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alcium pyrophosphate deposition (CPPD) disease is arthritis From the Division of Rheumatology, De-
caused by calcium pyrophosphate (CPP) crystals (Fig. 1). Until recently, partment of Medicine, Medical College
of Wisconsin (A.K.R., L.M.R.), and the
CPPD disease has been referred to as pseudogout. This term stems from an Department of Medicine, Zablocki Veter-
early description of this disease in patients with an acute goutlike arthritis whose ans Affairs Medical Center (A.K.R.) — both
synovial-fluid crystals were resistant to digestion by uricase and who thus did not in Milwaukee. Address reprint requests
to Dr. Rosenthal at the Rheumatology Di-
have gout.1 Almost simultaneously, a case series was published of 27 patients in vision, Department of Medicine, Medical
Hungary who had chronic episodic inflammatory oligoarthritis affecting primar- College of Wisconsin, 9200 W. Wisconsin
ily the knee.2 These patients shared a radiographic finding that was characterized Ave., Milwaukee, WI 53226, or at
arosenthal@mcw.edu.
by a “dense narrow band following the contour of the epiphysis” in the articular
cartilage, a finding that was termed chondrocalcinosis articularis (Fig. 2A and 2B). N Engl J Med 2016;374:2575-84.
DOI: 10.1056/NEJMra1511117
These two early descriptions foreshadowed the broad range of clinical presenta- Copyright © 2016 Massachusetts Medical Society.
tions that currently constitute CPPD disease.
Nomenclature issues have plagued CPPD disease since its original description.
Various cumbersome terms such as “calcium pyrophosphate dihydrate deposition
disease” achieved common use. In 2011, a group from the European League against
Rheumatism recommended that calcium pyrophosphate crystals be referred to as
CPP crystals, that the term “acute CPP crystal arthritis” refer to the acute inflamma-
tory arthritis that was formerly known as pseudogout, and that the term “chronic
CPP crystal arthritis” be used to denote other types of arthritis associated with CPP
crystals.3 The term “chondrocalcinosis” refers to the common radiographic correlate
of CPPD disease and does not imply clinical arthritis. We use the term “CPP deposi-
tion” (CPPD) to refer to the presence of CPP crystals and the term “CPPD disease” to
include all the related clinical presentations.
A B
flares of inflammatory signs and symptoms and tients, chondrocalcinosis is present without clin-
by unusually severe articular damage. The involve- ical arthritis. We believe that this condition rep-
ment of joints such as the glenohumeral joint, resents a presymptomatic phase of clinical arthritis,
the wrist, and the metacarpophalangeal joints, similar to that of hyperuricemia in gout, but the
which are not often affected by typical osteoar- proof of this will require further study.
thritis, should lead one to suspect the presence
of CPPD disease (Fig. 1B). A rarer form of poly- Patho gene sis
articular CPPD disease resembles rheumatoid ar-
thritis. Patients with this condition have persis- Although the pathogenesis of CPPD disease is
tent inflammatory arthritis that affects large and not fully understood, the formation of CPP crys-
small joints. Flares in this phenotypic variant of tals in the pericellular matrix of cartilage is the
CPPD disease often involve joints sequentially, essential first step in the disease process (Fig. 3).
and involvement is less symmetric than that seen CPP crystals rarely form in noncartilaginous tis-
with rheumatoid arthritis. McCarty estimated that sues.11 Thus, the cells and highly specialized extra-
the chronic degenerative polyarticular form of cellular matrix of cartilage are clearly conducive
CPPD disease accounts for roughly 50% of the to CPPD. For example, chondrocytes constitutively
cases of CPPD disease, whereas acute CPP crys- generate pericellular exosome-sized vesicles,
tal arthritis represents approximately 25% of the termed “articular cartilage vesicles,” which serve as
cases.5 important sites of crystal formation in cartilage
Other less common clinical presentations of (Fig. 3).12 Chondrocytes also produce high levels
CPPD disease have been described. CPP crystals are of extracellular inorganic pyrophosphate, which
commonly seen in spinal tissues, including inter- is critical to the formation of CPP crystals.13
vertebral disks and spinal ligaments.6,7 The crowned Inorganic pyrophosphate plays a central role in
dens syndrome is caused by the deposition of CPP CPPD that is analogous to that of urate in gout
crystals around the C2 vertebra and manifests as and may be a key therapeutic target. In cartilage,
acute severe neck pain, fever, and high levels of most inorganic pyrophosphate is generated from
inflammatory markers.8 This syndrome is often extracellular ATP.14 ATP efflux and thus the levels
confused with meningitis or sepsis. CPP crystals of inorganic pyrophosphate are critically regulat-
have also been associated with a severely destruc- ed by the multipass membrane protein known as
tive arthritis that is similar to neurotrophic (Char- ANKH (the human homologue of protein prod-
cot’s) arthropathy.9 Rarely, tumoral deposits of CPP uct of the murine progressive ankylosis gene).15
crystals occur in soft tissues, where they can cause ANKH may represent a therapeutic target in CPPD,
considerable tissue damage and may be mistaken and existing drugs, such as probenecid, act as po-
for cancers.10 In an unknown percentage of pa- tent antagonists of ANKH action in vitro.15 Extra-
A B
C D
cellular ATP is metabolized to inorganic pyrophos- important direct catabolic effects on chondro-
phate by enzymes with nucleoside triphosphate cytes18 and synoviocytes,19 eliciting the production
pyrophosphohydrolase activity, such as ectonucle- of destructive matrix metalloproteinases and pros-
otide pyrophosphatase 1, whereas alkaline phos- taglandins. CPP crystal deposits in articular carti-
phatase and other pyrophosphatases degrade inor- lage also alter the mechanical properties of car-
ganic pyrophosphate. In addition, growth factors, tilage, which may cause or accelerate joint damage
cytokines, and some pharmacologic agents mod- (Fig. 3, inset).20
ulate the levels of inorganic pyrophosphate in
cartilage (Fig. 3).14 Pr e va l ence
Once CPP crystals are generated, they medi-
ate tissue damage by means of multiple mecha- Estimates vary, but CPPD disease appears to affect
nisms. They initiate inflammation by activating 4 to 7% of the adult population in Europe and the
components of the NLRP3 inflammasome16 and United States.21,22 Unfortunately, our current un-
by creating neutrophil extracellular traps.17 Apart derstanding of the prevalence of CPPD disease is
from inducing inflammation, CPP crystals have based largely on radiographically detected chon-
FIBROCARTILAGE
OR HYALINE A Extracellular ATP and B Extracellular Factors That
CARTILAGE PPi Modulators Modulate Crystal Formation
↑ TGF-β ↑ Collagen 1
↓ IGF-1 ↓ Collagen 2
↑ Retinoic acid ↓ Proteoglycans
↑ Thyroxine ↑ Osteopontin
↑ Interleukin-1β ↑ Transglutaminase
↑ Ascorbate
↑ P2X purinergic receptor
agonists
↑ Hypotonic stress
ANKH
iATP
Cartilage Degeneration
ATP
CHONDROCYTE
ENPP1
iPPi
ADP
ANKH SYNOVIAL
Alkaline SPACE
phosphatase
ePPi + Calcium
Crystals Inflammasome Formation
ePPi
ePi
AMP ANKH
iPPi
5'-nucleotidase
ePi + Adenosine
ARTICULAR
CARTILAGE
VESICLE
ANKH
Matrix
metalloproteinase Matrix
and prostaglandin E2 metalloproteinase
and prostaglandin E2
Neutrophil
extracellular traps SYNOVIOCYTE
density and higher rates of vascular and soft- axis of the polarizer and yellow when they are
tissue calcification than those without chondro- perpendicular. In contrast, monosodium urate
calcinosis.43 crystals appear yellow when they are parallel to
the axis of the polarizer and blue when they are
Fa mil i a l CPPD perpendicular. The identification of CPP crystals
can be difficult, because these crystals are small
Although most CPPD disease is sporadic, multi- and often show weak birefringence. Intracellular
ple kindreds with premature or extensive CPPD and extracellular CPP crystals in synovial fluid
have been described worldwide. CPPD disease have equal significance. Cell counts in synovial
that occurs in patients younger than 60 years of fluid can vary widely.
age should prompt inquiry about similarly af- A single set of diagnostic criteria for CPPD dis-
fected family members. Interestingly, the first ease, which was proposed by Ryan and McCarty,
descriptions of CPPD disease in Hungary included has been published.34 Until validated diagnostic
five patients with affected relatives.2 Chondrocal- and classification criteria for CPPD disease are
cinosis develops in most affected patients before available, it seems prudent to define definite CPPD
the onset of clinical degenerative arthritis, a find- disease as the presence of CPP crystals in synovial
ing that supports a causative role for CPP crystals fluid or tissues with appropriate clinical findings.
in joint damage. Conventional radiography provides important
Two genetic loci are associated with familial support for the diagnosis of CPPD disease and
CPPD. Mutations in the CCAL2 locus on chromo- may assist in distinguishing CPPD disease from
some 5p produce an autosomal dominant pattern other types of arthritis. Although chondrocalci-
of inheritance (probably resulting from a gain of nosis is the radiographic finding that is most
function of the ANKH protein)44 and provide ad- closely aligned with CPPD disease, it should not
ditional support for a key role of ANKH in the be used as a sole diagnostic criterion in the ab-
pathogenesis of CPPD disease. The CCAL1 locus sence of clinical arthritis. Other useful radiograph-
on chromosome 8 has not yet been fully charac- ic clues that assist in differentiating primary osteo-
terized. Recently, a gain-of-function mutation in arthritis from CPPD disease include the following:
the TNFRSF11B (osteoprotegerin) gene was de- hooklike osteophytes; axial skeletal involvement,
scribed in a family with early-onset osteoarthri- such as annulus fibrosis calcification, severe disk
tis and chondrocalcinosis.45 degeneration with the vacuum phenomenon and
subchondral erosions, and the vacuum phenom-
enon of sacroiliac joints; radiocarpal- or patello-
Di agnosis
femoral-predominant narrowing of the joint space;
CPPD disease is underdiagnosed. It has been subchondral cyst formation; severe articular de-
shown that 20% of unselected patients who are struction, such as subchondral collapse, bony frag-
examined at the time of total joint replacement ments, and microfractures; and tendon or fascial
for osteoarthritis of the knee have CPP crystals calcifications, such as at the Achilles tendon,
in their synovial fluid.46 CPPD occurs at identical plantar fascia, gastrocnemius, quadriceps, rotator
rates in synovial-fluid samples and in tissue sam- cuff, or triceps at the elbow or shoulder.
ples that are obtained during knee or hip replace- The increasing use of musculoskeletal ultra-
ment due to osteoarthritis.23,47 sonography in the clinic may aid in the diagno-
CPPD disease is most accurately diagnosed by sis of CPPD disease. Chondrocalcinosis on ultra-
the finding of positively birefringent, rhomboid- sonography appears as linear densities in the
shaped crystals in synovial fluid from the af- hyaline cartilage or fibrocartilage (Fig. 2D). Al-
fected joint (Fig. 1A). Birefringence is a property though some early studies touted the higher
of highly ordered material such as crystals in sensitivity of ultrasonography as compared with
which the double refraction of light results in conventional radiography, it may be challenging
characteristic color changes with the movement to differentiate between gout and CPPD disease
of the crystal in relation to the light source. Under with ultrasonography.48
compensated polarizing light microscopy, which Advanced imaging techniques may be useful to
is typically performed with a red filter, CPP crys- detect CPPD disease in some contexts.49 Computed
tals appear blue when they are parallel to the tomographic (CT) scanning accurately detects cal-
M a nagemen t Yes No
Acute CPP crystal arthritis is managed with strat- Treat with Is treatment with
colchicine NSAID feasible?
egies that are aimed at reducing inflammation
and that are borrowed from therapies used for
acute gouty arthritis (Fig. 4). Intraarticular glu- Yes No
cocorticoids work well for patients with acute
CPP crystal arthritis, and this treatment is typi- Treat with NSAID
Is treatment with
prednisone
cally recommended as first-line therapy for joints feasible?
that are amenable to injection.4 Oral colchicine
at a daily dose of 0.6 to 1.2 mg is used in patients
without clinically significant renal or hepatic im- Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Treatment failure
neously at a dose of 15 mg per week, or placebo interleukin-1β inhibitors in patients with chronic
showed no difference between the drug and pla- CPP crystal arthritis, and further long-term stud-
cebo.55 Methotrexate was associated with few side ies of these agents are warranted.
effects in these patients and remains an option for We use a trial-and-error approach for the treat-
selected patients in whom other therapies have ment of patients with chronic CPP crystal arthritis,
failed. Anecdotal evidence supports the use of and we often combine low doses of several different
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