variable and largely dependent on various factors like their size, type, and level of maturation, as well as the technical parameters of the MRI.

Additional blood tests to screen for conditions that are linked to pseudogout can also be ordered.

How Is Pseudogout Different From Gout?

Pseudogout is different from gout in various ways:

Age of Onset:

• Pseudogout- 60 years and above.

• Gout- 40 years and above.

Etiology:

• Pseudogout- Accumulation of CPP crystals in the joint.

• Gout- Accumulation of urate crystals in the joint.

The Severity of Pain:

• Pseudogout- Moderate.

• Gout- Severe.

Diagnostic Tests:

• Pseudogout- Arthrocentesis, X-ray, magnetic resonance imaging (MRI), and ultrasound.

• Gout- Arthrocentesis, X-ray, MRI, ultrasound, and CT.

Swelling:

• Pseudogout- Chondrocalcinosis swelling.

• Gout- Soft tissue swelling evident after five to six years.

Location:

• Pseudogout- larger weight-bearing joints, often one at a time.

• Gout- multiple larger joints.

Crystal Properties:

• Pseudogout- Rhomboid and positive birefringence.

• Gout- Needle-like and negative birefringence.

How to Manage Pseudogout?

The treatment of pseudogout primarily focuses on lowering the symptoms of acute inflammation and stabilizing any underlying condition that aids in the precipitation of the CPP crystals.

In cases of limited acute inflammation, joint aspiration and intra-articular glucocorticoid administration are performed.

In more extensive inflammation, NSAIDs are prescribed. If NSAIDs are contraindicated, Colchicine can be given. In the case of joint sepsis, aspiration should be delayed till synovial fluid analysis is done. For chronic cases affecting multiple joints, Methotrexate or Hydroxychloroquine may be helpful.

Home remedy for Pseudogot includes the application of ice packs and joint rest, especially weight-bearing ones. Recurrent episodes can be decreased or managed with a daily dose of Colchicine. Since there is no medication to completely cure pseudogout, the treatment of CPPD relies on treating predisposing metabolic diseases, soft tissue inflammation, and symptomatology.

Dietary restrictions play a major role in managing gout, but there is no evidence of improvement in pseudogout with the same.

In case of excessive unmanageable damage, surgical joint replacement is the only mode of treatment.

What Is the Prognosis of Pseudogout?

The acute symptoms of pseudogout are short-lived and remit within a few weeks. Chronic pseudogout episodes may present overlapping manifestations with rheumatoid arthritis, carpal, or cubital tunnel syndrome involving multiple joins and lasting for months instead of a few weeks. Patients within the risk group carry comorbidities and are prone to pseudogout, and their prognosis is majorly dependent on managing the underlying comorbidity.

What Are the Complications of Pseudogout?

• Permanent joint damage.

• Degradation of menisci and synovial tissue (damage of the cartilage pad and other parts of the joint).

• Gout tophi (uric acid deposits).

• Ankylosing spondylitis (vertebral fusion).

• Diffuse idiopathic skeletal hyperostosis (DISH-hardening of the ligament attachment to the spine).

• Spinal cord compression (pressure on the spinal cord).

What Is the Differential Diagnosis of Pseudogout?

• Gout (arthritis due to uric acid crystal deposition).

• Rheumatoid arthritis (autoimmune arthritis-immunity attacks the joints).

• Ankylosing spondylitis.

• Erosive osteoarthritis (cartilage damage and erosion of the hand finger joints).

Conclusion

There is no permanent cure for pseudogout, but acute inflammations can be managed efficiently with an established treatment protocol. The focus should remain on preventing future episodes and managing the underlying disorder. In a few patients, the occurrence of a pseudogout inflammation acts as an alarm to remind them of their healthcare management and hence, may lead to the diagnosis of an underlying condition that can be treated or managed with its own protocol. Most importantly, regular follow up are essential to living a fairly normal life.