Imaging and Management of Calcium Pyrophosphate Deposition Disease

Abstract

The radiological manifestations of calcium pyrophosphate deposition (CPPD) revolve around two main axes: the asymptomatic form and CPPD disease. The latter is a consequence of an immune response to calcium phosphate crystals. Chondrocalcinosis is broadly considered as the radiographic manifestation of CPPD regardless of whether it is asymptomatic or associated with inflammatory arthritis. CPPD is associated with osteoarthritis although the direction of such association is still unclear. Apart from the detection of CPP crystals in synovial fluid, imaging (mainly conventional radiography, and increasingly ultrasound) plays a central role in the diagnosis of CPPD disease. Recently, CT has been added as diagnostic tool, especially in deep anatomic locations such as crowned dens. To date, no treatment is effective in dissolving CPP crystals. For now, the focus of current treatment strategies remains inflammation control. Our aim is to review the epidemiology, pathogenesis, clinical and imaging manifestations of asymptomatic and symptomatic CPPD. We will also discuss recent consensus definitions and classifications of CPPD disease.

Introduction:

Calcium pyrophosphate (CPP) crystals were first identified by use of polarized light macroscopy and distinguished from monosodium urate in the 1960s¹. Radiographically detected calcification of the cartilage and menisci (chondrocalcinosis, meniscocalcinosis) is broadly considered as the radiographic manifestation of CPP deposition (CPPD), which is most often asymptomatic. CPPD disease, on the other hand, is the consequence of an immune response to the CPP crystals inside joints, causing acute or chronic crystalline inflammatory arthritis. CPPD has also been strongly associated with cartilage degradation and osteoarthritis², although the direction of causality is unclear. CPPD disease is thought to be the most common of arthritis among patients aged 60 and older; however, it is less well researched compared to other types of arthritis.³ This is in part a consequence of variable reliance on synovial fluid polarized light microscopy for diagnosis, and heterogeneous clinical manifestations (acute vs. chronic arthritis, crowned dens syndrome, osteoarthritis with CPPD).³ Conventional radiography holds a central place in the diagnosis of CPPD and its various manifestations. Ultrasound is also gaining increasing interest, especially among rheumatologists. Recently, CT has been increasingly used in the research setting due to its higher sensitivity in comparison with radiographs and the diagnosis of crowned dens. In this paper, we review the epidemiology, pathogenesis, clinical and imaging manifestations of asymptomatic and symptomatic CPPD. We will also discuss recent consensus definitions and classifications of CPPD disease.

Demographics & Clinical Presentations:

The overall prevalence of imaging-detected chondrocalcinosis is known to increase with age. Radiographically detected chondrocalcinosis has been reported to be 7% in the US and UK ^4,5, whereas CT-detected intra-articular mineralization was found to increase from 3.4% among those aged 45-56, to 19.5% among those aged 65 and older. The prevalence of intra-articular mineralization is higher with CT than conventional radiographs (9.8 versus 5.8%).⁶ These numbers were obtained from epidemiologic studies and reflect the overall prevalence of asymptomatic CPPD. On the other hand, the prevalence of “symptomatic” CPPD disease is much less defined, although it is thought to be the most common cause of inflammatory arthritis in those aged 60 and older ^7–9. Common risk factors for CPPD include ageing and previous joint injury. ¹⁰

The prefix “pseudo” in pseudogout and pseudo-rheumatoid arthritis (older terms for acute and chronic CPPD arthritis, respectively) was intended to highlight the clinical similarities between the CPPD disease (and its various manifestations) and other common rheumatic diseases. In 2011, the European Alliance of Associations for Rheumatology (EULAR) consensus panel suggested the following terminology for clinical manifestations related to CPPD¹¹; Asymptomatic CPPD disease, acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, osteoarthritis (OA) with CPPD, with or without superimposed acute attacks, severe joint degeneration, and spinal involvement.

Acute CPP crystal arthritis typically presents as an acute mono or oligoarticular articular, severe, and self-limiting episodes of swelling and pain. Systemic manifestations can include fever, leukocytosis, and elevated acute-phase reactants. Although any joint can be involved, it is more common in the knee, wrist, and metacarpophalangeal (MCP) joints¹². Synovial fluid analysis is the gold standard for diagnosis showing rhomboid-shaped crystals that exhibit weakly positive birefringence or no birefringence under polarized light microscopy (Figure 1).

Figure 1:

Acute CPP arthritis in a 77-year-old female admitted to the hospital with bilateral hand pain worse on the right. The clinical presentation was concerning for cellulitis and/or septic arthritis. Aspiration revealed CPP crystals. Anteroposterior (A) and lateral (B) radiographs of the right-hand show marked soft tissue thickening along the dorsal aspect of the hand (white solid arrows) and chondrocalcinosis in multiple areas including the triangular fibrocartilage and in the third MCP joint (black dashed arrows). The constellation of clinical and radiographic findings was consistent with acute CPP arthritis. Patient dramatically improved after starting colchicine and prednisone.

Chronic CPP crystal arthritis previously referred to as pseudo-rheumatoid arthritis, and presents as a symmetric deforming polyarthritis that commonly affects the MCP joints and wrists¹². Aspiration of joint fluid and radiography are essential in establishing the correct diagnosis. Unlike rheumatoid arthritis, bony erosions are uncommon in chronic CPP arthritis (Figure 2). In a study comparing ultrasound features among 60 patients with CPPD versus 40 patients with rheumatoid arthritis, erosions were 10 times more prevalent in RA versus CPPD (50% versus 5%). ¹³

Figure 2:

66-year-old female with chronic CPPD arthritis. (A) Photograph of bilateral hands shows deforming arthropathy of the left second and third metacarpophalangeal (MCP) joints (solid arrows). Anteroposterior radiographs of the left (B) and right (C) hands show multiple radiographic findings consistent with CPPD arthropathy including diffuse mineralization of both radiocarpal joint more prominent at the triangular fibrocartilage on both sides (arrowheads), as well as widening of the right scapholunate interval consistent with ligament rupture (double-ended arrow). Right 2^nd and 3^rd MCP deformities as seen clinically (solid arrows). Additional evaluation with ultrasound at the rheumatology clinic was performed (D-F). (D, E) Longitudinal ultrasound images of the third MCP joint show osteophyte formation of the third metacarpal head (solid arrow) and intra-articular mineralization (arrowhead). The double contour appearance consistent with CPPD deposits is best displayed in image part (E) (arrowhead). (F) Longitudinal ultrasound images of the volar surface of the wrist shows hyperechoic material in the region of the carpal tunnel (solid arrow). This patient also had carpal tunnel symptoms.

Severe Joint Degeneration (pseudo-neuropathic) refers to a painful destructive monoarthritis resembling neuropathic joint, in absence of neurologic abnormalities. The pathogenesis of such presentation is unclear.¹²

OA with CPPD with or without superimposed acute attacks.

CPP crystals are commonly found in the synovial fluid of patients with OA (Figure 3), either alone (in 21 to 32%), or in combination with basic calcium phosphate (BCP) (in 16 to 48%).^14–16 In addition, chondrocalcinosis (often used as a surrogate for CPP deposition) can be associated with degenerative changes that have an unusual distribution. This presentation is characterized by a gradual onset of pain and slow progressive joint destruction (especially in the knee), without synovitis or morning stiffness. Acute CPP can be superimposed to the chronic symptoms.¹⁷ In the knee for example, OA with CPPD is traditionally described as predominantly involving the patellofemoral joint, which is out of proportion to the degree of tibiofemoral disease (Figure 4) and maybe associated with scalloping of the distal aspect of the anterior femoral cortex at the level of the patella. ^12,18,19

Figure 3:

CPPD and osteoarthritis in a 69-year-old woman with a long-standing history of bilateral knee pain from osteoarthritis (including prior intra-articular cortico-steroid injections and visco-supplementation). Anteroposterior (A, C) and lateral (B, D) radiographs of the left knee in 2006 (A and B) and 2024 (C and D) demonstrate progression of CPPD with increased burden of chondrocalcinosis in the medial and lateral menisci (dashed arrows) as well as the posterior capsule calcific deposits (solid arrows) between 2006 and 2024, as well as progression of osteoarthritis, more prominent at the patellofemoral joint which shows large superior patellar osteophyte in the follow-up visit (arrowhead). The association between CPPD and OA is often noted on imaging studies, though the direction is this association remains unknown.

Figure 4:

Frontal (A) and sunrise (B) views of the right knee in a 61-year-old female with long standing history of knee pain showing chondrocalcinosis projecting of the medial and lateral compartment (dashed arrows), as well as severe patellofemoral arthritis with bone-on-bone contact of the lateral patella and lateral trochlea. These findings are consistent with CPPD arthropathy. Lateral view of the left knee in another 68-year-old female patient shows anterior scalloping of the distal anterior femoral cortex, at the level pf the patella with severe patellofemoral joint space narrowing. Although chondrocalcinosis is not detected in this case, this finding may suggest CPPD arthropathy.

Spinal Involvement:

CPP crystal deposition can also be found in the intervertebral disks and spinal ligaments, and in the peri-odontoid ligaments (Figure 5) ^20,21. Spinal CPPD is better depicted on CT in comparison with conventional radiographs, especially at early stage of calcification deposits. Several studies have previously reported on the association between CPPD and spinal stenosis.²² For instance, a study comparing 102 surgical specimens from spinal decompression to 20 cadaveric controls found CPPD was present in the ligamentum flavum of 24.5% (20/102 cases) of the surgical specimens versus 5% (1/20 cases) of the cadaveric specimens, suggesting that CPPD may be associated with thickening of the ligamentum flavum which in turn may cause spinal stenosis symptoms.²³ In some cases, CPPD disease of the spinal facets result in marked distension of the facet resulting in compression of the spinal cord ²⁴. The term “Crowned dens” syndrome, which is also by CPPD crystals around the C2 vertebra is usually used when patient presents with acute severe neck pain, fever, and high levels of inflammatory markers.²⁵ Differential diagnosis can include meningitis and/or sepsis. ²⁶

Figure 5:

Cervical spine compression in a 78-year-old male who presented with signs of cervical myelopathy and C2 neuralgia in the setting of CPPD with retro-odontoid ligament and multilevel ligamentum flavum thickening. (A) Sagittal T2-weighted MRI shows severe cord compression at the cranio-cervical junction secondary to T2 hypointense thickening of the retro odontoid ligaments (arrow). (B) Axial and (C) sagittal CT reformatted images show diffuse mineralization involving the peri-odontoid ligaments (black solid arrows), as well as the ligamentum flavum (white solid arrows) and intervertebral disc spaces (black arrowhead).

“Tophaceous pseudogout”:

refers to mass-like mineralization within or around a joint, without any of the other typical manifestations of the disease. It is currently speculated that a subset of it is a form of calcified chondroid mesenchymal neoplasm (CCMN) with FN1-receptor tyrosine kinase gene fusion.²⁷ The lobulated growth of tophaceous pseudogout and the absence of additional signs of arthropathy favors the hypothesis that at least a subset of tophaceous pseudogout is related a neoplasm. CCMN most frequently involve the temporo-mandibular, knee and elbow joints (Figure 6).²⁷

Figure 6:

Calcified chondroid mesenchymal neoplasm (CCMN), previously known as “tophaceous pseudogout” in a 72-year-old female who presented with pain around the right ear and jaw, and changes to her bite for 2 years. Coronal (A) and sagittal (B) unenhanced CT reformatted images centered around the right temporomandibular joint (TMJ) show intra-articular bilobed mineralized mass (arrows), without substantial degenerative changes or joint destruction. Upon surgical resection and molecular analysis, the mass was found to have a FN1-FGFR2 gene fusion, which is characteristic of calcified chondroid mesenchymal neoplasm.

Pathogenesis of CPP deposition and CPPD disease:

The process of intra-articular calcium crystals deposition consists of 2 steps: a nucleation phase, during which amorphous calcium pyrophosphate precursors are formed, and a growth phase, during which CPP crystals are generated and grow in size ²⁸. Although there are three pathways for nucleation of calcium crystal, only one pathway is involved in CPP crystal nucleation, which is the hypertrophic differentiation of chondrocytes. Crystal growth starts in collagen fibrils (intrafibrillar) and continues between collagen fibrils (extrafibrillar). Both of the nucleation and growth steps are modulated by various factors, that include ion imbalance, inorganic pyrophosphate, reactive oxygen species, reactive nitrogen species, Fetuin-A, and matrix protein Osteopontin. ²⁸ The association between CPPD and certain metabolic conditions (such as hyperparathyroidism, haemochromatosis, hypomagnesaemia, and hypophosphatasia) ²⁹,³⁰ is secondary to ion imbalance (example: increased serum calcium or decreased magnesium). ²⁸ In CPPD disease, the various clinical manifestations are thought to be caused by elevated extracellular-pyrophosphate concentrations in the cartilage, triggering inflammation by activation of the NLRP3 inflammasome. ¹⁰

On the link between CPP and Osteoarthritis:

The relationship between CPPD and OA is supported by several epidemiological studies ^2,31,32 , and is often observed clinically (Figure 3). Liew et al. reported on 1,673 patients from the Multicenter Osteoarthritis Study (MOST) ³³ study and showed that CT detected intra-articular mineralization were associated with higher risk progression of cartilage damage on MRI in the same knee compartment and subregion (using the MRI-based multi-tissue knee osteoarthritis knee score “MOAKS”). These findings suggest a potential localized tissue specific effect of intra-articular mineralization on cartilage pathology in knee OA. Using data from the same cohort, CT-detected intra-articular mineralization were also found to associated with risk of having more frequent, persistent and worsening knee pain over 2 years of follow-up.³⁴ However other studies did not find any association chondrocalcinosis and progression of osteoarthritis.³⁵ Despite these findings, the direction of the association between intra-articular mineralization and osteoarthritis remains uncertain, both in terms of pathogenesis and clinical presentation. ¹⁰ Older age and prior trauma are both risk factors to CPPD and osteoarthritis, ³⁶ which makes it difficult to clarify the direction of causality between the two conditions. ³⁷ Alterations of the extracellular matrix in CPPD may contribute to the local production of proinflammatory cytokines, possibly leading to joint damage, and therefore resulting in a complex situation in which the comorbidity of these conditions could exacerbate each other. ¹⁰ Chondrocytes are the main cells of interest in the pathogenesis of OA, but other joint cells also react to the presence of calcium crystals, and all contribute to inflammation, cell death, and matrix breakdown, which are important features of OA. ²⁸

Imaging of CPPD Disease:

Conventional Radiography:

Conventional radiography is widely regarded as the first-line imaging modality because of its wide availability, low cost, and standardized acquisition. ¹⁰ As mentioned above, chondrocalcinosis is widely regarded a surrogate biomarker of CPPD. However, one should bear in mind that chondrocalcinosis is a common, but not universal, finding of CPPD arthropathy.

Chondrocalcinosis is seen as a wedge-shaped calcification in the fibrocartilaginous structures (meniscus for the knee or triangular fibrocartilage for the wrist), and a thin linear calcification in the hyaline cartilage paralleling the articular surfaces (femoral condyles and tibial plateaus in the case of the knee joint). Calcifications may also be seen in the synovium, as well as the surrounding tendons and ligaments ¹⁹. Preferential or isolated involvement of the patellofemoral joint should raise concern for CPPD arthropathy. Scalloping of the distal anterior femoral cortex at the level of the superior patella is secondary to the abutment of the patella in extension position. In some cases, osteoarthritic changes can become so severe that they may resemble a neuropathic joint. In the wrist, chondrocalcinosis is frequently identified in the triangular fibrocartilage and/or the hyaline cartilage. This may lead to the disruption of the scapholunate ligament resulting in instability and scapholunate advance collapse. Synovial and capsular mineralization are often observed ion the MCP joints. CPPD arthropathy in the hands is often confined to the MCP joints, while the interphalangeal joints are spared. Osteoarthritic changes of CPPD arthropathy of the hands have previously been described as “in the wrong distribution for primary osteoarthritis”.^3,10,19 Subchondral cyst formation may dominate the radiographic presentation, which is also suggestive of CPPD arthropathy.

In the hip, CPPD arthropathy may result in uniform joint space narrowing, large subchondral cysts, and axial migration of the femoral head within the acetabulum, in addition to chondrocalcinosis and other osteoarthritis related degenerative changes. Sometimes, bone collapse, destruction and fragmentation can be seen resembling neuropathic joint.

In 2023, a consensus based radiographic definition of chondrocalcinosis specific to CPPD was published ³⁸ stating linear or punctate opacities in the region of fibro or hyaline cartilage, or the synovial membrane or capsule, or within tendon or enthesis that are distinct from denser nummular radiopaque deposits due to BCP deposition. ³⁸ This radiographic definition was reported to have high reliability against histology with a 92% specificity, but only 54% sensitivity. ³⁹ Of note, to our knowledge, there is no reported evidence of BCP being identified in areas of radiographically detected chondrocalcinosis.

As mentioned above, lack of radiographic chondrocalcinosis should not exclude the diagnosis of CPPD, partly because radiography is a projectional modality and the superimposition of different structures may impede the detection of the calcium crystals.^10,39 Additionally, radiographs may provide important information that can assist in excluding other differential diagnoses (Figures 1–3).

Ultrasound:

The use of ultrasound in the diagnosis and detection of CPPD deposits has considerably risen due its low cost and wide availability. Ultrasound is particularly popular among rheumatologists and often used during the rheumatology clinic visits. ⁴⁰ Ultrasound is more sensitive, but slightly less specific than conventional radiography for the diagnosis of CPP deposits, though both techniques show excellent accuracy and are regarded as complementary to each other. ⁴¹

In the 2023 consensus definition, the presence of CPPD in the fibro- and hyaline cartilage, synovial membrane, capsule and tendons has been defined as “hyperechoic deposits of variable shape and size, that remain fixed or move along with the fibrocartilage/hyaline cartilage during dynamic assessment and do not create posterior shadowing” CPP deposits in the synovial membrane could possibly result in posterior shadowing if it reaches large dimensions. ³⁸

The Outcome Measures in Rheumatology (OMERACT) Ultrasound working group developed a sonographic CPPD scoring system aimed at providing a semiquantitative assessment of CPPD burden in the hyaline cartilage, meniscus and triangular fibrocartilage. ⁴² However, it is worth noting that ultrasound limitations lie in the restricted acoustic windows in particular joints and the need for trained sonographers (Figure 2). In addition, it is worth noting that unlike urate crystals, which is thought to deposit along the surface of the cartilage, CPP crystals are thought to develop within cartilage and other structures such as meniscus. ⁴²

Computed Tomography, Dual Energy Computed Tomography, and Photon Counting Computed Tomography:

Like conventional radiography, the identification of CPPD on CT relies on the morphology and density of calcifications. However CT offers the added value of providing a mapping CPP deposits. ⁴³ A semi quantitative scoring system has been developed to this effect to measure the burden of intraarticular mineralization in the knee joint (figure 7).⁴³

Figure 7:

Sagittal computed tomography reformats of a the right knee in a 78-year-old patient with chronic knee pain prior to total arthroplasty. There are punctate mineralizations of the hyaline cartilage of the posterior third of the medial femoral condyle involving less than 75% of the cartilage region (arrowhead), corresponding to grade 2 according to the Boston University Calcium Knee Score (BUCKS). Linear mineralization of the anterior horn of the meniscus are also shown (arrow).

CT is also the preferred modality for the diagnosis and assessment of axial CPPD involvement (example, crowned dens syndrome) ⁴⁴, but less routinely used for peripheral CPPD involvement in part due to the acceptable sensitivity of other more available modalities, which come with lower or no radiation, such as conventional radiographs and ultrasound, respectively. ¹⁰

In the 2023 consensus definition, CPPD deposits on CT were defined as “Generally well-defined, linear or punctate calcification, less dense than cortical bone”, located within the fibro- or hyaline cartilage, the synovial membrane or joint capsule, or within tendons.³⁸

Dual energy CT:

The role of DECT in detection of CPPD has previously been discussed ⁴⁵ with a few publications suggesting that DECT may help distinguish CPPD from BCP deposits. ^46,47 In fact, a 2023 consensus definition of CPPD adopted a dual energy index (DEI) range of 0.016-0.036, as one of its final criteria for the definition of CPPD. While DECT can allows material decomposition based on spectral properties, there must be “sufficient” differences in their atomic number (or effective atomic numbers). However, the effective atomic numbers of CPP and BCP are very close (15.24 vs 15.86, respectively) ⁴⁸. As a result, it would not be technically feasible to differentiate CPP from BCP based X-ray based spectral decomposition. In fact, a previous study reported on a specimen of meniscal calcinosis and chondrocalcinosis using discarded tissue from a patient undergoing total knee replacement that CPPD deposits had much higher DEI (0.09 to 0.12) and more importantly higher DEI than the subchondral trabecular bone. ⁴⁸ Similarly, Dossing et al. showed that although DECT could accurately differentiate monosodium urate crystal from CPP and BCP, it could not differentiation between CPP and BCP. ⁴⁹

Photon Counting CT:

Further investigation is required to determine whether photon counting CT, with its higher spatial resolution and whole energy spectrum available, can help better distinguish between CPPD and BCP deposits. We believe that the higher resolution of photon counting CT is unlikely to overcome the strong chemical similarities of CPP and BCP, both of which contain a comparable number of calcium and phosphate atoms. ⁴⁸

The 2023 American College of Rheumatology/ European Alliance of associations for Rheumatology Classification Criteria for CPPD Disease

The 2023 ACR/EULAR criteria for CPPD were recently published with the aim of bringing a validated classification criteria for symptomatic CPPD. This will facilitate entry of patients with CPPD disease into clinical trials and observational studies.³ In this classification, the presence of crowned dens or the identification of CPP crystals in the synovial fluid of a swollen joint were considered sufficient to classify as CPPD disease. However, in absence of the latter mentioned findings, this classification established a framework including 4 clinical, 1 laboratory and 3 imaging domains. The 3 imaging domains include: (1) Radiographic OA of hand/wrist (highest score when two or more of the following criteria are met: STT joint OA without 1^st CMC joint OA; 2^nd MCP joint OA; 3^rd MCP joint OA), (2) Imaging evidence of CPPD in a symptomatic peripheral joint (positive score only if CPPD is identified on either X-ray, ultrasound or dual energy CT), and (3) Number of peripheral joints with evidence of CPPD on imaging regardless of symptoms (highest score attributed if number is 4 or greater). ³ The imaging features used in this definition were developed in parallel with a previously published consensus definition from an international multidisciplinary working group. ³⁸

Management of CPPD arthropathy:

In vitro studies showed that CPP crystals can be solubilized by magnesium along with inhibition of their growth ⁵⁰. However, when magnesium supplementation was investigated in a double-blind, randomized controlled trial including 38 patients, the extent of radiographic chondrocalcinosis did not change after 6 months of treatment, although the results were promising with regards to pain relief and inflammatory symptoms. ⁵¹ These results were not confirmed in a large clinical trial. Another pharmacologic anticrystal option is probenecid, which may prevent CPP formation by lowering the free phosphate levels ⁵⁰. A phase 1 clinical trial for probenecid (NCT02243631) was not completed. In the absence of an effective treatment aiming to dissolve CPP crystals, the only remaining options are aimed at controlling pain and inflammation. ⁵²

The in-vitro demonstration that CPP crystals can activate the NLRP3 inflammasome, and therefore the production of IL-1 (and strong induction of IL-6 expression by monocytes/macrophages), has led to the consideration of using biologics that inhibit IL-1 and IL-6 for the treatment of refractory patients.⁵³ A double-blind clinical trial comparing an IL-1 receptor antagonist (anakinra) to prednisone was underpowered because of low recruitment (n=15) and showed similar effectiveness of both drugs to relieve pain in acute CPP-crystal arthritis. ⁵⁴ A small open label study of (Tocilizumab) in 11 consecutive patients with CPP arthritis found global improvement of disease among all 11 patients after 3 months of treatment. ⁵⁵

In an unblinded randomized controlled trial comparing oral colchicine to prednisone in acute CPP-crystal arthritis⁵⁶, the treatment response for both colchicine and prednisone was equivalent at 24 h of treatment. However, approximately 1 in 5 patients treated with colchicine had mild diarrhea, while prednisone was generally well tolerated. The authors advocated for the first-line use of 30 mg prednisone daily in acute CPP-crystal arthritis.⁵⁶ The intra-articular injection of corticosteroids can be considered in patients with monoarticular involvement once the possibility of septic arthritis is ruled out.¹⁰ Both Methotrexate and hydroxychloroquine have been tried in chronic CPPD arthritis, but their efficacy has not been confirmed, ^57–59 despite a small study of 10 patients that found encouraging results for methotrexate.⁶⁰

Summary:

Imaging plays a central role in the diagnosis and differential diagnosis of CPPD disease. The development of scoring systems assessing the burden of intraarticular mineralization, using both CT and ultrasound, is an important development for CPPD research. Differentiation between different types of calcium crystals using clinical imaging (ie DECT) remains elusive. The management continues to rely on inflammation control. Imaging will play an important role in the clinical research agenda of CPPD disease.