Calcium pyrophosphate dihydrate (CPPD) crystal deposition is a metabolic disorder that manifests substantially more often as joint pathology than it does as a symptomatic arthropathy.
The vast majority of CPPD crystal deposition is idiopathic/sporadic and is a disorder linked to aging, but other factors that promote CPPD deposition include prior joint trauma, osteoarthritis (OA), and possibly hypomagnesemia associated with diuretic use.
Diagnosis of CPPD deposition prior to age 50 to 55, particularly if CPPD deposition is widespread, should prompt differential diagnostic consideration of a primary metabolic disease (e.g., hemochromatosis, hyperparathyroidism, hypomagnesemia) or a familial disorder.
CPPD crystal deposition disease is a tremendous mimic and can clinically resemble (or coexist with) gout, septic arthritis, primary OA, and rheumatoid arthritis.
Chronic degenerative arthropathy in CPPD deposition commonly affects certain joints that are typically spared in primary OA, such as the metacarpophalangeal, wrist, and elbow joints.
Pseudogout is a major cause of acute monoarticular or oligoarticular arthritis in the elderly. The attacks typically involve a large joint, most often the knee, and less often the wrist or ankle; unlike gout, pseudogout rarely involves the first metatarsophalangeal joint.
Definitive diagnosis of CPPD crystal deposition requires demonstration of CPPD crystals (in synovial fluid or biopsy), typical calcifications on plain radiographs, and/or typical findings for CPPD crystal deposition in articular hyaline cartilage or fibrocartilage by high-resolution ultrasound. However, ultrasound is incompletely sensitive, diagnostic criteria are not fully validated, and false-positive and -negative results occur with ultrasound.
The guidelines for treatment of attacks of acute pseudogout in CPPD crystal deposition disease are predominantly expert opinion–based rather than evidence-based and have been modeled on treatment of acute gout.
Pseudogout can respond to nonsteroidal antiinflammatory drugs (NSAIDs) (or selective cyclooxygenase-2 inhibitors) and to colchicine but sometimes more slowly and, overall, less consistently than for acute gout treatment. Since comorbidities in the elderly often limit the aforementioned modalities, systemic glucocorticosteroids or intraarticular steroids, typically given as described for acute gout attack, are useful and broadly effective primary treatment choices in acute pseudogout and valuable in refractory cases.
Low-dose daily colchicine or NSAID prophylaxis, prescribed as is done to prevent gout attacks, is a useful treatment modality.
Hydroxychloroquine, methotrexate, and interleukin-1 antagonism have been suggested, without definitive proof, to be of some benefit to patients with refractory chronic polyarticular CPPD deposition disease. Moreover, these approaches also can have prophylactic efficacy for attacks of pseudogout.
There remains a lack of proven therapies to both inhibit CPPD crystal deposition and to effectively preserve articular cartilage already affected by the disorder. However, the clinical course and outcomes of CPPD deposition disease are variable, and the primary idiopathic disorder is not always anatomically progressive.
Dr. Terkeltaub’s work is supported by the VA Research Service.
The molecular genetics, molecular epidemiology, and pathogenesis of calcium pyrophosphate dihydrate (CPPD) deposition disease are reviewed in Chapter 20 , with this review focusing on clinical aspects of the condition.
The terminology, diagnostic criteria for CPPD deposition disease, and treatment strategies have recently undergone a timely, systematic examination by the European League Against Rheumatoid Arthritis (EULAR) ( Table 21-1 ). Several changes in terminology have been proposed, but the authors’ choice, in this chapter, was to use the more precise biochemical terminology for CPPD crystals, rather than the calcium pyrophosphate (CPP) terminology proposed by EULAR. In addition, this chapter uses the original, broadly employed and clinically attractive terminology for acute arthritis linked with CPPD crystals (i.e., “pseudogout”). This chapter also liberally applies the conventionally used term “chondrocalcinosis” to the major aspect of CPPD crystal deposition, with the caveat that CPPD crystallization is not the only type of pathologic calcification of articular cartilage. One difference between this chapter’s viewpoint and the EULAR guidelines is that this chapter views CPPD crystal deposition as a distinct primary cause of chronic degenerative arthropathy in a distinct subset of patients beyond those with familial CPPD deposition disease. EULAR has predominantly emphasized linkages between osteoarthritis (OA) and secondary CPPD deposition as drivers of chronic joint degeneration.
|No.||Proposition||LoE||SOR (95% CI)|
|1||Although often asymptomatic, CPPD can present variable clinical phenotypes, most commonly OA with CPPD, acute CPP crystal arthritis and chronic inflammatory arthritis.||IIb||90 (86 to 94)|
|2||The rapid development of severe joint pain, swelling and tenderness that reaches its maximum within 6 to 24 hours, especially with overlying erythema, is highly suggestive of acute crystal inflammation though not specific for acute CPP crystal arthritis.||IV||88 (84 to 93)|
|3||Presentation with features suggesting crystal inflammation involving the knee, wrist or shoulder of a patient over age 65 years is likely to be acute CPP crystal arthritis. The presence of radiographic CC and advanced age increases this likelihood, but definitive diagnosis needs to be crystal proven.||IIb||81 (74 to 89)|
|4||OA with CPPD particularly targets knees with chronic symptoms and/or acute attacks of crystal-induced inflammation. Compared to OA without CPPD, it may associate with more inflammatory symptoms and signs, an atypical distribution (e.g., radiocarpal or midcarpal, glenohumeral, hindfoot or midfoot involvement) and prominent cyst and osteophyte formation on radiographs.||Ib/IIb||53 (38 to 68)|
|5||Chronic CPP crystal inflammatory arthritis presents as chronic oligoarthritis or polyarthritis with inflammatory symptoms and signs and occasional systemic upset (with elevation of CRP and ESR); superimposed flares with characteristics of crystal inflammation support this diagnosis. It should be considered in the differential diagnosis of rheumatoid arthritis and other chronic inflammatory joint diseases in older adults. Radiographs may assist diagnosis, but the diagnosis should be crystal proven.||IIb||83 (72 to 93)|
|6||Definitive diagnosis of CPPD is by identification of characteristic CPP crystals (parallelepipedic, predominantly intracellular crystals with absent or weak positive birefringence) in synovial fluid, or occasionally biopsied tissue.||Ib||94 (90 to 97)|
|7||A routine search for CPP (and urate) crystals is recommended in all synovial fluid samples obtained from undiagnosed inflamed joints, especially from knees or wrists of older patients.||IV||99 (97 to 100)|
|8||Radiographic CC supports the diagnosis of CPPD, but its absence does not exclude it.||IIb||97 (92 to 102)|
|9||Ultrasonography can demonstrate CPPD in peripheral joints, appearing typically as thin hyperechoic bands within hyaline cartilage and hyperechoic sparkling spots in fibrocartilage. Sensitivity and specificity appear excellent and possibly better than those of conventional x-rays.||IIb||78 (70 to 87)|
|10||Acute CPP crystal arthritis and sepsis may coexist, so when infection is suspected microbiological investigation should be performed even if CPP crystals and/or CC are identified.||III||96 (93 to 100)|
|11||In patients with CPPD, risk factors and associated comorbidities should be assessed, including OA, prior joint injury, predisposing metabolic disease (including hemochromatosis, primary hyperparathyroidism, hypomagnesaemia) and rare familial predisposition. Metabolic or familial predisposition should particularly be considered in younger patients (<55) and if there is florid polyarticular CC.||Ib/IIb||94 (89 to 99)|
Epidemiology and Clinical Aspects of the Genetics of the Disorder
The vast majority of CPPD crystal deposition disease is idiopathic/sporadic and with onset in later life, but heritable early-onset disease does occur, and there are genetic influences on development of late-onset disease. These issues are discussed, in Chapter 20 , particularly with respect to ANKH in the molecular genetics of CPPD crystal deposition disease, and the low disease prevalence in Chinese in Beijing is cited later.
Most of what we know about the epidemiology of CPPD crystal deposition disease is the product of inexact science. Prior analyses of prevalence of CPPD deposition disease were principally built on plain radiographic features characteristic of the disease, with assessments confined to only a few joints. The limits in sensitivity and specificity of this approach are profound. Studies of CPPD deposition epidemiology via synovial fluid analyses (see Chapter 2 ) are also inherently limited. There is a need for definitive epidemiologic studies based on pathology of articular cartilages and other tissues and on imaging approaches more sensitive than plain radiography, such as high-resolution ultrasound. However, high-resolution ultrasound also has limits in sensitivity and specificity, as discussed later.
What we do know with certainty is that the prevalence of CPPD crystal deposition disease, including clinically silent disease, increases progressively with aging ( Figure 21-1 , Tables 21-2 and 21-3 ). The idiopathic/sporadic form of CPPD crystal deposition disease uncommonly presents before age 55, except with monoarticular disease following a history of joint trauma or knee meniscectomy. Studies of prevalence of CPPD crystal deposition disease, using plain radiographs as the screening tool, have estimated higher prevalence when the hands, wrists, pelvis, and knees have been the joints surveyed. Importantly, the majority of aged patients with CPPD crystal deposition disease of the knee also have chondrocalcinosis detected by plain radiography in other joints. Involvement of the meniscal fibrocartilage of the knee was detected in 16% of women aged 80 to 89 and in 30% of women older than 89, and this has been reproduced in other studies. In one plain x-ray survey study of hands, wrists, pelvis, and knees of patients admitted to a geriatrics ward, chondrocalcinosis was detected in 44% of patients older than 84 and in 36% of 75- to 84-year-olds, with a prevalence of 15% in 65- to 74-year-olds. Other studies of cohorts in the United Kingdom and Italy were limited to fewer joint regions (the knee, or knee and pelvis, respectively) and, predictably, gave lesser numbers for prevalence.
|High prevalence—strong association:|
|Moderate prevalence—strong association:|
|Low prevalence—questionable association (essentially based on case reports):|
|No. of Studies||No. of Subjects||OR (95% CI) ∗||References|
|Age (every 10 years from 40 to 90)||1||1851||2.25 (1.79 to 2.82)|
|Female gender||8||5042||0.89 (0.58 to 1.38)|
|BMI (WHO grade)||1||1851||0.90 (0.70 to 1.14)|
|Familial aggregation||2||2000||1.10 (0.58 to 2.08)|
|OA||9||4517||2.66 (2.00 to 3.54)|
|OST||3||1906||1.26 (0.76 to 2.09)|
|JSN||4||2043||1.24 (0.91 to 1.69)|
|Cysts||3||367||2.94 (0.92 to 4.96)|
|Trauma/injury||1||100||5.00 (1.77 to 14.11)|
|RA||2||818||0.18 (0.08 to 0.41)|
|Hyperparathyroidism||5||976||3.03 (1.15 to 8.02)|
|Hypomagnesemia||1||144||13.5 (2.76 to 127.3)|
|Diuretics||1||1727||2.17 (1.02 to 4.19)|
In a unique, and sizeable U.K. community study, adults over age 40 had an age-, sex-, and knee pain–adjusted prevalence of knee chondrocalcinosis of 4.5%. In this study, as in a meta-analysis by EULAR, there was no sex predisposition (unlike in some past studies that suggested a slight female predominance). However, a strong association between OA and chondrocalcinosis was present, which appeared linked more to presence of osteophytes than joint space narrowing with OA. The association between CPPD deposition disease and diuretic use in the U.K. community is potentially due to diuretic-induced hypomagnesemia.
Lack of uniformity of CPPD crystal deposition disease prevalence between populations has been illuminated by a comparison of a random sample of Beijing residents aged more than 60 years old with whites in the U.S. Framingham OA Study. The Chinese participants had a much lower prevalence of knee chondrocalcinosis, and wrist chondrocalcinosis was quite uncommon in the aged Chinese cohort. These findings were unexpected, because there is an excess of knee OA in Beijing and because of the common association between OA and secondary chondrocalcinosis, particularly in the knee joint. Whether the low prevalence of CPPD deposition in the Chinese in Beijing reflects a racial disparity, environmental influences, or both is not yet clear but is discussed further later, with respect to the relatively high levels of calcium in drinking water in Beijing.
Clinical Genetic Aspects of Epidemiology of CPPD Deposition Disease
Early-onset CPPD crystal deposition disease is variably defined as onset before age 50 or 55. Familial disease with such early onset is well recognized, and sporadic early-onset disease also occurs. In such cases, exclusion of metabolic diseases as primary etiology must be done. Major chromosomal linkages with 8q and 5p are established in studies of familial CPPD crystal deposition disease. Linkage to chromosome 8q of both early-onset OA and chondrocalcinosis has been designated CCAL1, but chromosome 5p–linked chondrocalcinosis (CCAL2) appears more common and has been better characterized, via linkage to ANKH on chromosome 5p studies. Biology and molecular genetics and structure-function of ANKH, a transmembrane protein with functions in inorganic pyrophosphate (PP i ) transport and other cell functions, is addressed in detail in Chapter 20 . Importantly, homozygosity for a single nucleotide substitution (–4 G to A) in the ANKH 5׳-untranslated region promotes increased ANKH mRNA expression and was detected in about 4% of subjects in the United Kingdom previously identified as having “idiopathic” CPPD crystal deposition disease related to aging. There are likely other, unrecognized genetic factors in late onset “sporadic” chondrocalcinosis.
The clinical heterogeneity of familial chondrocalcinosis, and associations with mixed forms of pathologic calcification, are noteworthy. For example, CPPD and basic calcium phosphate crystal (BCP), and cartilage and periarticular calcifications, in association with OA were described in one kindred, without a specific chromosomal linkage established. A syndrome of spondyloepiphyseal dysplasia tarda, brachydactyly, precocious OA, and intraarticular calcifications with CPPD and/or BCP crystals, in addition to periarticular calcifications, has been linked to mutation of the procollagen type II gene in indigenous natives of the Chiloe Islands in Chile. Importantly, this population has a high prevalence of familial CPPD deposition disease, for reasons that are not clear. Last, in the Azores Islands, families affected with diffuse idiopathic skeletal hyperostosis (DISH) and/or chondrocalcinosis have been described, posing as yet-unanswered questions on a potential, shared pathogenic mechanism.
CPPD Deposition Disease Secondary to Primary Metabolic Disorders
Hemochromatosis, hyperparathyroidism, hypophosphatasia, and hypomagnesemic conditions (including the Gitelman’s variant of Bartter syndrome) are the best-characterized primary metabolic disorders linked to secondary CPPD crystal deposition disease. A complete listing of such conditions, and EULAR weighting of risk factors, is provided in Tables 21-2 and 21-3 . The relationships of many of these disorders to disordered PP i metabolism and chondrocyte differentiation are discussed in Chapter 20 . CPPD crystal deposition disease linked to primary metabolic conditions (such as hemochromatosis, hyperparathyroidism, dialysis-dependent renal failure ) can present earlier than age 55. We do not understand the basis for the heterogeneous presentation of hemochromatosis either as premature degenerative joint disease, or with prominent CPPD crystal deposition. We now increasingly recognize that hypomagnesia can be caused by diuretic therapy, short bowel syndrome and malabsorption, and treatment with proton pump inhibitors, cyclosporine, and tacrolimus). Diagnostic approaches to these conditions are discussed in this chapter.
Development of CPPD crystal deposition disease in end-stage renal disease and hemodialysis, linked to secondary hyperparathyroidism, is a common problem and is reviewed in detail in Chapter 23 . Association of CPPD crystal deposition with gout is not rare in the clinic, particularly in elderly patients. It is likely that cartilage abnormalities and intraarticular inflammation from preexisting CPPD crystal deposition disease can promote urate crystal deposition in the joint, and possibly vice versa for CPPD deposition superimposed on gout. However, CPPD deposition disease and gout are both quite common conditions, and it is not surprising that they coexist in some patients, particularly among the elderly.
Although CPPD deposition is prevalent and a substantial public health problem in the elderly, the “disease and health-related quality of life impact” and the long-term course of various forms of CPPD-associated arthropathies have not been adequately evaluated. Furthermore, we do not yet understand the relative contributions, to each clinical phenotype of arthritis, of the forms of CPPD crystals deposited (i.e., monoclinic versus triclinic crystals), and the influences of host factors are poorly understood.
Clinical Presentations of CPPD Deposition Disease
Most aged individuals with CPPD deposition disease have a primary idiopathic/sporadic form of the disorder (see Table 21-1 ), which most often appears only after age 50 or 55, and favors large joints ( Figure 21-2 ). Those with antecedent repetitive joint trauma or knee meniscectomy can clinically present with nonsystemic (monoarticular) CPPD deposition disease before age 55, often first recognized on plain radiographs (see Tables 21-2 and 21-3 ).
The heterogeneous clinical presentations of familial CPPD crystal deposition disease are discussed next ( Tables 21-4 and 21-5 , Figures 21-3 and 21-4 ) Commonly, this is an asymptomatic disorder rather than a disease or a disorder that coexists with symptomatic OA and could contribute to baseline symptoms and/or flares of OA. Alternatively, CPPD crystal deposition disease is a versatile mimic. The disease can resemble primary OA (“pseudo-osteoarthritis”), gout (“pseudogout”) (see Figure 21-4 ), “pseudo-septic arthritis,” acute-onset or insidious RA (“pseudo rheumatoid arthritis”) (see Figures 21-3 and 21-4 ), or “pseudo-polymyalgia rheumatica” or present as a fever of unknown origin or “pseudo-neuropathic” arthropathy. Patients with CPPD crystal deposition disease also can present with episodic hemarthrosis, often post-traumatic and in the knee. In some patients, CPPD deposition disease and rheumatoid arthritis (RA) coexist, but this is likely by chance association in elderly subjects.
|1. Asymptomatic||Fortuitous radiographic or ultrasound finding|
|2. Acute CPP crystal arthritis||Generally called pseudogout; the rapid development of severe joint pain, swelling and tenderness that reaches its maximum within 6 to 24 hours, especially with overlying erythema, is highly suggestive of acute crystal inflammation though not specific for acute CPP crystal arthritis|
|3. Chronic CPP crystal inflammatory arthritis||Presents as chronic oligoarthritis or polyarthritis with inflammatory symptoms and signs, and occasional systemic upset (with elevation of CRP and ESR); superimposed flares with characteristics of crystal inflammation support this diagnosis. It should be considered in the differential diagnosis of rheumatoid arthritis and other chronic inflammatory joint diseases in older adults. Radiographs may assist diagnosis, but the diagnosis should be crystal proven.|
|4. Osteoarthritis with CPP deposition||Particularly targets knees with chronic symptoms and/or acute attacks of crystal-induced inflammation. Compared to OA without CPPD, it may associate with more inflammatory symptoms and signs, an atypical distribution (see Table 21-2 ). Some causal responsibility of CPP crystals is very likely but not well established, and the relationship is most probably in two directions (see text).|
|Clinical Presentations||Mimicked conditions||Peculiarities—Differences ∗|
|Chronic degenerative arthritis||Osteoarthritis||Unusual locations (radiocarpal, mediocarpal, mediotarsal, hindfoot-tarsal, MCPs, elbows, glenohumeral. Prominent cysts and osteophytes.|
|Recurrent acute inflammatory monoarticular or oligoarticular arthritis (“pseudogout”)||Gout||MTPs less often involved. Lower or absent effectiveness of colchicine|
|“Pseudoseptic Arthritis”||Septic arthritis||Clinically indistinguishable apart from the response to NSAIDs (that one cannot afford to wait; in principle, puncture always needed)|
|Chronic symmetric inflammatory polyarthritis (“pseudo rheumatoid arthritis”)||Rheumatoid arthritis||Rare rheumatoid factor and absent ACPAs. Mild or no local osteopenia but sclerosis and osteophytes on radiography notably on MCPs|
|Systemic illness with proximal limb pain and stiffness||Polymyalgia rheumatica||Frequent involvement of wrists, ankles, MCPs, PIPs, DIPs, knees, and MTPs. Common tendinous calcifications|
|Ligamentum flavum or transverse ligament of atlas involvement||Spondylodiscitis, cervical canal stenosis, cervical myelopathy, meningismus, foramen magnum syndrome, odontoid fracture||Cervical spine: calcification of the transverse ligament of atlas (crowned dens) most visible on CT scan. Dorsolumbar spine: possible discal thinning and erosions but no abscess. Response to NSAIDs|
|Rapidly destructive arthritis (frequently in dialysis-dependent renal failure)||Neuropathic arthropathy||Extensive and progressive joint destruction, but without neurologic signs. Responsibility of CPPD crystals in the destruction is likely but poorly demonstrated|
|Wrist pain and median nerve compression signs||Carpal tunnel syndrome||Improvement with NSAIDs and/or GC|
|Tumoral and pseudotophaceous CPPD crystal deposits||Gouty tophus, tumor||Generally painless. Histiocytes, giant cells and characteristic rhomboid shaped crystals with basophilic calcified material on microscopic examination|
Acute Synovitis of Pseudogout
Pseudogout, a common etiology of acute, inflammatory monoarticular or oligoarticular arthritis in the aged, presents as attacks typically involving a large joint. This is most often the knee, and less often the wrist or ankle and, rarely, the first metatarsophalangeal joint, unlike the case for gout. Acute attacks of pseudogout usually are sudden in onset and often excruciatingly painful and can be accompanied by periarticular erythema, warmth, and swelling, similar to gout attacks. In some patients, pseudogout can manifest as migratory, additive, polyarticular, and bilateral arthritis. For example, familial chondrocalcinosis and hyperparathyroidism can present with polyarticular pseudogout.
Factors that promote acute pseudogout include not only minor trauma but also illnesses that require hospitalization, such as intercurrent medical or surgical problems (e.g., pneumonia, myocardial infarction, cerebrovascular accident, and, in occasional cases, pregnancy). Parathyroid surgery for hyperparathyroidism commonly triggers acute pseudogout. Moreover, pseudogout of the knee can be precipitated by arthroscopy or by intraarticular hyaluronan injection, the latter possibly reflecting innate immune inflammation through Toll-like receptors, or triggering of CPPD crystal shedding from cartilage. Granulocyte colony-stimulating factor (G-CSF) and bisphosphonates also can trigger pseudogout attacks, the former likely by fueling an increase in smoldering, subclinical joint inflammation, and the latter possibly via pyrophosphatase inhibition, since bisphosphonates are nonhydrolyzable PP i analogues.
It has been suggested that initiation of thyroid hormone replacement can precipitate acute attacks of pseudogout. On the other hand, hypothyroidism (with the probable exception of myxedematous hypothyroidism) has not been tied to increased prevalence of CPPD crystal deposition disease in controlled studies, and both disorders are quite prevalent in the aged.
Acute and subacute cases of pseudogout, like gout, can be associated with fever, chills, elevated sedimentation rate and acute phase reactants, and systemic leukocytosis, particularly in those with polyarticular arthritis and in the aged. Synovial fluid leukocytosis (with a markedly elevated percentage of neutrophils) is present, and, on occasion, the joint fluid leukocyte count in pseudogout can exceed 50,000 per mm 3 with predominant neutrophilia (“pseudoseptic arthritis”). CPPD crystals (within and outside of phagocytes) are most often (but not universally) detectable by compensated polarized light microscopy in the acute phase of pseudogout (see Chapter 2 ). Although pseudogout attacks usually flare for 7 to 10 days, they also can be clustered and last for weeks to months, even with NSAID therapy. There has been reported to be a favorable prognosis for initial CPPD deposition disease in the knee presenting as acute pseudogout attacks alone.
CPPD Crystal Deposition in OA
Articular cartilage and synovial fluid CPPD crystals, frequently in association with BCP crystals, are commonly detectable (about 60%) in knee OA at the advanced stage of total joint arthroplasty. Higher mean radiographic scores correlated with the presence of these types of crystals. In a recent study, patients with primary OA and detectable CPPD crystals in joint fluids required knee arthroplasty more than those with OA without crystals. The clinical significance of BCP crystals is reviewed in Chapter 22 . The presence of CPPD crystals in joints with primary OA can contribute to OA symptoms (partially from synovitis) and flares, and potentially OA progression, since CPPD crystals induce synovial proliferation, and can cause chondrocyte cytotoxicity, and synovial and chondrocyte metalloproteinase expression.
Chronic Degenerative and Inflammatory Arthropathies Driven by CPPD Crystals
A small subset of subjects with CPPD deposition develop prolonged, recurring polyarticular inflammation. Progressive degenerative arthropathy is more common.
It has been suggested that acute flares of pseudogout become less common in those with established chronic degenerative CPPD deposition arthropathy, but acute pseudogout episodes still do occur in those with chronic arthropathy in CPPD crystal deposition disease. The chronic form of CPPD deposition disease often involves certain joints characteristically spared in primary OA (e.g., metacarpophalangeal joints, wrists, elbows, glenohumeral joints). The development of cartilage degenerative changes in CPPD deposition disease in typical as well as atypical joints for primary OA is consistent with CPPD deposition disease being a systemic disorder.
Not just familial CPPD crystal deposition disease, but also idiopathic/sporadic CPPD crystal deposition disease, can cause destructive arthropathy, but the aggressiveness of CPPD crystal arthropathy-associated degenerative disease is highly variable. Prospective analysis of CPPD deposition disease predominantly of the knee suggested relatively slow radiographic worsening of degenerative arthropathy, and a nonprogressive course in some patients. Although the majority of affected subjects develop changes in radiographic chondrocalcinosis with time, there is no clear correlation between the extent of calcification and progression of disease with CPPD deposition arthropathy.
Pseudo Rheumatoid Arthritis in CPPD Deposition Disease
Pseudo rheumatoid arthritis occurs in a small but significant fraction of patients with CPPD deposition disease. It presents as a chronic, bilateral, symmetric, inflammatory polyarthropathy (see Figures 21-3 and 21-4 ), and loss of joint motion and rheumatoid arthritis–like deformities may develop in the wrists and hands. Bilateral wrist and metacarpophalangeal joint involvement is a classic presentation, and wrist extensor tenosynovitis and tendon rupture and carpal tunnel syndrome may occur. Elbow cubital tunnel syndrome also may develop. Radiographic changes of CPPD deposition are characteristically present at the stage of pseudo rheumatoid disease associated with CPPD deposition disease.
Mechanisms driving synovial and tenosynovial proliferation, and synovitis, in response to CPPD crystal deposition, likely include uptake of CPPD crystals by synovial lining cells, and synovial proliferation, partly via solubilization of the crystalline calcium. Other mechanisms, including the role of the NLRP3 inflammasome and interleukin (IL)-1β release, are discussed in Chapter 20 .
Other Clinical Presentations of Idiopathic CPPD Crystal Deposition
Concentrated (tumoral or pseudotophaceous) CPPD crystal deposition can develop in bone and in periarticular structures such as tendons, ligaments, and bursae. CPPD deposits in tendons (e.g., Achilles, triceps, obturator tendons) are usually fine and linear on plain radiography and readily detected on high-resolution ultrasound. Plantar fascial involvement also occurs. Pseudotophaceous CPPD crystal deposition has also been reported in the temporal bone, the knee and hip regions, and in the acromioclavicular, temporomandibular, elbow, and small hand joints. Tumoral CPPD crystal deposits can present with acute attacks of arthritis and, in the knee region, can clinically mimic osteonecrosis. Tumoral deposits of CPPD crystals are characteristically associated with chondroid metaplasia and clinical behavior equivalent to a locally aggressive but benign chondroid tumor. CPPD crystal–induced metalloproteinase expression and other inflammatory responses likely drive the connective tissue invasion and destruction in this condition.
CPPD crystal deposition in the axial skeleton occasionally involves the intervertebral disc and the sacroiliac or lumbar facet joints, and spinal ankylosis may develop. Among the clinical syndromes reported are meningismus and clinical manifestations that mimic intervertebral disc herniation and ankylosing spondylitis; acute pseudogout of lumbar facet joints has been reported.
Notably, CPPD deposition disease can present as neurologic disturbance and painful cervical mass, especially in the aged. Specifically, CPPD crystal deposition in the ligamentum flavum or the transverse ligament of atlas can be quite robust and may progress to cause symptomatic cervical spinal canal stenosis, cervical myelopathy, and foramen magnum syndrome. Odontoid fracture due to the calcification of the atlantoaxial joint also has been reported.
Familial CPPD Crystal Deposition Disease
Familial CPPD crystal deposition disease often declares itself clinically in the third or fourth decades of life but is sometimes detected, or clinically present, later than that or before age 20. Familial CPPD deposition disease has been reported in numerous countries and ethnic groups. This includes kindreds from Czechoslovakia, Holland, France, England, Germany, Sweden, Israel, the United States, Canada, and Japan, and the familial disease may be most prevalent in Chile and Spain. Multiple members of a British kindred with CPPD deposition disease linked to ANKH mutation manifested recurrent childhood seizures strongly associated with later development of CPPD deposition disease. Kindreds with ANKH linkage have had heterogeneous phenotypes. Early-onset polyarthritis, including ankylosing intervertebral and sacroiliac joint disease, has been seen in some, whereas others have presented with late-onset CPPD crystal deposition disease. In some kindreds, mild oligoarticular disease resembling idiopathic CPPD deposition disease has been observed. Argentinian and Alsatian French ANKH mutant–linked kindreds had similar phenotypic features of CPPD crystal deposition, including early onset (third decade of life), premature OA in many, and some with pseudo rheumatoid arthritis peripheral joint disease. Commonly affected joints and regions in these kindreds were knees, wrists, symphysis pubis, and intervertebral discs.