Best Practice & Research Clinical Rheumatology: John Stack, Geraldine Mccarthy

Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Contents lists available at ScienceDirect
Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh
Calcium pyrophosphate deposition (CPPD)

disease e Treatment options
John Stack a, b, *, Geraldine McCarthy a, b
a
Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland
b
University College Dublin, Ireland
a b s t r a c t
Keywords:
Calcium pyrophosphate deposition (CPPD) In contrast to gout, no disease-modifying therapies currently exist
disease that reduce articular crystal deposition of calcium pyrophosphate
Treatment crystals (CPPs). Treatment is aimed at ameliorating the inflam-
Management matory response and reducing the frequency and severity of
Colchicine clinical symptoms due to CPP deposition (CPPD). Despite being one
Corticosteroid
of the most common forms of inflammatory arthritis, CPPD re-
NSAIDs
Anakinra
mains under-studied and evidence-based treatment guidelines
Tocilizumab remain lacking. Commonly used treatments for clinical manifes-
Methotrexate tations of CPPD (non-steroidal anti-inflammatory drugs [NSAIDs],
Hydroxychloroquine colchicine and corticosteroids [CSs]) are extrapolated from use in
gout. Anakinra and tocilizumab can be used in refractory cases.
Though no current crystal-targeted treatments exist, studies sug-
gest that nucleoside analogues and phosphocitrate can attenuate
calcification of human cartilage ex-vivo. Hindering research, is the
lack of a well-defined description of CPPD. However, international
working groups have convened to establish classification criteria
and validated outcome domains for CPPD. This should help facil-
itate the setting up of large multicentre studies, with well-defined
cohorts, which can evaluate suitable therapies, providing high
levels of evidence to guide clinicians. Here, we summarise and
discuss the currently available anti-inflammatory treatment op-
tions for CPPD and discuss potential future crystal-targeted
approaches.
© 2021 The Authors. Published by Elsevier Ltd. This is an open
access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).
* Corresponding author. Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland.
E-mail addresses: johnstack@mater.ie (J. Stack), g.mccarthy@ucd.ie (G. McCarthy).
https://doi.org/10.1016/j.berh.2021.101720
1521-6942/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
Please cite this article as: J. Stack, G. McCarthy, Calcium pyrophosphate deposition (CPPD) disease e
Treatment options, Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/
j.berh.2021.101720
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J. Stack, G. McCarthy Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Introduction
Calcium pyrophosphate deposition (CPPD) disease can be broadly categorised into three subtypes:
acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis and osteoarthritis (OA) with CPPD
[1]. In contrast to gout, where crystal-targeted therapies in the form of urate-lowering therapies exist,
no such targeted therapies are currently available for the treatment of CPPD. Therapy is aimed at
ameliorating the inflammatory response and reducing the frequency and severity of CPPD flares.
Despite being one of the most common forms of inflammatory arthritis, CPPD remains under-studied
and evidence-based treatment guidelines remain lacking [2]. There have only been three randomised
control trials (RCT) conducted to date which were small in size and most likely underpowered [3e5].
Furthermore, the most commonly used treatments in CPPD are extrapolated from use in gout and have
not been studied extensively, or in some cases at all, in CPPD. Treatment of CPPD and its associated
clinical syndromes is therefore still largely based on expert consensus opinion [6]. Here, we summarise
and discuss the currently available treatment options for clinical management of CPPD and potential
disease-modifying agents.
Acute CPP crystal arthritis
Acute CPP crystal arthritis can be considered an auto-inflammatory disease. CPP crystals are rec-
ognised by the innate immune system as damage-associated molecular patterns (DAMPs), capable of
activating the NLRP3 inflammasome-a molecular platform which, when stimulated, cleaves and ex-
presses interleukin-1b (IL-1b) [7]. This is key step in activation of the inflammatory response seen in
acute CPP crystal arthritis. Patients typically present with rapid onset acute painful swelling of a joint
with overlying erythema, often associated with fever. Therapies which target this acute inflammatory
response therefore represent biologically plausible treatment options for acute CPP crystal arthritis.
Colchicine
Colchicine is an ancient drug that has established efficacy in the treatment of diseases characterised
by auto-inflammation [8]. These include gout, familial Mediterranean fever and recurrent idiopathic
pericarditis [9e12]. It exerts an anti-inflammatory effect by disrupting microtubule polymerisation
leading to impaired neutrophil chemotaxis and cell adhesion. It can also attenuate CPP and mono-
sodium urate (MSU) crystal-induced IL-1b expression in-vitro. The exact mechanism of action is
incompletely understood, but occurs upstream of the NLRP3 inflammasome possibly at the level of
crystal-endocytosis or crystal-presentation to the inflammasome [13]. Of note, colchicine is metab-
olised by the cytochrome P450 enzyme CYP3A4 and therefore drugedrug interactions can occur when
it is co-prescribed with other CYP3A4 inhibitors, for example, clarithromycin, verapamil, diltiazem and
ketoconazole. It also interacts with the transport protein P-gp and similar drugedrug interactions can
occur, potentially resulting in toxicity. Though colchicineestatin drugedrug interactions can in theory
lead to increased risk of statin-induced myopathy, no cases of myopathy were observed among 2366
patients treated with colchicine in a large RTC evaluating the use of colchicine in patients post-
myocardial infarction, despite statins being co-prescribed in >99% of patients [14]. Colchicine
toxicity typically manifests with diarrhoea and in severe cases (e.g. overdose) with cytopenias and liver
failure. It should be prescribed with caution and dosing adjustments in patients with chronic kidney
and liver disease [8].
Its proven efficacy in the treatment of gout has led to clinicians prescribing colchicine for acute
CPPD. There is, however, a paucity of evidence evaluating the use of colchicine in CPPD. There have
been two small open-label studies published in the 1980s with a combined total of 21 patients
recruited [2]. These studies appeared to show reduced rates of disease flare and associated pain in
patients who were treated with colchicine. Rationale for its use in CPPD is largely extrapolated from its
proven efficacy in gout. The European Alliance of Associations for Rheumatology (EULAR) currently
recommends prescribing 0.5 mg up to three to four times per day for acute CPP crystal arthritis with or
without an initial dose of 1 mg. Colchicine can also be prescribed 0.5e1 mg per day as prophylaxis in
patients prone to recurrent acute CPP crystal arthritis attacks [6].
NSAIDs
Non-steroidal anti-inflammatory drugs (NSAIDs) are identified in the CPPD EULAR guidelines as an
effective treatment for acute CPP arthritis and prophylaxis based on expert consensus opinion [6].
Surprisingly, there have been no retrospective or prospective studies published investigating the use of
NSAIDs in CPPD [2],[6]. Again, as with colchicine, the use of NSAIDs in CPPD is largely extrapolated from
experience of using NSAIDs in gout. Unfortunately, the use of NSAIDs in patients with CPPD is often
limited due to co-morbidities and adverse side effects which are more likely to occur in this older
cohort (e.g. NSAID-induced nephropathy, cardiovascular ischaemia and gastrointestinal bleeding).
Corticosteroids
Whilst corticosteroids (CSs) are used widely and recommended as part of the EULAR treatment
guidelines, there have been few studies evaluating their efficacy in CPPD [6]. Intra-articular CSs are
generally preferred in patients with monoarticular disease affecting large joints. A small retrospective
case series found that acute CPP crystal arthritis attacks resolved more quickly when patients under-
went joint aspiration plus intra-articular steroid injection compared with joint aspiration alone or
aspiration combined with NSAIDs [15]. Short courses of low-dose oral CS are generally preferred for
patients with acute polyarticular CPPD or patients who are intolerant of colchicine, however, studies
are lacking. Intravenous (IV) and intramuscular CS administration has been evaluated in a small open-
label study appearing to show benefit in terms of pain reduction in acute CPPD [6]. The growing
recognition of CS-associated side effects especially in this aged population is a limiting factor for use in
chronic CPPD.
Synthetic ACTH (Tetracosactide)
Synthetic adrenocorticotropic hormone (ACTH) is administered when testing for adrenal insuffi-
ciency and is usually readily available in most clinical settings. Synthetic ACTH can be a useful alter-
native to treating acute episodes of CPP arthritis in patients in whom CS, NSAID and colchicine are
contraindicated. A small retrospective study that evaluated the use of synthetic ACTH in 14 patients
with acute CPP arthritis reported significant pain reduction within 24 h in 13/14 patients [16]. Another
case series of five patients with acute CPP-reported resolution of acute attacks within an average of 4.2
days following administration of ACTH. Side effects included mild hypokalaemia that was self-limiting
[17].
Anakinra
Anakinra is an IL-1R antagonist which has proven efficacy in auto-inflammatory disease [18]. It is
given as a daily 100 mg subcutaneous injection. Several case series have described use of anakinra in
the treatment of acute CPP crystal arthritis. A recent systematic literature review identified a total of 76
patients who had been treated with anakinra, the majority of whom were described as having
recurrent acute CPP arthritis [19]. All patients were documented as being intolerant or as having
inadequate response to standard therapies. The majority (68.9%) received a short 3-day course of
treatment. A total of 21.6% were treated for 5e9 days and 9.5% for 30e365 days. Physician-reported
efficacy was evident with reductions in C-reactive protein (CRP) levels in 73% of cases, improvement
in physician VAS in 70.3% of cases. The mean reduction in patient VAS for pain was 44þ/10.9. These
studies were all retrospective, non-blinded with no comparator arm and are therefore subject to high
risk of bias. Nevertheless, anakinra remains a good option for patients with refractory CPPD. Further
randomised controlled studies with well-defined disease cohorts are needed to better characterise the
optimum dose and duration of anakinra in the treatment of CPPD.
Oral NLRP3 inflammasome inhibitors
In considering acute CPP arthritis flare treatment and prevention, oral NLRP3 inflammasome in-
hibitors, such as dapansutrile, represent a promising emerging class of drugs. In an open-label, dose-
adaptive, proof-of-concept, phase 2a trial, dapansutrile demonstrated an acceptable safety profile and
showed efficacy in reducing target joint pain in patients with acute gout flares. In theory, such agents
could be applied in the treatment and prevention of acute CPP arthritis [20]. These drugs would have an
advantage over anakinra due to their oral rather than subcutaneous mode of administration. Future
studies evaluating the use of oral NLRP3 inhibitors in the treatment of crystal arthritis, including acute
CPP arthritis are required.
Chronic CPP crystal inflammatory arthritis
Some patients with CPPD develop a chronic inflammatory arthritis which can mimic rheumatoid
arthritis. Again, evidence-based treatments remain lacking, although there have been a small number
of studies evaluating methotrexate, tocilizumab and hydroxychloroquine (HCQ) which are discussed
below.
Methotrexate
Methotrexate is a csDMARD, which is used as an anchor drug in the treatment of rheumatoid

arthritis with established benefits in terms of reduced inflammation, disease activity and disease
progression [21]. Based upon the successful reduction of pain scores as measured by patient VAS in two
small case series, methotrexate was previously recommended as a treatment for severe, refractory
CPPD by EULAR [6].
This recommendation has, however, subsequently been superseded by the results of a small,
double-blind, randomised crossover trial consisting of 26 patients which did not meet its primary
endpoint in demonstrating a significant improvement of DAS44 score in patients with CPPD
arthropathy [4]. There are, however, several caveats with this study that need to be considered. Firstly,
due to the small number of patients enrolled, the study was likely underpowered and the result could
represent a type 2 error, that is, false-negative result. The use of DAS44 has not been validated as an
outcome measure in CPPD. The authors included a mixture of CPPD phenotypes e acute and chronic,
mono, oligo and polyarticular diseases. Ideally, these phenotypes should be studied separately. In
addition, patients entering the study after an acute flare had subsided may have had a low baseline
disease activity when entering the study. This potentially could have obscured the observation of
improvement in DAS44 in such patients. Lastly, the authors of this study acknowledge the difficulty in
studying a disease which is very heterogeneous and characterised by flares and often long periods of
disease inactivity which can make capturing changes in disease activity challenging. This study
highlights the need for larger studies of longer duration, with clearly defined cohorts and validated
outcome measures. In summary, whilst there are insufficient data to support the use of methotrexate in
the treatment of CPPD, more studies are needed to definitively assess the use of this potential therapy
which is inexpensive, safe and very familiar to rheumatologists.
Tocilizumab
CPP crystals have been shown to induce expression of the pro-inflammatory cytokine IL-6 [22]. IL-6
is therefore a plausible therapeutic target in the treatment of clinical symptoms due to CPPD. Tocili-
zumab is an IL-6 receptor monoclonal antibody which binds to the IL-6 receptor thereby blocking
signalling from IL-6 expression [23]. Experience of tocilizumab in the treatment of CPPD disease has
been described in case series and case reports. The largest case series included 11 patients, seven of
whom had previously been treated with anakinra [24]. Seven patients had chronic CPP inflammatory
arthritis, whilst four patients had recurrent episodes of acute CPP crystal arthritis. All patients had
evidence of chondrocalcinosis on x-ray, but only one patient had crystal proven disease. Tocilizumab
was given by either monthly IV or weekly subcutaneous administration. After 3 months, the median
global assessment (visual analogue scale [VAS]) reduced from 60 to 15. This response was sustained out
to 10 months post-treatment. In addition, three patients, who were dependent on 7e10 mg of daily
prednisone, were able to taper their dose and two were able to stop completely. There were three
adverse events, including one hospitalisation for a lung abscess which required surgical drainage and
IV antibiotics [24].
Tocilizumab, therefore, warrants further evaluation in the treatment of CPPD disease. Perhaps, the
main caveat is that there is a slightly increased risk of infection with tocilizumab compared with other
biologic disease-modifying antirheumatic drugs (DMARDs), especially in older individuals to whom
CPPD disease affects [25]. This can be partly explained by the fact that tocilizumab suppresses CRP
irrespective of the therapeutic effect which can mask the CRP rise usually seen with infection. It also
makes the assessment of treatment efficacy in clinical trials more difficult.
Hydroxychloroquine
HCQ is an anti-malarial drug which has clearly demonstrated efficacy in the treatment of lupus and
to a lesser extent rheumatoid arthritis [21],[26]. It has been evaluated in CPPD disease in one double-
blind, randomised crossover study of 36 patients (19 in treatment arm vs 17 in placebo) [3]. Patients in
the treatment arm received HCQ 100 mg per day titrating each month up to 400 mg per day in non-
responders. A response rate (as defined by at least a 30% reduction in the number of swollen and
tender joints) was seen in 76% of the treatment group compared with 32% in the placebo group.
Furthermore in the open-label period of the study, treatment responses were observed in 85% of pa-
tients who crossed over from placebo. It should be noted that this was a small study that was con-
ducted over 20 years ago. The study population was not clearly defined and the authors used non-
validated outcome measures. Given the established safety profile of HCQ, further studies with
clearly defined cohorts and endpoints should be considered.
OA with CPPD
EULAR recommendations advise that the management of OA with CPPD is the same as the man-
agement of OA [1]. The National Institute for Health and Care Excellence (NICE) have recently published
an updated guideline for the management of OA which favours a holistic approach [27]. Local muscle
strengthening for the affected joints, aerobic conditioning and weight loss in obese individuals are
recommended in all patients. In terms of pharmacotherapy, paracetamol is recommended as first line,
sometimes given regularly, with NSAIDs and opioids reserved for patients intolerant to or who respond
inadequately to first line treatment. Again, NSAIDs and opioids are more likely to be problematic in this
older, more vulnerable cohort and there is a growing concern regarding the widespread prescribing of
opioids in some countries resulting in opioid dependency [28]. Opioids and NSAIDs should therefore be
prescribed with caution and for short courses only, avoiding chronic opioid/NSAID use. Joint
replacement remains an option for some patients with refractory/advanced disease who are fit to
undergo surgery [27].
Other considerations
Treatment of underlying disease
There are well-established associations with CPPD and metabolic diseases that alter inorganic
pyrophosphate (PPi) homeostasis and promote CPP crystal formation [7]. These include primary hy-
perparathyroidism, congenital hypophosphatasia and hypomagnesaemia (e.g. as seen in Gitelman's
syndrome). There is currently no evidence that treatment of primary hyperparathyroidism or hypo-
phosphatasia changes the course or severity of CPPD pathogenesis [2]. There is, however, some evi-
dence that magnesium supplementation may be beneficial in the treatment of CPPD irrespective of
whether or not magnesium deficiency is present. In a small double-blind, randomised placebo
controlled trial which included a total of 38 patients, 19 were assigned to the treatment arm of 30 mEq
of magnesium carbonate daily for 6 months. A significant improvement in patient-reported pain score
as well as physician-observed joint swelling and tenderness was observed in the treatment arm. No
changes in serum biochemistry, synovial fluid or radiographic chondrocalcinosis were observed. This
would suggest that the treatment effect in this study was anti-inflammatory rather than disease-
modifying, however, the 6-month duration may have limited the ability to detect changes in radio-
graphic chondrocalcinosis. The authors noted that this treatment effect was independent of baseline
magnesium [5]. The role of magnesium supplementation therefore warrants further investigation.
Further exploration of iatrogenic hypomagnesaemia, for example, in setting of proton pump inhibitor
prescription was suggested by crystal arthritis experts in a recent online survey regarding the unmet
needs of CPPD [29].
Radiation synovectomy
Radiation synovectomy was evaluated in a small double-blind, self-controlled study which

included 15 patients with bilateral knee CPPD. Patients received intra-articular (IA) yttrium-90
(5 mCi) plus CS (triamcinolone hexacetonide 20 mg) into one knee and saline plus CS into the
contralateral control knee. Significant reductions in pain, inactivity stiffness, joint line tenderness
and effusion were observed in the treated knees compared with controls after 6 months (p < 0.05)
[30]. Synovial destruction by laser irradiation was evaluated in another small study of 49 patients,
26 of whom were assigned to the treatment arm. The comparator arm received oral diclofenac.
Response was defined as a 60e100% reduction in pain and was observed in 69.2% of the treatment
group and 60.8% of the diclofenac group (p < 0.05). Gastrointestinal side effects were observed in
the diclofenac group, whilst no side effects were observed in the radiation synovectomy group
[31].
Asymptomatic CPP crystal deposition and disease prevention
Treatment of asymptomatic CPPD is not required and no preventative treatments currently exist [6].
Treatment of CPPD lies in stark contrast to gout in terms of availability of crystal-targeted therapies.
With gout, urate-lowering therapy leads to improvement or resolution of MSU crystal deposition over
time in patients who achieve a target serum urate [32]. No such targeted therapies have been devel-
oped for CPPD. In-vitro studies have shown that phosphocitrate, a naturally occurring compound can
inhibit BCP and CPP crystal-induced activation of mitogen-activated protein (MAP)-kinase cascade
signal transduction pathway, thus inhibiting the OA-inducing effects of calcium crystals [33].Unfor-
tunately, phosphocitrate has yet to be developed as a potential disease-modifying therapy.
More recent studies have examined the effects of nucleoside analogues which inhibit the activity of
PPi-producing enzymes, such as ecto-nucleotide pyrophosphatase/phosphodiesterase (eNPP1). Danino
et al. demonstrated that SK4A, a novel eNPP1-specific inhibitor could attenuate ATP-induced CPP
crystal formation in human cartilage obtained from patients undergoing arthroplasty [34]. The same
group has gone on to develop second-generation eNPP1 inhibitors which are highly selective against
eNPP1 [35]. It will be interesting to see whether these ATP derivatives can be developed into disease-
modifying treatments. There may be caveats with developing such therapies as lowering PPi could in
theory increase the risk of arterial calcification as eNPP1 is known to protect against arterial calcifi-
cation. It is therefore not known whether targeting eNPP1 in attempts to treat CPPD could uninten-
tionally accelerate arterial calcification and premature atherosclerosis [29]. Potentially, local
administered treatments could avoid this side effect. However, such approaches remain theoretical at
present.
Summary
The aging demographics of developed countries is likely to result in an increase in the incidence and
prevalence of CPPD. The evidence base for treatment of CPPD at present is limited; there is a paucity of
data published in the literature. There are, however, reasons to hopeful. Working groups have
convened to establish international classification criteria and validated outcome domains for CPPD
[36],[37]. This should help facilitate the setting up of large multicentre studies, with well-defined
cohorts, which can evaluate suitable therapies, providing high levels of evidence to guide clinicians.
Practice Points
Commonly used treatments in calcium pyrophosphate deposition (CPPD: Non-steroidal anti-

inflammatory drugs [NSAIDs], colchicine and corticosteroids [CSs]) are extrapolated from
use in gout.
Anakinra and tocilizumab can be used in refractory cases.
No disease-modifying therapies currently exist that reduce articular calcification in CPPD.
Research agenda
Well-designed randomised control trials (RCTs), with clearly defined disease cohorts and
outcomes are needed to identify evidence-based treatment strategies in calcium pyrophos-
phate deposition (CPPD).
Translational research identifying therapeutic targets of reducing articular calcification in
CPPD are needed.
Oral NLRP3 inhibitors, phosphocitrate and eNPP1 inhibitors are potential therapeutics worthy
of further investigation in CPPD.
Financial disclosure
The authors received no funding or sponsorship in preparing this manuscript.
Declaration of competing interest
The authors declare no conflict of interest with regard to this publication.
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Best Practice & Research Clinical Rheumatology: John Stack, Geraldine Mccarthy

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Best Practice & Research Clinical

Calcium pyrophosphate deposition (CPPD)

Acute CPP crystal arthritis

Synthetic ACTH (Tetracosactide)

Oral NLRP3 inﬂammasome inhibitors

Chronic CPP crystal inﬂammatory arthritis

Methotrexate is a csDMARD, which is used as an anchor drug in the treatment of rheumatoid

Treatment of underlying disease

Radiation synovectomy was evaluated in a small double-blind, self-controlled study which

Asymptomatic CPP crystal deposition and disease prevention

Commonly used treatments in calcium pyrophosphate deposition (CPPD: Non-steroidal anti-

The authors received no funding or sponsorship in preparing this manuscript.

Declaration of competing interest

The authors declare no conﬂict of interest with regard to this publication.

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