Chondrocalcinosis

Chondrocalcinosis
Chondrocalcinosis of the articular and fibrocartilage of the left knee in a patient with calcium pyrophosphate dihydrate deposition disease (CPPD)
ICD-10	M11.1-M11.2
ICD-9	712.3
DiseasesDB	10832
MedlinePlus	000421
MeSH	D002805

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2] Luke Rusowicz-Orazem, B.S.

Synonyms and keywords: Pyrophosphate arthropathy; chondrocalcinosis; pseudogout; CPPD; Calcium pyrophosphate dihydrate deposition disease; CPPD disease

Overview

Calcium pyrophosphate deposition disease (CPPD) is a rheumatologic disorder with varied clinical manifestations due to precipitation of calcium pyrophosphate dihydrate crystals in the connective tissues. It is more commonly known by alternative names that specify certain clinical or radiographic findings, although neither is synonymous with CPPD. Pseudogout refers to the clinically evident acute synovitis with red, tender, and swollen joints that may resemble gouty arthritis (a similar condition with joint deposition of monosodium urate crystals). Chondrocalcinosis, on the other hand, refers to the radiographic evidence of calcification in hyaline and/or fibrocartilage. Pyrophosphate arthropathy is a term that may refer to either of the above, but is uncommonly used.

Causes

Life Threatening Causes

• Wilson's disease 

Causes in Alphabetical Order

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Epidemiology

Calcium pyrophosphate crystal deposition (CPPD) disease has been estimated to affect 4 to 7 percent of the adult populations of Europe and the United States [7,8], especially among persons of advanced age. However, an estimate of the prevalence of clinically significant CPPD disease has been more difficult to attain, in large part because the available prevalence estimates have relied primarily upon radiographically detected cartilage calcification rather than clinical evaluation, and also because prevalence data concerning patients less than about 60 years of age are not available.

The average age at diagnosis of CPPD disease in one study was 72 years [3]. Radiographic surveys have demonstrated an age-related increase in the prevalence of cartilage calcification [9,10]. This was illustrated in a report that supplemented radiographs of the knees with radiographs of the hands, wrists, and pelvis [10]. The prevalence of radiographic calcium pyrophosphate deposition according to age, among 100 consecutive patients admitted to an acute geriatric unit, was:

●65 to 74 years – 15 percent

●75 to 84 years – 36 percent

●>84 years – Almost 50 percent

The gender distribution of CPPD disease has differed among large series [3,11,12], but no major gender predominance appears likely. Attacks of acute arthritis may occur more frequently in men, while typical osteoarthritis (OA) with calcium pyrophosphate crystal deposition or the atypical pattern of OA characteristic of CPPD are more common in women.

Pathogenesis

CPP crystal formation and deposition

Calcium pyrophosphate dihydrate (CPP) crystal formation is initiated in cartilage located near the surface of chondrocytes, cells which are embedded in and contribute to the collagen- and proteoglycan-containing cartilage matrix [3,4]. Crystal formation may reflect elevated levels of either calcium or inorganic pyrophosphate, matrix changes that enhance local calcium pyrophosphate supersaturation, or a combination of these factors. Aberrations in both mineral and organic phase metabolism are probably variably involved in calcium pyrophosphate crystal deposition (CPPD) disease.

Two lines of inquiry relate to evidence suggesting that the disorder is associated with excessive cartilage inorganic pyrophosphate production, which leads to local calcium pyrophosphate supersaturation and CPP crystal formation or deposition:

●Some of these data suggest that excessive pyrophosphate levels, arising from nucleoside triphosphate pyrophosphohydrolase (NTPPPH) enzyme overactivity, provide the substrate for CPP crystal formation in the immediate environment of chondrocytes. Increased concentrations of substrate (adenosine triphosphate [ATP]) for this enzyme are also present in joint fluids from persons with CPPD [5].

●In addition, substantial evidence suggests a role for polymorphisms in the ANKH gene in both familial and sporadic human CPPD disease.

First, several observations indicate that augmented pyrophosphate production in cartilage extracts from some patients appears to result from overactivity of one or more of a group of NTPPPH enzymes [6-8]. These enzymes are associated with the external surface of the chondrocyte cell membrane and are capable of catalyzing the production of pyrophosphate by the extracellular hydrolysis of nucleoside triphosphates, especially adenosine triphosphate (ATP) [8]. One function of extracellular pyrophosphate appears to be to bind to and inhibit the growth of basic calcium phosphate (BCP) crystals. In addition, studies in mice (the “tiptoe-walking” mouse strain) provide evidence that deficiency in NTPPPH enzyme activity can disrupt the normal reciprocal relationship between extracellular pyrophosphate levels and BCP crystal growth and deposition [9]. In this mouse strain a point mutation and deficiency in the NTPPPH enzyme PC-1 (phosphodiesterase; nucleoside pyrophosphatase) is associated with excessive axial skeletal mineralization with BCP crystals and eventual myelopathy. Thus, in CPPD, excessive pyrophosphate levels arising from NTPPPH overactivity could provide the substrate for CPP crystal formation in the immediate environment of chondrocytes.

One mechanism that might lead to CPP crystal formation and deposition involves enhanced ecto-NTPPPH activity, resulting from vesicles that play a role in normal bone calcification. Vesicles derived from collagenase digestion of articular cartilage are selectively rich in NTPPPH activity [10,11]. These NTPPPH-rich vesicles promote the formation of a calcium- and pyrophosphate-containing mineral that resembles CPP crystals when incubated with ATP. Such vesicles are similar to the matrix vesicles of normal epiphyseal cartilage. Among the isozymes with ecto-NTPPPH activity, PC-1 (originally described as a plasma cell membrane protein), when over-expressed through gene transfer to cultured chondrocytes, is associated with increased chondrocyte apoptosis and matrix calcification [12].

The second line of evidence confirming enhanced pyrophosphate production in CPPD involves findings in another mouse disorder, murine progressive ankylosis, in which homozygous nonsense mutations in the ank gene result in reduced extracellular pyrophosphate levels and extensive peripheral and axial skeleton ankylosis with basic calcium phosphate-containing material [13]. The ankgene product is a transmembrane protein, strongly expressed in chondrocytes, which serves either as a pyrophosphate transporter or as a regulator of a channel transporting pyrophosphate or a pyrophosphate precursor. Expression of the normal ank allele in transgenic mutant mice prevents the phenotypic and physiological defects of progressive ankylosis, and the overexpression of the normal ank allele in cells from mutant mice results in excessive extracellular pyrophosphate levels [13]. These findings suggest that circumstances enhancing activity of the ank gene could promote CPP crystal formation and deposition. In addition to a putative role of the human homolog of the ank gene (ANKH) in pyrophosphate transport, there is now evidence that the ANKH gene product also promotes release of ATP by chondrocytes [14], thereby providing substrate for ecto-NTPPPH enzymes that generate extracellular pyrophosphate. However, the results of these studies should be applied with caution, given the artificial milieu in which in vitro studies of chondrocytes and cartilage are performed. The native environment of cartilage is hypoxic and chondrocytes are subject to mechanical stresses, both of which can alter ank expression [15,16].

Nevertheless, there is substantial evidence for a role of ANKH in both familial and sporadic human CPPD disease. In five instances of familial CPPD disease, segregation of the chondrocalcinosis phenotype with specific mutations in ANKH was observed [17-20]. In addition, mutations/polymorphisms in or just upstream of the chromosome 5p locus of ANKH have also been identified in some individuals with idiopathic or sporadic CPPD deposition disease [18,21]. Of interest, one such ANKH variant, a -4bp G→A polymorphism in the 5’ untranslated promoter region of ANKH, correlates with radiographic chondrocalcinosis that is independent of age or the presence of osteoarthritis, the two most common risk factors for chondrocalcinosis [22]. Finally, ANKH transcripts and ANKH protein levels are reported to be increased in surgical cartilage specimens from patients with CPP deposition when compared with control specimens from osteoarthritis patients with no CPP deposition [23].

Role of CPP crystals in disease

Proof of a definitive causal role of CPP crystals in all of the clinical manifestations with which deposition is associated has not been established, particularly for the degenerative, noninflammatory manifestations of CPPD arthropathy. Nevertheless, compelling evidence for a role of the CPP crystal in acute and subacute joint inflammation is provided by the following observations:

●There are striking similarities in the pathophysiologic mechanisms and clinical appearances of acute urate gout and CPP crystal-induced arthritis [24]. Of particular note is the shared capacity of both crystal types to induce Nacht Domain-, Leucine-Rich Repeat-, and PYD-Containing Protein 3 (NALP3)-dependent inflammasome assembly and activation in synovial mononuclear phagocytes and neutrophils. Activation of the NALP3 inflammasome, in turn, activates latent caspase-1, resulting in interleukin (IL)-1 precursor processing and release of the pro-inflammatory cytokine IL-1beta [25].

●The apparent biologic consequences of the interaction of CPP crystals with phagocytic cells (which include mitogenic activation and the release of proinflammatory cytokines) provide a potential basis for the more subacute inflammatory synovitis of CPPD arthropathy [24,26].

●An etiologic or an amplifying role for CPP crystals in the destructive changes in osteoarthritis appears highly likely. The degenerative arthritis accompanying CPPD frequently involves such joints as the metacarpophalangeal and wrist joints, which are commonly spared in classical osteoarthritis [27], and chondrocalcinosis appears to be a primary determinant of the rate of radiographically-determined joint deterioration in osteoarthritis. Interestingly, in usual osteoarthritis, CPP crystals may not be present in early disease but appear to be secondarily associated with progression of the severity of the osteoarthritis [28]. In a study of cadaveric knees from Japanese older adults (mean age of 78), the deposition of CPP crystals correlated with the degree and depth of cartilage degeneration [29].

Spontaneous resolution of acute attacks — Acute attacks of CPP crystal arthritis are typically self-limited. Although possible mechanisms for ameliorating inflammation due to CPP crystals have been suggested, a generally accepted explanation is lacking. Phagocytosis and dissolution of crystals may play a role, but observations in patients together with data from animal models indicate that inflammation can abate while crystals are still present in tissue or fluid.

Adhesion of components of extracellular fluid or plasma to crystals may decrease their inflammatory potential. As an example, addition of lipoproteins to CPP crystals reduces their ability to provoke neutrophil phagocytosis and cell lysis in vitro [30]. In an experimental model, the local low-density lipoprotein (LDL) concentration rose within hours after instillation of CPPD crystals in association with decreasing inflammation [31].

A variety of metabolic and endocrine disorders other than hemochromatosis may be associated with CPPD. Clinical or radiographic evidence for CPPD disease therefore warrants exclusion of these disorders, particularly among younger individuals (table 1). Although a cause-and-effect relationship is unproven (and, in some instances, a chance association is possible), the importance of recognizing these associations lies in the opportunity to identify and to treat a significant illness such as hemochromatosis or hyperparathyroidism prior to the expression of additional clinical manifestations of these disorders.

Clinical presentation

●Asymptomatic CPPD disease: Most joints in which CPP crystal deposition is readily apparent on radiographs are asymptomatic, even among patients in whom acute or chronic clinical manifestations of CPPD disease in one or several other joints have occurred. However, patients with apparent asymptomatic CPPD may be found to have manifestations of an arthritic disorder upon close questioning.

●Acute CPP crystal arthritis: The knee is affected in over 50 percent of all acute attacks of acute CPP crystal arthritis, while the first metatarsophalangeal (MTP) joint is the most frequently affected in urate gout. Other joints typically affected in acute CPP crystal arthritis include wrists, shoulders, ankles, feet, and elbows. Initial episodes of acute CPP crystal arthritis may persist longer before remitting than the one or two weeks commonly encountered in urate gout, and an upper extremity site of inflammation (wrist, elbow, shoulder) for a first attack should raise suspicion for acute CPP crystal arthritis [13].

Trauma, surgery, or severe medical illness often provoke acute attacks. In particular, flares of acute CPP crystal arthritis after parathyroidectomy have been observed [14]; these episodes may be related to abrupt reduction in serum calcium and magnesium levels during postoperative hypoparathyroidism (see "Hungry bone syndrome following parathyroidectomy"). Such reduction may cause partial dissolution of crystals with subsequent release from the cartilage matrix into the joint fluid, allowing phagocytosis and the phlogistic response of inflammatory cells.

Intraarticular hyaluronate injection and treatment with pamidronate or granulocyte-macrophage colony-stimulating factor (GM-CSF) [15-17] have also been reported to precipitate acute attacks of pseudogout. However, patients affected with CPPD who experience acute joint inflammation following hyaluronate injection do not demonstrate crystals in their joint fluids [18].

●Chronic CPP crystal inflammatory arthritis: the chronic inflammatory arthritis of CPPD disease involves multiple joints, frequently involving peripheral joints of the upper and lower extremities, including the wrists and metacarpophalangeal (MCP) joints, as well as the knees and elbows, in a symmetric or nearly symmetric pattern. Articular inflammation may last up to several months, and inflammation in affected joints tends to wax and wane independently of one another, in distinction to RA, where synchronous flare and remission is the rule.

Chronic CPP crystal inflammatory arthritis occurs in 5 percent or less of patients with symptomatic CPPD disease. A rare subtype of chronic CPP crystal inflammatory arthritis, occurring most often in older adult patients during an acute polyarticular attack, is characterized by prominent systemic features, such as leukocytosis, fever, and mental confusion, closely mimicking systemic sepsis [19]. In such patients, the delirium is reported to resolve with resolution of the acute polyarticular flare.

●Severe joint degeneration: A number of reports have documented CPP crystal deposition in association with severe joint degeneration which closely resembles neuropathic arthropathy [21-23]. Neuropathic arthropathy is characterized by severe joint degeneration and disruption occurring in the course of neurologic disorders leading to joint denervation; the affected joint is often called a Charcot joint. Underlying disorders associated with Charcot joints include diabetes mellitus (most common), tabes dorsalis, and syringomyelia. (See "Diabetic neuropathic arthropathy".)

●Spinal involvement: CPP crystal deposition in and about the spine has been associated with a number of clinical manifestations, including spine stiffness, sometimes associated with bony ankylosis, which can resemble the spinal changes of ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis (DISH). Such symptoms have been most commonly encountered in familial CPPD disease [24]. In addition, crystal deposition in the ligamentum flavum at the cervical spine level or in the posterior longitudinal ligament at lower levels of the spine may lead to spinal cord compression syndromes or to symptoms either of acute nerve compression or of chronic spinal stenosis [25-27].

Diagnosis

●Synovial fluid – Examination of synovial fluid for CPP crystals should be carried out promptly after joint aspiration, because successful identification of the crystals diminishes as the time elapsed between joint aspiration and microscopic examination increases. Another technical source of error is that positively birefringent material other than CPP crystals may be identified in joint fluid samples unless care is taken to clean and remove dust from the microscope slide and cover slip. Lack of attention to these details may contribute to reports of a relatively low specificity and sensitivity in identifying CPP crystals in synovial fluid, particularly when the observers carrying out the analysis are relatively inexperienced [46-48]. The European League Against Rheumatism (EULAR) recommendations for CPPD disease suggest refinement of an optimal protocol (including training) and standards for identification of CPP crystals in joint fluids [4].

●Synovial tissue – CPP crystals may also be present in synovial tissue, although tissue sections stained with hematoxylin and eosin (H&E) are less likely to demonstrate typical birefringent crystals, possibly due to the dissolution of crystalline CPP in the acid reagents. Use of alizarin red has been reported to preserve the crystals and reduces the likelihood of a false negative result, but false positive or negative staining may occur [49]. A nonaqueous stain, such as Wright's, is another alternative to routine H&E staining for synovial tissue.

Radiological findings

Three main manifestations of CPPD deposition:

1. chondrocalcinosis
2. crystal induced synovitis (pseudogout syndrome)
3. pyrophosphate arthropathy

Plain film radiography

●Cartilage – Among affected fibrocartilages in CPPD disease are the menisci of the knee (usually bilaterally), the symphysis pubis, the triangular discs of the wrist joints, and the glenoid and acetabular labra. CPP crystal deposits in hyaline cartilage frequently appear as a radiopaque line paralleling the surface of the underlying bone.

●Joints – Larger joints, such as the knee, wrist, elbow, shoulder, and hip, are most frequently involved in CPPD disease, but almost any diarthrodial joint may be affected radiographically. Articular capsule or synovial calcification is often fainter and more diffuse than cartilage calcification.

Linear calcifications involving the Achilles tendon or plantar fascia are often seen in CPPD disease [32].

Degenerative changes

CPP crystal deposition is often associated with degenerative changes in joints, even in the absence of radiographic cartilage calcification. Characteristic degenerative changes in CPPD disease include subchondral cysts, osteophyte formation, and bone and cartilage fragmentation.

CPPD disease may also underlie the occurrence of radiographic features of osteoarthritis (OA) in joints not commonly affected by primary OA (see 'Diagnostic criteria' below and 'Differential diagnosis'below). Cartilage calcification that is apparent at the onset of degenerative changes or which occurs earlier in life than usual and without a pertinent vocational or avocational history is also characteristic of CPPD disease, whether in joints typical or atypical for OA.

Stress fractures or osteonecrosis (avascular necrosis), particularly in structures of the knee, may be consequences of or may be promoted by CPP crystal deposition.

Ultrasonographic findings

The following findings on ultrasonography of articular and fibrocartilage may be indicative of the presence of deposits of CPP crystals [39,40]:

●A thin hyperechoic band paralleling the bone cortex and separated from it by a hypoechoic region representing cartilage. The resulting ultrasonographic appearance resembles the double contour sign (DCS) initially described in gout [41], but it often exhibits a thin, stippled appearance rather than the smooth pattern characteristic of gout.

●Small hyperechoic rounded amorphous shaped regions, often with acoustic shadowing, which are most often found in images of fibrocartilage of the wrist (image 2) and menisci of the knee, and in tendons.

●Nodular hyperechoic deposits in bursae and articular recesses.

●Hyperechoic lines of calcification running parallel to tendon fibers.

In contrast to urate crystal deposits in gout, CPP crystals often deposit within the substance of hyaline cartilage, providing a potentially attractive means to distinguish between these crystal deposition arthropathies.

Ultrasonography is a promising modality for clinical use in the diagnosis of CPPD disease and tracking the efficacy of CPPD disease therapies; however, further studies are warranted for: validation of ultrasound criteria unique to CPP crystal deposition, resolution of differences reported with regard to the sensitivity and specificity of the procedure for the diagnosis of CPPD disease [39,42-45], and comparison of imaging findings with corresponding histopathology as the gold standard.

Differential diagnosis

Acute arthritis

Acute CPP crystal arthritis closely resembles gout in its clinical features (hence the term "pseudogout"), including acute or subacute attacks in a single or only a few joints, with prominent signs of local inflammation and sometimes systemic signs such as leukocytosis and elevated acute phase reactants. In addition, trauma, surgery, or severe medical illness may provoke acute attacks in both of these crystal-induced disorders. Despite these similarities, the joints most commonly involved in an acute episode differ between gout and pseudogout. The knee is affected in over 50 percent of all acute attacks of pseudogout, whereas the first metatarsophalangeal (MTP) joint is more frequently involved in gout. The distinction between these conditions is made based upon identification of crystals under polarizing light microscopy that are characteristic of one or the other condition.

The broader differential diagnosis of an acute monoarthritis is discussed in detail separately; however, infection, trauma, bleeding, and other crystal-associated diseases (eg, gout) are among the important disorders to consider. These conditions can usually be distinguished from pseudogout by synovial fluid analysis and joint radiography, although the presence of CPP crystals in joint fluid does not exclude infection. Thus, Gram stain, as well as joint fluid and blood cultures, is generally necessary to exclude an infectious etiology.

Chronic inflammatory arthritis

Chronic CPP inflammatory arthritis ("pseudo-rheumatoid arthritis [RA]") may present in a similar fashion to other forms of chronic inflammatory arthritis, particularly RA, and must be distinguished from RA and other causes of polyarthralgia or polyarthritis. In chronic CPPD inflammatory arthritis, the multiple inflamed joints typically flare independently of one another, unlike in RA, where multiple joints usually flare and improve in parallel. Radiographic changes in chronic CPPD inflammatory arthritis are more typical of osteoarthritis (OA) than RA, despite the pattern of clinical joint involvement suggestive of the latter disorder (see 'Imaging findings' above). The diagnostic approach to adults with polyarticular joint pain is presented in detail elsewhere.

Diagnostic confusion between pseudo-RA and RA may arise when inflammation is more or less symmetrical and, particularly, when rheumatoid factor is detectable (as is the case in a substantial proportion of normal older individuals). Generally, the identification of CPP crystals and radiographic changes typical of CPPD disease will help distinguish the disorders. However, unlike gout, which is negatively associated with RA (occurring less often together than would be predicted from the prevalence of each condition in the population), CPPD disease and RA appear to coexist about as frequently as would be expected from the individual prevalence of the two disorders. It is important to distinguish between the coexistence of RA and CPPD disease and the expression of one masquerading as the other because of the substantial difference in management between these conditions.

A rare subtype of chronic CPP inflammatory arthritis is characterized by prominent systemic features such as leukocytosis, fever, mental confusion, and inflammatory polyarthritis [19] In older adults, this clinical presentation can closely mimic systemic sepsis, from which it is distinguishable both by the presence of CPP crystals in synovial fluid from affected joints and by reversal of the clinical features during antiinflammatory drug treatment.

Other forms of subacute and chronic inflammatory arthritis, such as peripheral spondyloarthritis, including reactive arthritis and arthritis associated with inflammatory bowel disease, as well as psoriatic arthritis, can generally be distinguished from CPPD-related arthritis by the presence of other clinical features typical of these disorders and the absence of CPP crystals from synovial fluid and of radiographic findings of cartilage calcification.

Treatment

Treatment of CPPD is mostly aimed at preventing further crystal formation and reducing symptoms from crystal deposition. CPPD crystal deposition cannot be reversed. If CPPD results from underlying metabolic abnormalities (hyperparathyroidism, hemochromatosis, hypophosphatasia, or hypomagnesemia), these can be treated directly.

For symptomatic joints, treatment is similar to treatment of gout. When a single joint is involved, joint aspiration and intra-articular corticosteroid injection is often used, in addition to NSAIDs and/or colchicine. When multiple joints are involved, joint injection is often impractical, or limited only to the most severely involved joint, and oral systemic treatment is chosen instead.

Because pyrophosphate complexes with magnesium prior to its degradation , and CPPD can result from pathologically low magnesium levels, magnesium supplementation may be of help, particularly in a few patients with underlying hypomagnesemia. It may be possible to end attacks by ingesting large (maximum RDA) doses of magnesium supplement accompanied by vitamin B6 to help absorption. What that does is assist the body in re-dissolving the calcium in the joint fluid, and with maintenance doses, often in the form of snacking on magnesium-rich foods such as almonds, further attacks can be prevented altogether - without medication.

Antiinflammatory medication, usually by intraarticular injection, supported by local measures to reduce symptoms:

Joint fluid aspiration and glucocorticoid injection usually provide relief in pain and swelling within 8 to 24 hours.

application of ice or cool packs and immobilization and resting of the joint by restriction of weightbearing.

systemic antiinflammatory therapy is warranted, employing agents typically used for the treatment of acute gout.

These include: NSAIDs, which may, however, be contraindicated in older adults, the population especially susceptible to acute attacks of pseudogout; 

colchicine, which is particularly useful if a low-dose regimen is initiated within hours of attack onset;

glucocorticoids, which are efficacious in patients unable to take NSAIDs or colchicine.

contraindications to NSAIDs:

●Chronic kidney disease with creatinine clearance (CrCl) of less than 60 mL/min per 1.73 m² (see "Nonselective NSAIDs: Overview of adverse effects", section on 'Renal effects' and "Overview of the management of chronic kidney disease in adults", section on 'Definition and classification' and "Assessment of kidney function")

●Active duodenal or gastric ulcer (see "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity")

●Cardiovascular disease, particularly heart failure or hypertension that is difficult to control (see "Nonselective NSAIDs: Adverse cardiovascular effects" and "COX-2 selective inhibitors: Adverse cardiovascular effects")

●NSAID allergy

●Ongoing treatment with anticoagulants

Colchicine

In patients in whom treatment for acute CPP crystal arthritis is initiated within about 24 hours of onset and whose clinical and concomitant medication profiles permit its consideration, we suggest oral colchicine in a low-dose regimen as initially recommended for the treatment of acute gout, rather than using oral glucocorticoids [7,9]. For regimens using low-dose colchicine, no more than 1.8 mg of colchicine is taken orally in the first 24 hours of treatment, followed by 0.6 mg colchicine taken twice daily until the attack abates [9]. This strategy is based upon a treatment regimen for acute gout and not on studies of acute CPP crystal arthritis.

Common adverse effects of colchicine may include diarrhea and abdominal cramping, but these are less likely in patients who receive no more than 1.8 mg in total on the first day compared with patients receiving higher doses, such as 0.6 mg every one to two hours until symptom relief or intolerance (as was historically employed) [11]. Gastrointestinal symptoms (diarrhea, abdominal pain, nausea and vomiting) are the most common adverse effects. A readily reversible peripheral neuropathy, another common toxicity, does not occur frequently during the brief period of colchicine administration for acute pseudogout. More severe colchicine toxicities, which may include combinations of serious, life-threatening or fatal adverse events such as blood cytopenias, rhabdomyolysis or myopathy, peripheral neuropathy, liver failure, or severe cutaneous eruption, have only rarely been reported in patients receiving brief administration of this agent [12].

In patients in whom glucocorticoid therapy is inadequate, it is important to confirm the absence of hepatic disease that might impair the conversion of prednisone to prednisolone, in which case the glucocorticoid therapy can be switched to oral prednisolone (in similar doses to those employed for prednisone). Since pseudogout attacks are self-limited, an alternative option is managing the symptoms using supportive measures until they resolve with analgesics, rest, splinting, and icing. (See 'Initial treatment/one or two joints' above.)

●Need for parenteral (non-intraarticular) therapy – In patients who are unable to take oral agents and who are not appropriate candidates for intraarticular injection, we use parenteral glucocorticoids in doses equivalent to those suggested above for oral glucocorticoids. Although corticotropin (adrenocorticotropic hormone [ACTH]) has been reported to be beneficial for acute gout flare treatment, cost and limited availability restrict the use of parenteral ACTH treatment for gout, and ACTH therapy has been less well-studied for acute pseudogout than for gouty arthritis. (See "Treatment of gout flares", section on 'Parenteral glucocorticoids'.)

We do not administer colchicine intravenously, and we strongly advise against such use because of the risk of serious adverse effects, including death, which are associated with the intravenous administration of this drug. Although intravenous colchicine can reduce the inflammation of pseudogout, the potential dangers of this approach have led to withdrawal of approval in the United States for the distribution of colchicine for administration by the intravenous route.

Resistant disease

The management of patients with persistent symptoms due to a confirmed acute flare of pseudogout depends upon the prior therapy and upon the patients' comorbidities:

●In some patients being treated with NSAIDs, a more prolonged than usual course of therapy may be required, especially if treatment was not started until the flare was ongoing for several days. Patients with a flare that appears resistant to an adequate course of NSAID therapy may respond to treatment with glucocorticoids. (See 'Unable to use oral NSAIDs and colchicine' above.)

●In patients who are being treated with colchicine but who do not have contraindications to NSAIDs, it may be necessary to switch to NSAID therapy if no improvement is seen within several days, especially if the attack was not treated early. In patients in whom NSAIDs are contraindicated, glucocorticoids may be required. (See 'NSAIDs' above and 'Unable to use oral NSAIDs and colchicine' above.)

●The management of recurrent (or "rebound") attacks following treatment with glucocorticoids may require slower tapering of the glucocorticoid dose with extension of the course to 10 to 14 or even 21 days if needed. (See 'Unable to use oral NSAIDs and colchicine' above.)

●Interleukin (IL)-1 inhibitors show promise for suppressing crystal-induced inflammation, but sufficient data are not available to support treatment of acute pseudogout with these agents. We use anakinra, an IL-1 receptor antagonist protein, only in gout patients with frequent flares in whom all other available treatments have failed or in whom "rebound flares" occur even when glucocorticoid treatment is appropriately tapered. Although IL-1 antagonist agents are available in some countries for the treatment of other conditions, such as anakinra for rheumatoid arthritis and canakinumab and rilonacept for cryopyrin-associated periodic syndromes, only the first two have shown clear efficacy in treatment of acute gout (see "Treatment of gout flares", section on 'Investigational therapy'). Use of IL-1 inhibitors for either acute gout or pseudogout remains investigational in the United States.

• In patients with three or more attacks of acute CPP crystal arthritis annually, we suggest prophylaxis with colchicine (0.6 mg twice daily) rather than limiting treatment to the period of each acute attack. Several reports indicate that oral colchicine taken chronically may be effective as a prophylactic agent at this dose. In one series of 10 patients with recurrent episodes, colchicine treatment was associated with a marked reduction in the number of episodes at one year compared with the year prior to the initiation of therapy (10 versus 32 episodes) [16].

• Methotrexate (MTX) may provide benefit in patients with an inadequate response to NSAIDs, colchicine, low-dose glucocorticoids, and HCQ as the sole disease-modifying antirheumatic drug (DMARD). The benefits of MTX are uncertain in these patients, but limited observational studies involving a total of 15 patients suggest that low-dose MTX (administered once weekly in doses comparable to those recommended for rheumatoid arthritis) may be useful in instances of refractory CPP crystal-induced inflammation, presenting either as recurrent acute CPP crystal arthritis or as a more chronic inflammatory arthritis resembling rheumatoid arthritis [17-19]. By contrast, a lack of efficacy was seen in a smaller experience with three patients and in a small randomized trial with a mixed population of patients with recurrent acute attacks and chronic persistent polyarthritis [20,21]. MTX may be used in combination with HCQ. The dosing, use, monitoring, and adverse effects of MTX are described in detail separately.

References

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