Calcium pyrophosphate deposition disease (pseudogout)

Introduction

Calcium pyrophosphate deposition disease (CPDD) is arthritis caused by calcium pyrophosphate (CPP) crystals. Although scattered descriptions of calcified cartilage exist in the literature dating back to the early 1900s, the significance of this finding was not fully appreciated until the early 1960s, when two groups of astute clinicians described clinical arthritis associated with CPP crystals. In Hungary, Zitnan and Sit’Aj described a group of patients with a severe osteoarthritis (OA)-like syndrome associated with linear calcific densities in articular cartilage on radiographs. Almost simultaneously, McCarty et al. described patients with gout-like arthritis who had synovial fluid CPP crystals. These two descriptions foreshadowed the clinical heterogeneity and many of the other characteristic features of CPDD. CPDD is a common and often unrecognized cause of arthritis in older adults. It has an interesting pathophysiology rooted in pyrophosphate metabolism. Management strategies for CPDD currently exist, but more specific and effective therapies are needed.

Nomenclature

One of the major challenges in the calcium crystal field is the lack of standard nomenclature. In 2011, a group of experts convened through the auspices of the European League Against Rheumatism (EULAR) valiantly attempted to deal with this issue. As shown in Table 196.1 , the EULAR suggested that the term pseudogout be eliminated and replaced with the term acute CPP crystal arthritis . It proposed that the widely variable terms used to refer to calcium pyrophosphate dihydrate crystals be replaced with the term calcium pyrophosphate crystals and that the presence of CPP crystals in tissues and fluids be referred to as CPP deposition (CPPD). They divided the multiple chronic clinical syndromes associated with CPP crystals, initially defined by Ryan and McCarty into (1) OA with CPPD and (2) chronic CPP crystal inflammatory arthritis. Although the term chondrocalcinosis was not replaced, it is important to remember that it refers only to the radiographic finding in this disease and should not be confused with the clinical syndrome. Last, many of us in this field use the term calcium pyrophosphate deposition disease , abbreviated CPDD, as an umbrella term to connote clinically important arthritis associated with CPP crystals. This new nomenclature has some limitations, and time and effort will be required to promote broad adoption by the medical community.

Epidemiology

The true prevalence of CPDD is unknown. Our current estimates are largely based on the prevalence of chondrocalcinosis, the radiographic correlate of CPPD ( Fig. 196.1 ). Even these data rely on relatively few large population-based studies. These include an American study that used the Framingham database to demonstrate a 3% prevalence of chondrocalcinosis of the knee in an adult population. In the United Kingdom, a similar study demonstrated a prevalence of knee chondrocalcinosis of 7% to 10% in people older than 60 years of age. The prevalence of chondrocalcinosis is clearly age dependent and rises dramatically with each decade over the age of 60 years. There is no clear sex preference, but chondrocalcinosis may be less common in certain populations, such as the Chinese. The prevalence of chondrocalcinosis is also dependent on which joint is examined. For example, in a study looking at chest radiographs, only 1.1% of people older than 50 years of age had chondrocalcinosis of the acromioclavicular joint. In contrast, a recent study of more than 1000 abdominal computed tomography (CT) scans found that 21.1% of randomly selected CT scans in patients demonstrated chondrocalcinosis of the pubic symphysis in patients older than the age of 65 years, and similar work showed a prevalence of 12.5% at age 55 years and 27.5% at age 95 years.

The prevalence of clinically important arthritis associated with CPP crystals is much more difficult to accurately assess. In a recent study of hospitalizations related to crystal arthritis, gout represented 48% of cases and CPDD accounted for 43%. Thus the burden of this disease in the inpatient setting may be similar to that of gout. We know that CPP crystals are present in 20% to 30% of knee fluids at the time of surgery in patients diagnosed with OA. Interestingly, careful examination of tissues at the time of either knee or hip replacement suggests an identical prevalence. Because OA occurs in about 27 million Americans, extrapolating these data would result in a conservative estimate of between 5 and 8 million affected people in the United States.

Clinical Presentation

Calcium pyrophosphate deposition disease has a heterogeneous clinical presentation. McCarty described six different clinical presentations of this disease. As in many rheumatic diseases, the initial clinical manifestations may change with time. Taken together with the considerable clinical overlap with other common syndromes of aging, these issues render CPDD a challenging condition to define.

Acute Calcium Pyrophosphate Crystal Arthritis (Pseudogout)

Acute CPP crystal arthritis is the most broadly recognized form of CPDD. It presents with acute or subacute onset of pain and swelling in and around one or a few joints. Physical examination shows signs of inflammation with erythema, swelling, and warmth around the affected joint. Tenosynovitis may be seen. The initial clinical picture is identical to that of other common causes of acute monoarticular arthritis such as gout, infection, and trauma. The knee is the most commonly involved joint ( Fig. 196.2 ). The wrist is also a common site of involvement, and other joints such as the shoulders, elbows, and ankles are often involved. Podagra has been described but is rare. Synovial fluid is inflammatory with high white blood cell counts, and CPP crystals are visible with compensated polarizing light microscopy ( Fig. 196.3 ). Cell counts may be over 100,000 cells/μL. Radiographs demonstrating chondrocalcinosis may support the diagnosis and are helpful to rule out other processes, such as fractures. Acute CPP crystal arthritis has several important characteristics that may help differentiate it from gout ( Table 196.2 ). The first is the joint distribution. Second, the presence of blood-tinged synovial fluid is considered to be more common in acute CPP crystal arthritis than in gout ( Fig. 196.4 ). Last, an untreated acute attack in CPDD may last weeks to months compared with the 7 to 14 days of most untreated gout attacks.

Table 196.2

Differences Between Acute Gouty Arthritis and Acute Calcium Pyrophosphate Crystal Arthritis

Symptom or Sign	Acute Gout	Acute CPP Crystal Arthritis
Pattern of joint involvement	First MCP joint, other lower extremity joints	Knee, wrist, ankle, spine
Response to colchicine	Excellent in early attack	Variable
Blood in joint fluid	Unusual	Not unusual
Duration of attack	7–14 days	Days to weeks

CPP , Calcium pyrophosphate; MCP , metacarpophalangeal.

Osteoarthritis with Acute Attacks

Many patients with acute CPP arthritis present with a chronic arthritis punctuated by acute inflammatory attacks. They typically have involvement of joints that are not usually involved in OA, such as the second and third metacarpophalangeal (MCP) joints, shoulders, and wrists ( Fig. 196.5 ). Between attacks of acute inflammation, these patients describe typical chronic noninflammatory joint pain. This disease pattern may represent a significant number of patients with CPDD, but true percentages are unknown.

Other Forms of Calcium Pyrophosphate Deposition Disease

Crowned Dens Syndrome

Crowned dens syndrome is a distinctive presentation of spinal CPPD caused by inflammation from CPP crystal deposits around the dens. Affected patients have acute neck pain associated with fever, occipital headache, limited range of motion of the cervical spine, and elevated inflammatory markers. It may be confused with aseptic meningitis, tumor, or acute spinal cord compression. The diagnosis typically relies on observation of calcified deposits on CT scans ( Fig. 196.6 ). CPP deposition around the dens can occur in the absence of symptoms. Although crowned dens syndrome is typically managed medically, acute decompression can be effective and aspiration of crystals through an anterior approach has been successful. In this vulnerable older adult population, rapid diagnosis avoids unnecessary tests, invasive procedures, and inappropriate treatments.