Dr. KS Dhillon
Introduction
The ‘pseudogout syndrome’ was first described in 1962 by Kohn et al (1). The description accurately depicts acute attacks of synovitis induced by calcium pyrophosphate dihydrate (CPPD) crystals. It clinically resembles gouty arthritis due to monosodium urate (MSU) crystal deposition. CPPD deposition can cause symptoms similar to septic arthritis and polyarticular inflammatory arthritis such as rheumatoid arthritis (RA)] or degenerative osteoarthritis (OA) (2). Unlike gout, the treatment of CPPD-related arthropathies is usually difficult. This is partly due to patient characteristics, diagnostic uncertainty, and the lack of an effective agent to decrease crystal load (3). This article will review current approaches that are used in the treatment of acute pseudogout and the management of chronic CPPD-related arthropathies. Particular emphasis will be made on the use of available agents to target the ‘inflammasome’ that plays a crucial role in crystal-induced inflammation (4).
Clinical Presentation
CPPD crystal deposition disease can mimic most forms of inflammatory arthritis. A clinical classification of these phenomena has emerged from the studies of McCarty and colleagues (5,6,7). Along with acute pseudogout, there are at least six distinct presentations of this disorder. These include asymptomatic or lanthanic chondrocalcinosis, pseudo-RA, pseudo-polymyalgia rheumatica (pseudo-PMR), pseudo-OA (with or without acute attacks), and pseudo-neuropathic arthropathy.
Acute pseudogout
Classical pseudogout pattern of disease is exhibited in about 25% of patients with CPPD crystal deposition. Pseudogout attacks can take longer to reach peak intensity and can persist for up to 3 months despite therapy (8). Large joints are more often affected. The attacks are characterized by the cardinal signs of inflammation. The attacks may involve one or several red, hot, tender, and swollen joints (9). The knee is most often involved, followed by the wrist, ankle, elbow, toe, shoulder, and hip. The attacks can occur spontaneously or can be provoked by surgery, trauma, or severe medical illness (2,10). After parathyroidectomy flares of pseudogout have been described (10,11). This may reflect abrupt changes in serum calcium levels post-surgery. Pamidronate therapy for hypercalcemia can also trigger acute attacks of pseudogout (12). Patients are usually asymptomatic between acute attacks. Differentiation from true gout or septic joint requires arthrocentesis and synovial fluid analysis for Gram stain, culture, and cytology. Pseudogout is confirmed by the presence of CPPD crystals in synovial fluid. These crystals manifest as rhomboid-shaped rod-like structures that exhibit weakly positive or no birefringence by compensated polarized light microscopy. This is in contrast to the negatively birefringent needle-shaped MSU crystals found in gout. Gout and pseudogout can also coexist in a single inflammatory effusion. Twenty percent of patients with CPPD will have hyperuricemia and a quarter of these will develop gout at some stage (10).
Asymptomatic chondrocalcinosis
Radiographic calcification in hyaline and fibrocartilage is known as chondrocalcinosis. It is usually present in patients with CPPD deposition disease. It is neither sensitive nor specific for affected patients. CPPD crystal deposition accounts for approximately 95% of cases of chondrocalcinosis (13). A study by Fisseler-Eckhoff and Muller reported that a radiographic diagnosis was only made in about 40% of patients who had pathologically proven CPPD crystal deposition from samples obtained during arthroscopy (14). Some individuals can have radiographic or pathologic evidence of articular chondrocalcinosis and have no clinically apparent arthritis. This finding is referred to as lanthanic CPPD deposition. It is of uncertain significance (2). These patients are usually of advanced age and have not been rigorously studied to see whether they develop arthritis. There are reports that patients with apparently asymptomatic disease when subjected to closer scrutiny, have a higher frequency of knee and wrist complaints and associated degenerative changes as compared to age-matched controls without radiographic chondrocalcinosis (15).
Pseudo-osteoarthritis
Many patients with clinically apparent CPPD crystal deposition follow a progressive course of articular degeneration in multiple joints. The articular degeneration occurs in an oddly distributed pattern typically involving the wrists, knees, metacarpophalangeal (MCP) joints, spine, hips, shoulders, ankles, and elbows. About 50 percent of these patients will experience acute attacks of pseudogout superimposed on their chronic symptoms (2). The remainder will often present with complaints that are more typical of classical osteoarthritis. Although the clinical examination findings are similar to OA, there are certain features such as atypical distribution especially involving the wrists and MCP joints, the presence of contractures, and valgus knee deformities should highlight the possibility of CPPD deposition disease. When the degenerative process occurs in joints such as the hip and knee that are usually affected by OA it can be difficult to differentiate CPPD deposition disease from OA. There is a high prevalence of these crystals in samples taken from OA knees at the time of arthroplasty. One study reported that a third of these specimens displayed definite evidence of CPPD deposition (16). There is an emerging body of evidence that these and other calcium-containing crystals, such as basic calcium phosphate (BCP), play a pathogenic role in joint degeneration. It is well established that calcification of articular cartilage is a feature of OA (17). Furthermore, there is strong in-vitro evidence that such calcium deposition is inhibited by phosphocitrate (18). This is supported by complementary work using an animal model of OA (19).
Pseudo-rheumatoid arthritis
About less than 5% of patients with CPPD deposition develop asynchronous, non-erosive, inflammatory arthritis that mimics RA (10). The morning stiffness, synovial thickening, malaise, symmetrical involvement, flexion contractures, and elevated acute phase inflammatory markers can often lead to a misdiagnosis of RA. About 10% of these older individuals will have low titers of rheumatoid factor. This causes further diagnostic confusion (2). The presence of CPPD crystals in synovial fluid and radiographic changes of OA favor a diagnosis of pseudo-RA. Elevated titers of anti-cyclic citrullinated peptide (anti-CCP) antibodies and the presence of bony erosions on ultrasound or radiographic imaging indicate a diagnosis of RA. These two conditions, however, may occasionally coexist. A rare subtype of pseudo-RA can present with prominent systemic features such as leucocytosis, fever, altered mental status, and polyarthritis and can mimic sepsis, especially in older people (20).
Pseudo-polymyalgia rheumatica
Polymyalgia Rheumatic (PMR) is classically a disease of older people. It presents with a range of symptoms that include fatigue, morning stiffness, and proximal muscle weakness. It is often a challenge for the clinician to distinguish older patients with pure PMR from others presenting with symptoms resembling this condition. Recent work in many patients indicates that CPPD arthropathy should also be included in the wide spectrum of diseases mimicking classical PMR (21). Tendinous calcifications, knee OA, and episodic ankle arthritis are variables that predict older patients with PMR features who have an atypical pattern of CPPD arthropathy (21).
Pseudo-neuropathic arthropathy
There are some patients with CPPD deposition who have severe destructive monoarthritis that clinically resembles a neuropathic Charcot’s joint (22). Unlike the classical description of Charcot’s joints associated with tabes dorsalis, diabetes mellitus, syringomyelia, and alcoholic neuropathy, these patients have no underlying neurological disorder present with a painful, destructive monoarthritis. The natural history of this condition is not well understood. The management options are limited and surgical intervention may be required.
Epidemiology
CPPD crystal deposition is mainly a disease of older people. Several radiographic surveys have demonstrated an age-related increase in the prevalence of joint calcification with about half of all octogenarians displaying some evidence of articular chondrocalcinosis (15, 23). The prevalence of CPPD deposition among younger individuals is not known. Attacks of acute pseudogout occur more commonly in men, with women usually exhibiting the pseudo-OA pattern of the disease (10, 24).
Disease associations
Most cases of CPPD crystal deposition are idiopathic. However, there are several metabolic and endocrine disorders, a previous joint trauma, and the hereditary condition of familial chondrocalcinosis that are all associated with precocious articular calcification in young patients (25). Much is known about the pathogenic processes involved in pathological calcification from studying distinct pedigrees of autosomal dominant familial CPPD deposition and their association with a mutant ANKH gene located on the short arm of chromosome 5 (26). This gene produces a transmembrane transport protein that is critically involved in generating extracellular inorganic phosphate (PPi) which then acts as a substrate for CPPD crystal formation in the pericellular cartilage matrix ( 27).
Only hereditary haemochromatosis is associated with the full spectrum of CPPD-related arthropathy unlike other endocrine and metabolic conditions (25). Reports of CPPD crystal deposition in patients with secondary iron overload due to transfusion haemosiderosis and haemophilia show that Iron accumulation in joint tissues appears to be a key factor. Chronic hypomagnesemia due to Bartter’s and Gitelman’s syndromes has also been associated with both acute pseudogout and chondrocalcinosis thus forming the rationale for magnesium supplementation to prevent recurrent attacks of pseudogout (28,29).
There is a clear association with previous joint trauma, particularly involving the knee, and the likely role of chondrocalcinosis in contributing to joint degeneration (30,31). Gout, hyperparathyroidism, hypophosphatasia, and hypocalciuric hypercalcemia are all associated with acute attacks of pseudogout. The relationships between Wilson’s disease, acromegaly, diabetes mellitus, and CPPD deposition are less clear (25).
Pathogenesis
Understanding of the pathogenesis of pseudogout has been greatly increased with recent insights into the processes involved in both CPPD deposition and in the mechanisms whereby these crystals can interact with the inflammasome to cause joint inflammation.
There is evidence to support the hypothesis that elevated levels of PPi in the immediate extracellular environment of chondrocytes provide the substrate for the formation of CPPD crystals. These are then deposited in the cartilaginous matrix (32,33). The nucleoside triphosphatase pyrophosphohydrolase (NTPPPH) group of ectoenzymes are strongly associated with this process. Increased activity of these enzymes catalyzes the production of extracellular PPi at the external surface of the chondrocyte cell membrane (33). Deficiency of one of this group, the NTPPPH plasma cell membrane glycoprotein 1 (PC-1) enzyme leads to excessive mineralization with BCP rather than CPPD crystals in a mouse model of pathological ossification (34). This is supported by data involving murine progressive ankylosis, a mouse disorder in which a homozygous nonsense mutation of the ANK gene results in reduced extracellular PPi levels and excessive peripheral and axial skeleton ankylosis with BCP crystal material (35). Hence, one function of extracellular PPi appears to be the inhibition of the growth of BCP crystals. Excessive PPi levels, arising from NTPPPH overactivity or gain of function mutations in the ANK transmembrane transporter protein, can provide the substrate for CPPD crystal formation. Matrix vesicles that play a role in normal bone formation are also implicated. Studies have shown that these vesicles can generate CPPD crystals in vitro (36,37). These matrix vesicles are rich in NTPPPH activity. Gene transfer experiments involving the NTPPPH PC-1 enzyme and cultured chondrocytes demonstrate increased chondrocyte apoptosis and matrix calcification (38).
A dose-related auto-inflammatory response to CPPD crystals shed from cartilaginous tissues into the synovial cavity causes acute attacks of pseudogout (2). There is recent data that describes how CPPD crystals interact with the caspase-1-activating NACHT, LRR, and PYD domains-containing protein 3 (NALP-3) inflammasome of the innate immune system. This data provides novel insights into the mechanisms by which these crystals cause episodic bouts of joint inflammation (39). This results in the production of several proinflammatory cytokines, particularly interleukin (IL)-1β, by macrophages and monocytes, which initiates an inflammatory cascade. This cascade produces an influx of fibroblast-like synoviocytes, neutrophils, and recruitment of other inflammatory pathways via tumour necrosis factor α (TNFα) (40). Colchicine is used for the treatment of several auto-inflammatory conditions, including gout and pseudogout. It has recently been shown to completely block crystal-induced maturation of IL-1β in vitro, indicating that the drug acts upstream of inflammasome activation (4). Combining this observation with the known mode of action of colchicine as an inhibitor of microtubule assembly (41), it is likely that the drug acts at the level of crystal endocytosis and/or presentation to the inflammasome (4). Taken together, these data support a pivotal role for the inflammasome in pseudogout. It provides a series of novel molecular targets for prophylaxis and the treatment of acute episodes of pseudogout and other CPPD-related arthropathies.
Investigations
The diagnosis of pseudogout is most often accurately made by identifying CPPD crystals, by compensated polarized light microscopy, in the synovial fluid of affected joints (2). All patients presenting with suspected CPPD deposition can be screened for chondrocalcinosis using the following radiographs: an AP view of the pelvis for visualization of the symphysis pubis and hips, a non-weight-bearing anteroposterior (AP) view of both knees and a posteroanterior (PA) view of each hand to include the triangular ligament of the wrists. Changes in the MCP joints, such as squaring of the bone ends, and the presence of subchondral cysts and hook-like osteophytes, are characteristic features of arthropathy of hemochromatosis. These changes are also found in patients with CPPD deposition alone (2). A probable diagnosis of CPPD arthropathy can be made in patients who present with acute or chronic arthritis of the hip, knee, wrist, shoulder, or MCP joints with radiographs, even without direct demonstration of CPPD crystals by microscopy (42).
Most patients with CPPD deposition, especially those who are relatively young, should undergo screening for abnormal serum calcium, magnesium, phosphate, alkaline phosphatase, thyroid-stimulating hormone levels, and any evidence of iron overload by haemetinic analyses (ferritin, iron saturation, and transferrin) (10). This is especially true about hemochromatosis in light of the strong association between this condition and all forms of CPPD-related arthropathy, and the deleterious consequences of delayed diagnosis (25).
Treatment
Strategies used in ameliorating CPPD-related joint disease include the following:
Those directed against correcting underlying metabolic abnormalities and treating associated conditions.
General treatment with nonsteroidal anti-inflammatory drugs and/or corticosteroids (either by local intra-articular injection or systemic therapy).
Low-dose oral colchicine (43).
The potential future therapies include agents targeted against crystal formation, such as probenecid and phosphocitrate, and more potent anti-inflammatory medications such as methotrexate and anti-cytokine drugs that target the IL-1 pathway (3).
Associated conditions
There is no evidence that targeted treatment of associated disorders such as decreasing iron load with phlebotomy in hemochromatosis, has any effect on CPPD crystal deposition (44). There is, however, recent data that suggests that reversal of iron overload may lead to symptomatic relief in the long term (45).
Magnesium acts as a cofactor in the regulation of certain phosphatases. There is a known association between chronic hypomagnesaemic states and chondrocalcinosis (46). Hence, magnesium supplementation has often been recommended as a safe prophylactic agent to decrease the frequency of acute attacks of pseudogout. A 10-year follow-up study showed reduced meniscal calcification in patients with familial hypokalaemia/hypomagnesemia and chondrocalcinosis who were given magnesium supplementation (47). There was one small placebo-controlled study in CPPD-related arthropathy, not specifically associated with hypomagnesemia, which showed that the use of magnesium carbonate supplements produced improvement at 6 months (3).
Anti-inflammatory medications
Corticosteroids, NSAIDs, and colchicine have been used for the treatment of acute pseudogout and episodic inflammatory arthritis that is seen in pseudo-OA (48). NSAIDs are the mainstay of treatment. They are often of insufficient efficacy and also relatively contraindicated in older population due to the increased risk of gastrointestinal haemorrhage and associated renal impairment (3). When only one joint such as the knee is involved, aspiration and intra-articular injection of corticosteroids can be very effective (10). Short courses of oral steroids (0.5–1 mg/kg) or even intramuscular injections are also useful for recurrent flares of polyarticular CPPD-related arthritis (49).
There is evidence of the ability of hydroxychloroquine to inhibit matrix metalloproteinase activity in an animal model of CPPD arthritis. It does not have a role in the management of acute pseudogout. The current European League Against Rheumatism guidelines, however, recommend its use as an adjunctive agent in patients with chronic CPPD arthropathy (50).
Besides the aforementioned inhibitory effects of colchicine on crystal-induced IL-1β production by the inflammasome, its disruption of normal cytoskeletal function leads to the impairment of a variety of cellular functions, including the secretion of other chemokines and mediators, and reduced cell migration and division (51). These effects along with its plasma half-life of 20–30 h, large volume of distribution, partial renal excretion (20%), and preferential accumulation in red blood cells and neutrophils result in a relatively narrow therapeutic index and significant potential for toxicity, especially regarding bone marrow suppression (51). Colchicine, therefore, is nowadays only used in low-dose preparations (0.5 mg twice daily) for both pseudogout and gout. Although there have been no major trials of the treatment of acute pseudogout with colchicine, it is commonly used for this purpose (48). There is some evidence for its role in the prevention of both acute attacks of pseudogout and recurrent episodes of the other CPPD-related arthritides (52). The recent mechanistic insights into its effects on crystal uptake into cells and inhibition of their subsequent interaction with the inflammasome have generated renewed interest in this medication as a potential anchor drug in the prophylaxis of pseudogout.
Anticrystal agents
Unlike gout, there are no agents available that directly target crystal load in CPPD deposition disease. Probenecid is a transmembrane-transport inhibitor that reduces the production of extracellular PPi in vitro (53). Probecid has never been demonstrated to decrease CPPD crystal deposition in humans. The clear contribution of CPPD crystals to the acceleration of joint degeneration in the various CPPD-related arthropathies and the possible pathological role of these crystals in OA (54) has resulted in interest in the potential of phosphocitrate to target crystal deposition in both of these diseases directly (18). Calcification of articular cartilage is well recognized as an indissociable feature of OA (55). There is strong in vitro evidence that such calcium deposition is inhibited by phosphocitrate (18). Previous work has demonstrated that CPPD crystals accelerate joint degeneration in a rabbit model of OA (56). This suggests that agents that directly target articular calcification have the potential to treat CPPD-related arthropathy as well as OA.
Targeting the inflammasome
There have been recent advances in the understanding of the mechanisms involved in crystal-induced joint inflammation. Special attention has been focused on the ability of methotrexate to decrease the frequency and intensity of recurrent attacks of pseudogout, especially in relation to polyarticular disease (57). Methotrexate is relatively contraindicated in patients with haemochromatosis-associated arthropathy because of concomitant liver disease and the potential for increased toxicity,
due to its broad-spectrum ability to inhibit most cytokine pathways involved in joint inflammation. This generally well tolerated molecule represents an attractive alternative in the treatment and prophylaxis of the entire spectrum of pseudogout syndrome (3). The anti-inflammatory effect of methotrexate is mediated mainly by an increase in extracellular adenosine levels (58). This activates membrane receptors on macrophages and other inflammatory cells, thereby inhibiting the release of several cytokines, most notably IL-1β (59). By acting in this proximal manner, methotrexate has a potent indirect effect on the ability of the inflammasome to generate IL-1β. There are several multicentre clinical trials currently underway to further assess the potential impact of this widely available and affordable medication.
Insights into the role of IL-1β in various auto-inflammatory diseases have resulted in several case reports documenting the efficacy of anakinra, an IL-1 receptor antagonist, in difficult-to-treat polyarticular pseudogout (60).
A newly developed monoclonal antibody to IL-1β known as canakinumab, has proven to be very effective in treating refractory cases of gouty arthritis (61). A novel soluble fusion protein known as IL-1 Trap, has recently been licensed for the treatment of several auto-inflammatory conditions (62). These drugs may find a new place as disease-modifying agents in the treatment of CPPD-crystal-related arthropathy. Their immunosuppressive effects in a largely older patient population and relative high cost ensure that their use should be reserved for particularly difficult cases.
Although there are several reports of gout being successfully treated with anti-TNFα drugs, published reports of pseudogout successfully treated with these agents are lacking (3). As with many auto-inflammatory conditions, it appears that CPPD-related arthritis responds poorly to this class of drugs. The experimental data indicating that TNFα appears to exert its influence downstream of IL-1β in the acute inflammatory cascade associated with pseudogout would appear to be borne out clinically.
Conclusion
There is likely to be an increase in the prevalence of pseudogout and the associated CPPD-related arthropathies due to the demographic drift towards an aging population. Hence, the management of these conditions will continue to present challenges in the future. The use of colchicine as a prophylactic agent against acute attacks of pseudogout will probably become more widespread. In severe refractory disease, drugs targeting the IL-1 pathway offer considerable potential. In contrast to MSU crystals in gout, there is no practical way to remove CPPD crystals from the joint. The current management strategies remain symptomatic but not disease modifying. Further research into ways of reducing the CPPD crystal burden is necessary.
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