Dermatology

Pseudogout (Calcium Phyrophosphate Deposition Disease)

Are You Confident of the Diagnosis?

Pseudogout refers to the clinical entity of acute joint inflammation that occurs because of an inflammatory response to deposited calcium-containing crystals. The term chondrocalcinosis refers to deposition of these crystals within the articular cartilage (Figure 1). The most common crystal causing this is calcium pyrophosphate dihydrate (CPPD). Most joints that have chondrocalcinosis remain asymptomatic. Chondrocalcinosis is routinely detected by plain radiography, most often as an incidental finding. While calcium crystals are necessary for an attack of pseudogout to occur, some joints with pseudogout may lack enough chondrocalcinosis be detectable on plain radiographs.

Figure 1.

Radiograph of hip joint showing linear calcification (arrow) due to calcium pyrophosphate dihydrate (CPPD) within the articular cartilage.

  • What you should be alert for in the history

By far the most common presentation of CPPD deposition disease (CPPDD) is acute monoarthritis resembling gout. In fact, the patient may have been erroneously diagnosed with gout (although there are a few patients with gout and pseudogout occurring simultaneously). The patient usually reports the sudden onset of severe pain and swelling of the affected joint. There may or may not be a history of minor trauma or overuse. Frequently, there is a history of pre-existing osteoarthritis.

By far the most commonly affected joint is the knee, followed by the shoulder, hip and the wrist. Occasionally attacks can be polyarticular. Pseudogout patients are older on average at the time of their first attack than gout patients. As with gout, pseudogout has a propensity to attack patients when they are ill or hospitalized for an unrelated reason.

Patient demographics can be helpful to distinguish between the two conditions. For example, a female octogenarian who is hospitalized for pneumonia and who suddenly develops inflammation of one knee (without a previous history of podagra) is overwhelmingly more likely to have pseudogout than gout. As in the case with gout, polyarticular attacks occur with signs of systemic inflammation, but this is much less common than in gout. Patients with familial chondrocalcinosis will often present prior to age 40, sometimes as young as 20 years.

  • Characteristic findings on physical examination

Because various aberrant genes have been associated with the phenotype of chondrocalcinosis, it follows that the clinical presentation vary among kindreds. Many persons are asymptomatic. If symptomatic, the most common pattern is sudden, severe monoarthritis, most commonly of the knee. Other common presentations include the pseudo-rheumatoid pattern and the pseudo-osteoarthritis pattern (Figure 2, Figure 3). Other tissues such as synovium, tendons and tendon sheaths can occasionally be infiltrated with CPPD (Figure 4, Figure 5).

Figure 2.

Hand radiograph of a 30-year-old male with familial chondrocalcinosis and premature, polyarticular osteoarthritis. Note calcification of the triangular fibrocartilage (A), "squared off" metacarpal heads (B) suggestive of hereditary epiphyseal dysplasia (an associated feature in this particular kindred) and faint linear chondrocalcinosis within the second MCP joint (C). The radiocarpal joint is slightly misshapen or "indented," a typical feature of CPPDD.

Figure 3.

Radiograph from a 73-year -ld woman with a 30-year history of the pseudo-osteoarthritic pattern of CPPDD. Arthrocentesis was performed on several occasions and always yielded abundant CPPD crystals. Note the absence of erosions in the joints typically affected by rheumatoid arthritis (such as the MCP joints). Sclerosis and numerous small erosions are typical of CPPDD.

Figure 4.

Calcified Achilles tendon (arrow) of a 45-year-old woman with familial chondrocalcinosis who had recurrent attacks of Achilles tendinitis and retrocalcaneal bursitis. Surgical debridement of the tendon sheath and bursa yielded CPPD.

Figure 5.

CT scan of right hip of 35-year-old woman with recurrent episodes of right groin and right proximal thigh pain. Note calcification of iliopsoas tendon (arrow). Episodes of pain gradually diminished in frequency and severity, but calcifications remained.

A few persons will present with recurrent acute hemarthrosis or with a pseudo-neuropathic joint (Charcot joint) pattern. Some people present with either an acute or chronic carpal tunnel syndrome. Dialysis patients tend to develop a severe, destructive calcific arthropathy.

A small number of patients may develop tophaceous, soft tissue collections of CPPD, sometimes mixed with basic calcium phosphates (BCP). The most common area for this rare condition is in the vicinity of the temporomandibular joint. A firm mass is palpable in such cases and imaging studies often demonstrate erosion of the adjacent bone; this finding raises the suspicion of malignancy, which could result in more extensive surgery than is actually necessary. Simple excisional surgery is usually curative.

A potentially serious consequence of CPPDD is acute inflammation occurring at the level of C1-C2, the "crowned dens" syndrome. Approximately 70% of persons with chondrocalcinosis have calcific deposits at the level of the transverse ligament of C1 (Figure 6). The sudden onset of inflammation in or around these crystalline deposits can result in severe neck pain and possibly permanent neurological sequelae due to edema of the proximal spinal cord. This condition may be accompanied by fever and by meningeal signs on physical examination.

Figure 6.

Coronal slice of CT scan showing calcification of the transverse ligament of C1 (A). C1-C2 articulation is bone-on-bone and demonstrates subchondral sclerosis (B). The patient had episodic attacks of severe neck pain. Same patient as in Figure 3.

One of the clues on physical examination is pain with head rotation, in contrast to those patients with simple spondylosis, in which there is normally pain only with bending of the spine. A few persons with the crowned dens syndrome have such voluminous calcific deposits in the region of C1-C2 that chronic cord compression occurs, even in the absence of acute inflammation. Some subacute cases have been reported to mimic polymyalgia rheumatica.

The clinical syndrome of pseudogout occurs when previously asymptomatic crystals trigger acute inflammation. Frequently the precipitant is a minor trauma that dislodges crystals from the cartilage surface into the synovial fluid where they trigger the inflammatory cascade. Within several hours the joint becomes warm and swollen and a large joint effusion develops.

CPPD and other calcium crystals can deposit asymptomatically within soft tissues until such time that inflammation is triggered, mimicking infectious cellulitis. If enough inflammation develops, the patient may exhibit fever, leukocytosis and dramatically elevated serum markers of inflammation. The classic pseudogout attack is self-limited, but tends to persist longer than the classic gout attack, often lasting several weeks.

  • Expected results of diagnostic studies

Imaging

Chondrocalcinosis is typically detectable by plain radiography, although occasionally a patient may present with an attack of pseudogout without enough CPPD deposition in the cartilage to be visible on plain radiographs (Figure 1). Chondrocalcinosis is visible as a linear band of calcification within the substance of the articular cartilage. It is most readily detectable in radiographs of the knees, the wrists (particularly the triangular fibrocartilage on the ulnar aspect of the wrist) and the symphysis pubis.

Calcification is also readily detectable by computed tomography (CT) imaging, but is easily missed on magnetic resonance imaging (MRI), which tends to show calcium crystals as a signal void or as background density. For evaluation of the crowned dens syndrome, CT scanning is best for detecting the extent of calcification (Figure 6), while MRI scanning is best for detecting the degree of inflammation associated with the condition. Bone scintigraphy is the most sensitive imaging modality to detect the early inflammatory phase of heterotopic ossification.

Laboratory

Most persons with pseudogout or with chondrocalcinosis have normal laboratory findings. A serum calcium level that is elevated or near the upper limit of normal should raise the suspicion of hyperparathyroidism. Hypophosphatasia (a predisposing but rare condition for chondrocalcinosis) would be suggested by a low serum alkaline phosphatase level. There are usually no clues to hypomagnesemia, so it is worth obtaining a serum magnesium level in most chondrocalcinosis patients.

Patients younger than 60 years should be screened for hereditary hemochromatosis. If suspicion is high, or if there is a family history of hemochromatosis, the best screening consists of serum ferritin, serum transferrin saturation (approximated as serum iron divided by serum transferrin) and determination for the presence of the HFE gene (C282Y). Mildly elevated transaminases are nonspecific, but can be a clue to the presence of hemochromatosis. As mentioned previously, alkaline phosphatase may be elevated severalfold in acute heterotopic calcification, but will be normal in classic pseudogout patients.

Synovial fluid from the joint affected with pseudogout will typically be inflammatory (cell count >1000/mm3), appearing mildly to moderately cloudy. CPPD crystals are slightly rectangular or rhomboid in shape, compared to needle-like monosodium urate (MSU) crystals. They can usually (but not always) be distinguished by shape alone, without the aid of polarized light.

Under polarized light, CPPD crystals are only weakly birefringent while MSU crystals are strongly birefringent. Under compensated polarized light, CPPD crystals exhibit "positive" birefringence. In other words, a CPPD crystal will appear blue (a pale blue because CPPD crystals are only weakly birefringent) when the long axis of the crystal is aligned with the direction of slow vibration of the compensating filter, and yellow when the crystal is perpendicular to this direction. Occasionally CPPD crystals may be so weakly birefringent as to appear non-birefringent. MSU crystals on the other hand exhibit strong "negative" birefringence. They are bright yellow when aligned parallel to the axis of slow vibration of the compensating filter, and bright blue when perpendicular to this axis.

Hydroxyapatite crystals are non-birefringent. They have no brightness under polarized light, and no color under compensated polarized light. The shape of hydroxyapatite crystals is chunk-like under the light microscope. They have no visible regularity of shape. Without special staining they cannot be reliably distinguished from intracellular granules or from extracellular debris. Alizarin red stain is used to identify calcium-containing crystals under ordinary light (Figure 7). Hydroxyapatite crystals stain bright orange-red while CPPD crystals stain less intensely. MSU crystals are not stained by alizarin red.

Figure 7.

Alizarin red stain of material aspirated from acutely inflamed periarticular calcific deposit. Note intense staining of irregularly shaped crystals of varying sizes, and the absence of leukocytes.

  • Diagnosis confirmation

The pseudo-rheumatoid pattern of CPPDD clinically resembles rheumatoid arthritis with polyarticular involvement, often with morning stiffness and chronic joint inflammation. Radiographically this entity lacks the classic features of rheumatoid arthritis. Chondrocalcinosis is usually evident. Arthrocentesis will show typical intracellular CPPD crystals. Rheumatoid factor and anti-CCP antibodies (anti-cyclic citrullinated protein) are typically negative.

The pseudo-osteoarthritis pattern is much more common. The pattern is one of "inflammatory osteoarthritis" or "erosive osteoarthritis" (Figure 3). While superficially this can also resemble rheumatoid arthritis, the pattern of joint involvement is more typical of osteoarthritis. Principally involved are the knees, the wrists (particularly the first carpometacarpal joints), other large joints including the hips and shoulders, and frequently the distal interphalangeal (DIP) joints. Some persons have prominent degenerative spinal involvement as well, with variable degrees of annular calcification, facet involvement and bony overgrowth, sometimes resembling diffuse idiopathic skeletal hyperostosis (DISH).

If the MCP joints are significantly involved along with the wrists, this disease may be confused with rheumatoid arthritis. This is frequently a painful disease with relentless, severe degenerative changes and with variable degrees of chronic and acute inflammation, accelerated joint destruction and unusually aggressive radiographic changes. In fact, as the disease progresses and cartilage degenerates, the chondrocalcinosis becomes more difficult to see on radiographs. In such a case, the diagnosis of CPPDD may be missed (Figure 3).

There are three serious but treatable underlying conditions that should always be considered when making a diagnosis of pseudogout. These are hyperparathyroidism, hemochromatosis and hypomagnesemia. Hemochromatosis has been called "the bronze diabetes." Associated findings may include skin hyperpigmentation, glucose intolerance, cardiac conduction defects or cardiomyopathy; the associated arthritis can resemble either rheumatoid arthritis or osteoarthritis, characteristically affecting the second and third metacarpophalangeal (MCP) joints of the hands.

There are no specific dermatologic manifestations of CPPDD. As noted above, prominent soft tissue inflammation will occasionally accompany pseudogout, particularly if inflammation proceeds within tendon sheaths.

In contrast to CPPDD, calcification and inflammation of the skin and soft tissues is more commonly associated with the basic calcium phosphates (BCP), usually those of the apatite family. Hydroxyapatite is the best-known of this family because of its importance in teeth and in bones. In the region of joints, apatites are best known for their role in acute calcific bursitis or acute calcific tendinitis. Local inflammation can be so acute and severe as to mimic septic arthritis or cellulitis (Figure 8), but is ultimately self-limited over days or weeks. The usual precipitant appears to be minor trauma or overuse, but frequently there is no obvious precipitating factor.

Figure 8.

A 30-year-old male who presented to the emergency department with acute, severe pain, swelling and erythema of left third MCP joint. Note cloudlike, amorphous, periarticular calcification (A) suggestive of acute apatite deposition. Aspiration of the calcification yielded chunk-like crystals without birefringence that stained intensely with alizarin red (see Figure 7). Lack of a trabecular pattern in apatite calcification allows differentiation from a normal sesamoid bone (B). Patient recovered completely with 7 days of indomethacin treatment. Cultures were negative.

Apatite deposition is visible on plain radiographs as an amorphous "cloud" of calcification adjacent to a joint. The calcification is typically outside the joint proper, giving rise to prominent soft tissue inflammation with a relatively small, noninflammatory synovial effusion. This is in contrast to the classic synovial fluid findings in gout or in pseudogout. Radiographs of other joints and tendons of the same patient will frequently show other, asymptomatic areas of apatite deposition, suggesting that most apatite deposition occurs silently, as is the case with CPPDD.

Apatite deposition is much more likely to come to the attention of the dermatologist than is CPPD. For instance, cutaneous apatite deposition is frequently seen in both scleroderma and in dermatomyositis, particularly in the childhood form of dermatomyositis (Figure 9, Figure 10. Figure 11). If deposits become large, or if trauma or ischemia occurs, the deposits may drain a white, pasty material. If ulcerations occur on the digital tips, as is often the case in scleroderma, granular apatite may drain; such lesions may require months for complete healing. Microscopic examination of the exuded material allows rapid differentiation from both monosodium urate (MSU) and CPPD. Apatite crystals are small, amorphous, chunk-like crystals that exhibit either little or no birefringence under polarized light (depending on the exact chemical composition).

Figure 9.

Extensive cutaneous calcifications in a patient with dermatomyositis.

Figure 10.

Elbow of a middle-aged woman with 15-year history of dermatomyositis. Cutaneous calcifications are not as prominent as in patient shown in Figure 7, but are visible as hills and valleys in the skin surface. Radiograph of this patient's elbow is shown in Figure 10.

Figure 11.

Radiograph of the elbow shown in shown in Figure 10 from patient with dermatomyositis. Note extensive cutaneous calcifications. CT scan showed that calcifications were confined almost exclusively to the skin.

Some persons exhibit a familial tendency to form deposits of apatite at sites of minor, repetitive trauma. Figure 12 shows an extreme example of calcific pre-patellar bursitis ("housemaid’s knee").

Figure 12.

Unusually severe case of bilateral calcific prepatellar bursitis ("housemaid's knee") associated with years of frequent kneeling.

Hydroxyapatite is the main crystal involved in heterotopic ossification. This is a painful, inflammatory condition that occurs for unknown reasons in some persons following joint surgery or following paralysis, as from a cerebrovascular accident, or more commonly following spinal cord injury. Hydroxyapatite is deposited in the soft tissues, and if left untreated it may result in ankylosis of the affected joint. In muscle, progressive ossification of the hydroxyapatite deposits may ultimately lead to myositis ossificans (Figure 13). The fever and the signs of local inflammation can be of such intensity that this entity may be mistaken for septic arthritis, cellulitis or osteomyelitis. If inflammation and calcification are superficial enough to affect the skin, ulceration and post-inflammatory hyperpigmentation may occur (Figure 14).

Figure 13.

Severe heterotopic ossification about right hip, with milder disease about the left hip.

Figure 14.

A 28-year-old male with left-sided traumatic brain injury and right hemiparesis who developed severe pain and inflammation about the right knee and the right hip. MRI scan showed extensive inflammation of soft tissues about the right hip and the right knee joints. Radiographs showed extensive heterotopic calcification. Palpation of the swollen right knee revealed soft tissue induration and areas of stony hardness.

Heterotopic ossification is a particularly serious problem if it occurs following hip replacement surgery. Clinically significant heterotopic ossification occurs in 2-7% of hip replacements. It often presents as the sudden onset of pain several weeks (3-12 weeks) after total joint arthroplasty, raising the suspicion of prosthetic joint infection. Bone scintigraphy (Figure 15) and CT scan are helpful for the diagnosis. Tagged leukocyte scanning may assist in excluding infection. Magnetic resonance imaging may be misleading due to the inability of this modality to adequately visualize calcium deposits. Alkaline phosphatase is frequently elevated severalfold, which offers a clue to the diagnosis.

Figure 15.

Technetium bone scan showing intense radioisotope uptake by heterotopic calcification about the elbow.

Apatite deposition is also associated with a destructive form of osteoarthritis of the shoulder known as Milwaukee shoulder, occurring principally in elderly females. The primary event in such cases appears to be a complete rotator cuff tear that destabilizes the glenohumeral joint, leading to excessive wear of the glenohumeral joint in persons who are believed to be predisposed to osteoarthritis. In this condition, large noninflammatory joint effusions occur, often with free hydroxyapatite crystals in the fluid, but with scant white cells. Nevertheless, the condition is very painful and debilitating and normally requires joint replacement surgery for significant relief.

Calciphylaxis is a particularly virulent form of cutaneous calcification and necrosis. It is most frequently associated with end-stage renal disease or dialysis, although the presence of an underlying connective tissue disease such as lupus or dermatomyositis has been identified as a risk factor for this condition.

Who is at Risk for Developing this Disease?

Chondrocalcinosis is a necessary prerequisite for the development of pseudogout, yet it is quite common to diagnose pseudogout in persons who have no prior knowledge of their chondrocalcinosis. The risk of chondrocalcinosis increases with age. Approximately 40% of octogenarians will have (usually asymptomatic) chondrocalcinosis.

When one considers how common chondrocalcinosis is, one wonders why pseudogout is not more common. Most persons with chondrocalcinosis will never have an attack of pseudogout. A history of trauma to a joint (or even prior arthroscopy) can accelerate the formation of chondrocalcinosis, resulting in an unexpected and unwelcome attack of pseudogout several years later.

A number of conditions are associated with the development of chondrocalcinosis. These include hemochromatosis, hyperparathyroidism, hypomagnesemia, and hypophosphatasia. While there are many causes of hypomagnesemia, those most closely associated with chondrocalcinosis are the Bartter syndrome (hypomagnesemia, hypokalemia and metabolic alkalosis) and Gitelman’s syndrome (hypomagnesemia, tubular hypokalemia and hypocalciuria).

There has been speculation that hypomagnesemia induced by diuretic use in the elderly could play a role, but so far there are no adequate studies to support this. One condition common to these conditions is an excess of cartilage-bound pyrophosphate. Chondrocalcinosis is also associated with a number of rare conditions including Wilson disease, and ochronosis. There are rare reports of tacrolimus triggering soft tissue calcification.

In the past decade a number of enzyme defects have been associated with chondrocalcinosis. For example, hereditary hypophosphatasia is due to missense mutations of the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP). It is believed that families with chondrocalcinosis are heterogeneous with respect to the genetic defects involved. Several mutations in the ankylosis human (ANKH) gene have been recently described in some kindreds. This gene codes for what has been described by Zaka and Williams as a multipass transmembrane protein that regulates the transport of inorganic pyrophosphate, and which may affect several key enzymes.

An aberrant gene on the long arm of chromosome 8 is responsible for a particularly severe form of chondrocalcinosis with destructive osteoarthritis while other mutations on the short arm of chromosome 5 are associated with different phenotypes in other families. The specific enzymes that are thought to play critical roles in the process of calcification are being targeted for genetic studies. The few mutations identified so far do not seem to explain the vast majority of sporadic cases of chondrocalcinosis.

There is also a large group of familial chondrocalcinosis patients in whom the underlying metabolic defect is unknown. In some kindreds, chondrocalcinosis is associated with other inborn musculoskeletal defects such as spondyloepiphyseal dysplasia, brachydactyly and premature degenerative joint disease. Some familial cases are associated with diffuse idiopathic skeletal hyperostosis (DISH). A family with CPPDD and familial hpocalciuric hypercalcemia has been described by Volpe and colleagues. In the past it was thought that hypothyroidism was also associated with chondrocalcinosis, but this association has not been borne out in more recent rigorous studies, although there may be an association with flagrant myxedema.

CPPD is frequently associated with deposition of basic calcium phosphates (BCP) in close proximity. This is perhaps best illustrated in the case of Milwaukee shoulder and the pseudo-osteoarthritis pattern of CPPDD. BCP alone has been reported to cause chondrocalcinosis, including familial types.

What is the Cause of the Disease?

In addition to the presence of calcium crystals within cartilage, the other necessary ingredient is phagocytosis of crystals by inflammatory cells, usually neutrophils. It is only then that the chondrocalcinosis becomes symptomatic.

Systemic Implications and Complications

Given that some underlying causes of chondrocalcinosis are treatable, it is most important to evaluate younger persons (particularly those <60 years of age) who present with chondrocalcinosis or with pseudogout. The main underlying conditions that should be sought in such individuals include hemochromatosis, hyperparathyroidism, and hypomagnesemia. Evaluation would include two serum calcium levels (or one serum calcium and a parathyroid hormone [PTH] determination), a serum magnesium level and either a serum iron/transferrin ratio or a serum ferritin level. As a rule, patients older than 70 years of age do not require evaluation (with the exception of serum calcium) unless there are obvious signs of a predisposing condition.

Most cases of pseudogout are idiopathic, especially in the elderly. The three most important systemic underlying conditions that should be sought are hyperparathyroidism, hemochromatosis and hypomagnesemia. Fortunately, screening for these three entities is relatively straightforward.

If hypomagnesemia is discovered, then further evaluation will be needed to determine an etiology. Causes of hypomagnesemia associated with CPPD include the Bartter syndrome (hypomagnesemia, hypokalemia and metabolic alkalosis) and Gitelman’s syndrome (hypomagnesemia, tubular hypokalemia and hypocalciuria). Other common causes include diuretic use, diarrhea, inadequate intake, ethanol abuse, hypercalcemic states, short bowel syndrome, and medications such as cyclosporine, aminoglycosides, amphotericin, pentamidine and others. However, most of these have not been associated with CPPDD.

Rarely, cases of chondrocalcinosis are associated with ochronosis, Wilson disease and hypophosphatasia. Ochronosis and Wilson disease have additional physical findings that can be sought easily. For instance, simple transillumination of the pinna of the ear is a reasonable screening test for ochronosis. Wilson disease is rare after age 40. Sometimes a Kayser-Fleischer ring is visible on simple inspection, and a serum ceruloplasmin is a useful screening test. Hypophosphatasia is easily screened for using a complete metabolic panel.

Familial forms of chondrocalcinosis are frequently associated with varying degrees of osteoarthritis of a large joint, small joints, and/or the spine, depending upon the kindred affected. Hemochromatosis is sometimes called "the bronze diabetes." Associated findings may include skin hyperpigmentation, glucose intolerance, cardiac conduction defects or cardiomyopathy; the associated arthritis may resemble either rheumatoid arthritis or osteoarthritis.

Unfortunately, treatment of underlying conditions does not reverse or prevent joint damage, and pseudogout attacks tend to continue. Attacks of pseudogout may increase in frequency following parathyroid surgery. There is no effective treatment for the osteoarthritis associated with chondrocalcinosis. There is some evidence that as a group, patients with chondrocalcinosis are prone to faster progression of osteoarthritis.

Treatment Options

Treatment options are summarized in Table I. Preventive measures against attacks are listed in Table II.

Table I.

Treatment options
Ice, rest, elevation
Aspiration of CPPD crystals
Intra-articular injection of depot corticosteroid
NSAIDs
Systemic corticosteroids
Possibly interleukin-1 inhibitors (unapproved use)
NSAIDS, noninflammatory steroidal antiinflammmatory drugs

Table II.

Prevention of attacks
Colchicine
NSAIDs
Low-dose prednisone
Possibly hydroxychloroquine
Possibly methotrexate
Treat underlying disease (if any)

Optimal Therapeutic Approach for this Disease

As with gout, there are several ways to manage the acute attack. On average, pseudogout attacks tend to be more resistant to all forms of treatment than gout attacks and may persist longer. The preferred treatment option, if possible, is to aspirate the crystal-containing synovial fluid and inject depot corticosteroids. In the case of pseudogout, more so than gout, it is important to aspirate as much fluid as possible in order to achieve a rapid response.

If for some reason intraarticular corticosteroids cannot be given (such as when waiting for synovial fluid culture results to rule out septic arthritis), then serial aspiration alone is a reasonably effective treatment approach. The usual dose of triamcinolone acetonide for a knee is 20-4 mg mixed with 2-3 ml of 1-2% lidocaine without epinephrine. The lidocaine will provide some immediate relief for the patient. We have injected as many as six joints at one sitting.

For mild attacks, NSAIDs are an alternative, but may take days to work. Antiinflammatory doses may carry significant risks in the elderly, particularly those with comorbidities such as a history of peptic ulcer disease, hypertension, congestive heart failure, renal insufficiency or hepatic insufficiency. Even among the healthy elderly, the risk of acute peptic ulcer disease increases dramatically in the eighth and ninth decades.

If NSAIDs are used, they should be taken with food, and some thought should be given to use of one of the proton pump inhibitors (PPIs) that is FDA-approved for gastric ulcer prophylaxis in high risk users of NSAIDs. Not all PPIs are equally effective in this regard. Those PPIs so approved include lansoprazole and esomeprazole.

For severe, polyarticular or recalcitrant attacks, systemic corticosteroids are indicated. Oral prednisone must be given at least twice a day to be reliably effective. Once-daily dosing is largely ineffective because of the short half-life of this agent. A dose of 30 mg twice a day or 20 mg three times a day normally suffices. Corticosteroids carry both short-term and long-term risks in the elderly. It is important to follow glucose and potassium levels closely. Occasionally significant fluid retention can occur, although this is not common with prednisone as compared with hydrocortisone. A few persons will develop corticosteroid- induced insomnia or psychosis. Osteoporosis, fragility fractures, cataracts, purpura and striae are all risks if used more than 2-3 weeks in the elderly.

As is the case with gout, tumor necrosis faction (TNF) inhibitors do not seem to be frequently effective for treatment, although there are case reports of success. In gout, interleukin one inhibitors seem to be more successful than TNF inhibitors. There are reports suggesting that the same is true for pseudogout.

Unfortunately, oral colchicine does not work well for pseudogout, and FDA approval for the intravenous formulation of colchicine was rescinded in the USA in 2008. It is appropriate to begin oral colchicine 0.6 mg twice a day (the dose must be adjusted in those with renal or hepatic insufficiency) as a prophylactic agent while treating the acute attack, since colchicine will take several days to achieve steady state.

An alternative for prophylaxis is a low dose of an NSAID, such as naproxen 375 mg once daily if there are no contraindications. Some persons do not require prophylaxis, such as an elderly patient with his/her first attack who has a clear precipitating event. When given, prophylaxis is generally continued for 2-3 weeks, or chronically in those who are prone to recurrent attacks.

In all cases of acute pseudogout, rest and ice are appropriate and have been shown to reduce inflammation. Elevation of the affected part may also be helpful. Even injected joints that may improve within 24 hours should be rested for at least an additional 24-48 hours before resuming normal activities to help prevent recurrence.

In the case of cutaneous calcinosis associated with either dermatomyositis or scleroderma, no treatment has been shown to be effective in reducing calcifications that are already present. For calcifications that become inflamed and are painful to the patient, ice and NSAIDs may be helpful (if there are no contraindications; for instance, ice can severely aggravate Raynaud’s phenomenon), and local corticosteroid injections are helpful for lesions that are not near the digital tips. In the case of dermatomyositis, there is some evidence that aggressive treatment for the myositis itself, particularly in the childhood form of the disease may help to prevent cutaneous calcinosis.

Patient Management

Most pseudogout is treated on an outpatient basis. It is prudent to have the patient telephone the office 24 hours after the office visit. If the patient is not improving, the diagnosis must be questioned and/or further evidence of infection should be sought. Occasionally, an initial treatment for pseudogout will not be effective and more intensive treatment (such as with systemic corticosteroids) must be instituted.

It is also important to explain the risks of medications and how to take them properly. It is best to use preprinted patient handouts since patients may forget (particularly if in pain). NSAIDs must be taken with food or milk. The patient should watch for melena. The patient should be instructed to taper NSAIDs or colchicineto a maintenance dose over 7-21 days, depending upon the rapidity of improvement. If taking colchicine, the need for oral rehydration if significant diarrhea develops should be discussed, and the need to reduce the dose in such a case. If colchicine is being used, it is essential that the dose (both loading dose and maintenance dose) be adjusted in the setting of renal insufficiency or hepatic insufficiency.

Patients taking corticosteroids must be instructed to monitor their serum glucose and potassium. Patients taking warfarin should have their PT/INR checked after 3-5 days, since illness and medications can affect warfarin activity. Hypertensive patients taking NSAIDs or corticosteroids may need to have their blood pressure checked in several days, but only a few patients are significantly sensitive to the hypertensive effects of these agents. If there is evidence of an underlying condition, the patient should be referred for the appropriate medical care.

The patient should be seen back in the office 1 to 2 weeks after the attack. It is important to reassure the patient that swelling may take weeks to resolve even though pain is completely gone. Since chondrocalcinosis is associated with osteoarthritis, it may be appropriate to further evaluate this possibility or refer as needed.

It is appropriate to give prophylaxis for at least 3-4 weeks using either a low daily dose of an NSAID or the appropriate maintenance dose of colchicine. NSAIDs are preferred in patients with coexistent osteoarthritis since they provide some pain relief for that condition as well. Colchicine may be used in most other patients. Persons with normal hepatic and renal function can be prescribed 0.6 mg of colchicine twice daily for prophylaxis. Unlike the case with gout, there is no clear evidence that lower doses are effective, as pseudogout tends to be more resistant to the effects of colchicine.

It is important that patients understand that colchicine does nothing to prevent chondrocalcinosis or to retard progression of osteoarthritis. Chroni colchicine toxicity can occur in persons with mild renal insufficiency taking as little as two tablets per day. The toxicity will not be in the form of diarrhea or bone marrow suppression, but rather in the form of a characteristic myoneuropathy. The patient usually experiences somewhat uncomfortable distal paresthesias. The creatine kinase (CK) is usually mildly to moderately elevated, although muscle weakness may not be present. It is reversible when discovered early.

In persons who cannot take NSAIDs or colchicine, low-dose prednisone is sometimes used if prophylaxis is necessary. In the elderly, the most worrisome side effect of prednisone is the development of fragility fractures, either with or without osteoporosis. Prednisone weakens bone much more than would be expected based on the decline of bone density alone. A daily dose of prednisone of 5 mg/d for 3 months or more is associated with an increase in fracture risk. Bisphosphonates provide effective prophylaxis, however.

There are no well-accepted alternatives to NSAIDs, colchicine and prednisone for prophylaxis. Reasonable alternatives based on small published series include low-dose methotrexate (as for rheumatoid arthritis; this is well tolerated in the elderly) and hydroxychloroquine. The latter may have some retardive of activity against small joint arthritis in patients with either the pseudo-rheumatoid or the pseudo-osteoarthritis patterns of CPPDD.

There is also anecdotal evidence that omega-3 fatty acids may reduce the frequency of attacks in persons with polyarticular disease. One report suggests that magnesium supplementation is helpful, even in persons who do not have hypomagnesemia. Our experience with magnesium supplementation suggests that it is not dramatically effective.

If the patient has obvious soft tissue calcific deposits that are painful or that interfere with activities of daily living, it may be appropriate to consider surgical resection.

There is no specific treatment for the dermatologic manifestations of calcinosis. Chronically draining sinus tracts should receive appropriate local care. In the case of scleroderma, attention to prevention of Raynaud’s phenomenon and maintenance of peripheral circulation is important. Vasodilating calcium channel blockers such as nifedipine, amlodipine and diltiazem help to provide symptomatic relief. Some patients find that 2% nitroglycerin ointment applied to affected fingers four times a day helps to maintain blood flow. This agent should be started in miniscule quantities to help avoid headache.

Unusual Clinical Scenarios to Consider in Patient Management

In all cases, it is appropriate to consider screening for the three major treatable underlying conditions that may provoke pseudogout (hyperparathyroidism, hemochromatosis and hypomagnesemia). Hyperparathyroidism in particular tends to increase in prevalence in the elderly. Hemochromatosis and hypomagnesemia are much less likely to present in the elderly. Unfortunately, progress in the treatment and prevention of pseudogout lags far behind that of gout. As various biochemical defects are discovered that contribute to dystrophic calcification, there are likely to be new treatments in the years ahead.

What is the Evidence?

Acknowledgement

The author would like to acknowledge his mentor of 20 years, the late Antonio J. Reginato, a superlative diagnostician, author and teacher who also provided some of the patients whose photographs are shown.

Sekijima, Y, Yoshida, T, Ikeda, S. "CPPD crystal deposition disease of the cervical spine: a common cause of acute neck pain encountered in the neurology department". J Neurol Sci. vol. 296. 2010. pp. 79-82.

(The crowned dens syndrome is a more serious form of the more general problem of crystal-induced cervical spine disease. Crystal-induced cervical spine inflammation can mimic meningitis or polymyalgia rheumatica.)

Schlesinger, N, Hassett, AL, Neustadter, L, Schumacher, HR. "Does acute synovitis (pseudogout) occur in patients with chronic pyrophosphate arthropathy (pseudo-osteoarthritis)?". Clin Exp Rheumatol. vol. 27. 2009. pp. 940-4.

(The various subtypes of CPPDD are not associated with equal risk of acute pseudogout attacks. Acute-onset synovitis is more often associated with classic chondrocalcinosis. The "pseudo-osteoarthritis" pattern is less associated with acute synovitis, but tends to have more alizarin red positive crystals [suggestive of hydroxyapatite]).

Ea, HK, Liote, F. "Advances in understanding calcium-containing crystal disease". Curr Opin Rheumatol. vol. 21. 2009. pp. 150-7.

(Excellent review of what has been learned in recent years regarding the pathogenesis of crystal-induced arthritis. A key mediator is interleukin-1.)

Reynolds, JL, Matthew, IR, Chalmers, A. "Tophaceous calcium pyrophosphate dihydrate deposition disease of the temporomandibular joint". J Rheumatol. vol. 35. 2008. pp. 717-21.

(Tophaceous deposits of CPPD are relatively rare. When they occur, the TMJ is the most commonly affected area. As with tophaceous deposits of monosodium urate, bony erosion can occur, mimicking a malignant process.)

Announ, N, Guerne, PA. "Treating difficult crystal pyrophosphate dihydrate deposition disease". Curr Rheumatol Repl. vol. 10. 2008. pp. 228-34.

(Unusually frank discussion of current and future treatments for difficult-to-treat CPPD-induced inflammation.)

Wise, CM. "Crystal-associated arthritis in the elderly". Rheum Dis Clin North Am. vol. 33. 2007. pp. 33-55.

(Good general discussion of considerations for treating crystal-induced inflammation in the elderly.)

Lam, HY, Cheung, KY, Law, SW, Fung, KY. "Crystal arthropathy of the lumbar spine: a report of 4 cases". J Orthop Surg (Hong Kong). vol. 15. 2007. pp. 94-101.

(Both gout and pseudogout can occur in the lumbar spine, sometimes a mimicking acute infection and potentially leading to unnecessary surgery. Considering the diagnosis beforehand is key.)

Doumas, C, Vazirani, RM, Clifford, PD, Owens, P. "Acute calcific periarthritis of the hand and wrist: a series and review of the literature". Emerg Radiol. vol. 14. 2007. pp. 199-203.

(Acute calcific periarthritis (pseudopseudogout) is the less well-known cousin of gout and pseudogout.)

Al-Khodairy, AT, Gobelet, C, Nancoz, R, De Preux, J. "Iliopsoas bursitis and pseudogout of the knee mimicking L2-L3 radiculopathy: case report and review of the literature". Eur Spine J. vol. 6. 1997. pp. 336-41.

(Iliopsoas bursitis [calcific or non-calcific] can mimic a variety of hip and pelvic problems.)

Fam, AG, Rubenstein, J. "Hydroxyapatite pseudopodagra. A syndrome of young women". Arthritis Rheum.. vol. 32. Jun 1989. pp. 741-7.

(The classic description of calcific periarthritis.)

Wu, Y, Chen, K, Terkeltaub, R. "Systematic review and quality analysis of emerging diagnostic measures for calcium pyrophosphate crystal deposition disease". RMD Open. vol. 2. 2016 Nov 3. pp. e000339.

(A review of the literature focusing on conventional compared to new diagnostic tests and criteria. They conclude that ultrasound is superior to conventional radiology.)
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