Current Rheumatology Reports (2018) 20:31

https://doi.org/10.1007/s11926-018-0739-z

CRYSTAL ARTHRITIS (L STAMP, SECTION EDITOR)

Therapy for CPPD: Options and Evidence

Mariano Andrés 1,2 & Francisca Sivera 3 & Eliseo Pascual 4

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review Current evidence and accumulated experience for the management of calcium pyrophosphate deposition
disease (CPPD) are presented.
Recent Findings Contrary to other rheumatic inflammatory conditions that account for high interest and growing research,
advances in treating CPPD are still very limited and mostly derive from those achieved in gout.
Summary Once formed, calcium pyrophosphate crystals cannot be dissolved; therefore, management relies on the control of
crystal-derived inflammation. Besides classical agents—such as colchicine, glucocorticoids, or NSAIDs—the use of targeted
therapies, mostly against interleukin-1, has provided a relevant relief for refractory CPPD patients in recent years. Meanwhile,
former enthusiasm about conventional disease-modifying agents such as methotrexate is currently controversial.

Keywords Calcium pyrophosphate . Chondrocalcinosis . Therapy . Colchicine . Methotrexate . Anakinra

Introduction with early severe osteoarthritis (OA)—occur in younger peo-

Even though calcium pyrophosphate deposition disease
(CPPD) [1] is a common disease and a frequent cause of visits
to the emergency services, it has received scant attention in the
published literature [2]. CPPD encompasses the consequences
of the formation of calcium pyrophosphate dihydrate (CPP)
crystals in the middle zone of the articular cartilage, but also in
tendons and ligaments [3]. It usually affects the elderly,
though occasionally aggressive forms—that can associate
Mariano Andrés and Francisca Sivera equally contributed in the making
of this manuscript and share first authorship.
This article is part of the Topical Collection on Crystal Arthritis
* Mariano Andrés
drmarianoandres@gmail.com
1 [4]. Contrary to gout, where the main aim of its treatment is to
Sección de Reumatología, Instituto de Investigación Sanitaria y
Biomédica de Alicante (ISABIAL), Hospital General Universitario
de Alicante, Pintor Baeza 12, 03010 Alicante, Spain
2
Departamento de Medicina Clínica, Universidad Miguel Hernández,
Alicante, Spain
3
Sección de Reumatología, Hospital General Universitario de Elda,
Alicante, Spain
4
Instituto de Investigación Sanitaria y Biomédica de Alicante
(ISABIAL), Universidad Miguel Hernández, Alicante, Spain
ple (in familial or sporadic forms). The usual clinical presen-
tation is that of an acute arthritis, most frequently affecting the
knee joint and clinically similar to gout. This similarity gave
rise to the name “pseudogout.” Though inflammatory symp-
toms are commonly short-lived and limited to a single joint,
oligo or polyarticular distributions and more persistent forms
also occur. OA can be associated with any type of inflamma-
tory presentation and may have an atypical distribution. In
some chronic, oligo or polyarticular presentations confusion
may arise with other arthropathies. However, the asymptom-
atic finding of radiological chondrocalcinosis or of calcifica-
tions in the mid-zone of articular cartilage or fibrocartilage
through ultrasound is common. It remains unclear why these
crystals produce symptoms in only a proportion of patients.
CPPD management remains eminence-based, rather than
evidence-based; very few controlled clinical trials have been
published in the last decades, most with disappointing results
cure the disease by eliminating the monosodium urate (MSU)
crystals which are causative of the disease [5], in CPPD, a
means of eliminating the crystals has not been attained yet.
Therefore, the aims of CPPD treatment are constrained to (1)
to treat the acute flares (when they occur), (2) to prevent such
flares (if frequent), and (3) to manage the associated OA. Most
of the patients with symptomatic CPPD will only develop
isolated—albeit recurrent—episodes of acute arthritis. In this
31 Page 2 of 6
context, the aim is to resolve these episodes quickly; non-
steroidal anti-inflammatory agents (NSAIDs), colchicine,
and glucocorticoids are commonly used alternatives [6].
Treatment aimed at disease modification would be especially
useful for patients suffering from frequent or persistent inflam-
mation. A common difficulty is lack of recognition of the
disease—or confusion with septic arthritis—by unacquainted
health personnel.
NSAIDs
Clinical experience supports the effectiveness of NSAIDs in
CPP arthritis; however, to our knowledge, there are no clinical
trials of NSAIDs in this condition. Despite this, they are rec-
ommended as one of the first-line treatments for acute CPP
crystal arthritis. There is no evidence to show differences in
effectiveness between different NSAIDs; both traditional
NSAIDs and selective cox-2 inhibitors can be used in this
context. As with gout, early initiation of NSAIDs at full doses
is probably key to early success. Given that most patients are
elderly, the safety profile of NSAIDs must be carefully con-
sidered before they are recommended. Recent data suggests
that one in 20 patients on ibuprofen, naproxen, or celecoxib
will experience a major toxicity over 1 to 2 years [7]. Rates of
major toxicities with ibuprofen or naproxen were higher than
with celecoxib.
In most patients, there is no need for maintenance therapy,
but a subgroup will require continuous therapy due to fre-
quently recurring or persistent inflammatory features.
Further epidemiologic studies are needed to ascertain the pro-
portion of patients with this need. When needed, a low-dose
NSAID (e.g. naproxen 250 mg, indomethacin 50 mg daily)
can be considered.
Glucocorticoids
Glucocorticoids (Gc), given through one of several routes—
intra-articular, intramuscular, oral or intravenous in selected
cases—, are an alternative to NSAIDs. This is particularly
relevant in elderly individuals with comorbidities. No recent
data has added to our knowledge of the use of Gc in CPPD.
Oral Gc used for gout attacks seem to be similarly effective:
30–35 mg/day of prednisone is recommended by the 2016
EULAR guidelines [5] while ACR 2012 guidelines [8] sug-
gest either the use of prednisone or prednisolone at a starting
dose of at least 0.5 mg/kg per day for 5–10 days, followed by
discontinuation or 2–5 days at full dose, and tapering for 7–
10 days. Shorter schemes are generally sufficient in the usual
monoarticular flares, and duration can be modified according
to response. When needed, low-dose Gc (e.g., prednisone
5 mg daily) can be used for prolonged time periods.
Curr Rheumatol Rep (2018) 20:31
ACTH is included as an option for polyarticular flares in
the EULAR recommendations [6], but this is based on a very
limited number of case reports. A recent retrospective review
presented the results from an additional 14 hospitalized pa-
tients with crystal-proven monoarticular acute CPP crystal
arthritis treated with a single dose of 100 IU of intramuscular
depot ACTH as first-line therapy [9]. Thirteen out of the 14
patients showed a response (defined as “attenuation of signs of
inflammation”) within 24 h. There were no rebound attacks
and no serious adverse events were recorded. A mild (non-
significant) increase in fasting glucose on the first post-
injection day was reported.
Colchicine
The use of the alkaloid agent colchicine in acute CPP arthritis
has been communicated in case reports and small studies,
where both oral and intravenous colchicines seem effective.
Although formal comparisons are lacking, expert opinion sug-
gests that the response to colchicine is probably worse in acute
CPP attacks than in acute gout arthritis. As extrapolated from
gout, low doses of oral colchicine (e.g., 1.5–1.8 mg daily)
should be used and intravenous colchicine should be avoided
due to increased toxicity [10].
Given the favorable safety profile at low doses, colchicine
should be considered when chronic or prolonged therapy is
needed in order to prevent recurrences. Daily low doses of
colchicine (0.5–1 mg daily) successfully reduced further acute
attacks of arthritis and controlled persistent inflammation in
small uncontrolled studies [11, 12]. A randomized controlled
trial evaluating the addition of colchicine 0.5 mg twice daily
(to a scheme of intra-articular glucocorticoids plus oral
piroxicam) in patients with knee OA and inflammatory signs
found increased pain relief [13]. Of the 39 enrolled patients,
75% had CPP crystals in the SF.
Traditional Immunosuppressive Agents
Disease-modifying treatment would be welcomed for those
CPPD patients with persistent or frequent symptomatic dis-
ease considered as refractory—unresponsive to usual treat-
ments—or in whom, because of comorbidities, the usual treat-
ments are contraindicated. A difficulty is that under the label
of chronic CPP arthropathy, rather than a continuum, there
appear to exist a cluster of discrete entities, with a potential
for differential responses to the same drugs. Under the label of
refractory CPPD, we can include both patients with frequently
recurring mono or oligoarthritides and those with OA with
CPPD. Some elderly patients present with chronic
oligoarthritis or polyarthritis—that may be symmetrical and
clinically indistinguishable from seronegative RA [14–16].
Curr Rheumatol Rep (2018) 20:31
To date, antimalarials and methotrexate have been tried in
CPPD with some success. Hydroxychloroquine was assessed
in a sole prospective, placebo-controlled study [17] enrolling
36 patients with persistent arthritis and X-ray findings of
CPPD. The patients in the active treatment showed significant
reductions in both tender and swollen joint counts after
6 months of follow-up. Indeed, good responses were also seen
in the placebo group after crossing-over to
hydroxychloroquine. Though these findings should be con-
firmed in further studies, the good benefit-risk profile of this
drug warrants a trial in patients with refractory forms of CPP
crystal arthritis.
Methotrexate (MTX) has received attention as a potential
DMARD in CPPD. A first report [18] described five patients
(ages 54–90 years); none of the patients had features consis-
tent with RA. Three of the patients are described as having
intermittent flares and two as persistent disease with intermit-
tent flares. Numbers of swollen and tender joints before MTX
were 4–8 and 7–17. The patients obtained an excellent clinical
response, with marked improvement within a short period
(mean time to response 7.4 weeks), with a decrease in pain
intensity and in the swollen and tender joint counts. A second
report [19] included three patients (ages 56–74 years), one
with symptoms in a single knee, another with wrist and shoul-
der involvement, and a third with a polyarticular distribution
(wrist, MCP, PIP, DIP). These patients received methotrexate
at dose of 10 mg/week (4 months), 7.5 mg/week (3 months),
and 12.5 mg/week (3 months) without improvement; the ad-
ministration route of methotrexate is not provided. A third
report from the authors of this review presented data on ten
patients [20] (five elderly patients presenting a persistent RA-
like polyarthritis, three patients with a persistent oligoarthritis,
two patients with a frequently recurring monoarthritis). In five
of the patients, MTX was escalated because of the lack of
initial response. Response was considered by attending phy-
sicians as moderate in the two recurring monoarthritis and in
one persistent oligoarthritis while in the remaining, it was
considered good or excellent. Patients rated their response to
treatment on a VAS scale ranging from 0 to 10; three patients
rated 9, three rated 8, and the remaining patients rated 7 and 6
and two 5, both coinciding with the two moderate responses
given by physicians. Long awaited, the results of a controlled
trial were published in 2014 [21]. Twenty-six patients were
recruited with only 19 completing the trial, discontinuations
mostly relating to liver toxicity. Overall, patients failed to
show an improvement with MTX treatment. Only 12 had
persistent polyarthritis (of which further characteristics were
not provided). As a whole, 14 were annotated as chronic ar-
thritides. The response of the subgroup with polyarticular dis-
tribution was no different from the mono-oligoarticular
pattern.
The question arose whether MTX should be abandoned
after these results and the authors of this review were asked
Page 3 of 6 31
to write an editorial on the subject [22••]. A potential expla-
nation is that CPP might not be the cause of the symptoms in
some of the patients treated with MTX with a good response.
CPP crystals are a common finding in elderly patients—16 to
43% of persons > 80 years of age [23–27]. If they do not
protect from other inflammatory diseases, they may appear
in a synovial fluid analysis—or as CC in radiographs—of
patients with another inflammatory arthritis. The description
of a persistent polyarthritis as a presentation of CCPD (de-
scribed as “pseudo-rheumatoid arthritis” by Daniel McCarty)
facilitates the classification of seronegative rheumatoid arthri-
tis (RA) in elderly patients showing CC or CPP crystals in SF
as CPPD. However, their response to MTX could be ex-
plained if both seronegative rheumatoid arthritis and CCP
crystals coexisted. Interestingly, in a series of 113 RA patients,
CPP crystals were found by cytocentrifugation in 20 (17.7%)
[28]. In another study, CPP crystals have been found in a low
but significant proportion of SF samples of different joint
diseases, including rheumatoid arthritis (8.29%) [29]. Until
more data is available, treating polyarticular, RA-like chronic
arthritis in elderly patients showing signs of CPP deposition
with MTX might be considered.
Biologics
The major advance in the management of CPP crystal arthritis
over the last decade has been the use of biologic agents. Rapid
and significant responses have been reported, even in patients
with troublesome disease and/or significant comorbidities that
limit the use of traditional agents. Even though the available
evidence derives from case series and small prospective stud-
ies, results should be taken into account as difficult-to-treat
CPP cases are fortunately not so common, and thus, larger,
industry-led controlled studies on this setting are not expected.
The rationale behind this use relies on the inflammatory
properties of the CPP crystals. CPP crystals form and deposit
in the cartilage matrix but induce inflammation when coming
into the synovial space. Martinon et al. demonstrated that CPP
crystals are capable of activating the inflammasome NLR-P3-
caspase1-interleukin-1beta (IL-1b) pathway present in innate
immune cells such as neutrophils [30]. Why evolution ensured
a genetic predisposition to respond against CPP crystals re-
mains unknown. IL-1b is the cytokine responsible of CPP
crystal-led inflammation, inducing the production and secre-
tion of other pro-inflammatory cytokines such as tumor ne-
crosis factor-alpha (TNFa) and IL-6, ultimately leading to the
inflammatory manifestation of the CPPD [31]. Following this,
main targeted therapies focused on the blockade of IL-1b.
Three IL-1b blocking agents are currently licensed for humans
by the FDA: a monoclonal antibody against IL-1b
(canakinumab); a recombinant IL-1 receptor antagonist
(anakinra); and a dimeric fusion protein of IL-1 receptor and
31 Page 4 of 6
IL-1 receptor accessory protein (rilonacept). To date, only
reports using anakinra in CPP crystal arthritis are available.
The effect of anakinra in CPP crystal arthritis mainly de-
rives from case reports and case series [32–37, 38•]. Anakinra,
administered at 100 mg/day subcutaneously, has produced
marked responses in patients who are refractory to colchicine
and/or NSAIDs. Generally, a 3-day scheme has been used for
managing acute episodes, but patients with very recurrent or
persistent arthritis may also benefit from daily doses or every
2 or 3 days as a maintenance therapy. To date, whether
anakinra would be superior to Gc remains unclear, especially
for acute flares. In chronic CPP crystal arthritis, long-term use
of Gc may lead to undesirable adverse events, especially in
elderly populations. Recently, a prospective controlled study
comparing both agents was communicated [39]. Limited data
can be taken as only 15 patients were included after 3 years of
recruitment, but no differences between anakinra and predni-
sone were noted in reducing pain scores over 72 h.
The role of other biological agents in CPP crystal arthritis
has not been established. TNFa inhibitors had been ineffective
in some of the reported patients who later responded to
anakinra [34]. Our group recently reported two cases of per-
sistent CPP crystal arthritis—one of them with concurrent
monosodium urate crystals—occurring in aged, female pa-
tients whom, despite poor response to anakinra, were success-
fully managed with the IL-6 receptor inhibitor tocilizumab
[40]. CPP crystals induced IL-6 production by synoviocytes
and monocytes, even in higher titres than IL-1b [41]. The
reason behind IL-6 blockade effectiveness while being unre-
sponsive to IL-1b inhibitors needs further research—again,
concurrent seronegative polyarthritis and CPP crystal deposi-
tion might be considered. In any case, this preliminary data
offers a new therapeutic option for CPPD patients.
Local Therapies
Intra-articular injections of a long-lasting formulated Gc
(methylprednisolone, triamcinolone) provide a fast and very
effective relief in patients with mono or oligoarticular attacks.
A concurrent infection—unusual but possible [42]—must be
ruled out prior to injection. The dose of Gc required for CPPD
acute attacks has not been studied, but in our practice, we tend
to employ reduced dosage—i.e., 10–20 mg triamcinolone for
large joints such as knees—, as in gout appears sufficient [43].
In refractory or very recurrent cases, synoviorthesis with
yttrium-90 may be of some help [44].
Patients with CPPD develop early osteoarthritis in relation
to crystal formation within the cartilage and crystal-derived
inflammation (both clinical and subclinical) [31] that may
end up requiring joint replacement. CPPD appears to not have
a deleterious impact on the outcomes of this procedure [45,
46], though may cause acute attacks presenting with pain and
Curr Rheumatol Rep (2018) 20:31
swelling of the prosthetic joint that might be taken for an
infection [47•]. Intra-articular hyaluronate, used frequently
for managing osteoarthritis, may trigger acute CPPD arthritis
[48].
Summary
As it is the case of gout, CPP crystals inflame because they are
recognized by the innate immune system with the subsequent
production of IL-1b and ensuing inflammatory cascade.
Contrary to gout, here the means to eliminate the causative
CPP crystals have not yet been found, so the only possible
treatment is to control inflammation. Fortunately in most oc-
casions, it is restricted to occasional acute monoarthritis flares
that respond rapidly to several drugs—often being the main
difficulty rapid recognition of the disease by health personnel.
The occasional patients whose joint inflammation is more
persistent, polyarticular, and causative of OA pose special
difficulty. Here, anti IL-1b biologic agents offer a clear possi-
bility of treatment. Finally, CPP crystals are common in joints
of aged persons; although speculative, the possibility that
those presenting an unrelated inflammatory arthropathy may
show CPP crystals in their joint fluid has to be considered. If
this occurs, the differential diagnosis with CPP-related ar-
thropathy—at least with those arthropathies which diagnosis
relies on clinical grounds—could be difficult and the results of
treatment difficult to interpret.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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