Early and accurate diagnosis is essential to allow adequate treatment of CPPD. After EULAR had agreed in 2011 that CPPD ‘should be the umbrella term that includes acute CPP crystal arthritis, OA with CPPD and chronic CPP crystal inflammatory arthritis’, chondrocalcinosis was defined as cartilage calcification most commonly due to CPPD and detected by imaging or histological examination [2]. Consequently, CPPD disease was diagnosed based on clinical signs and symptoms in combination with CPP crystals within leucocytes in synovial fluid samples or typical signs of chondrocalcinosis in conventional X-rays of joints not necessarily restricted to those clinically involved [8].

Only recently were classification criteria reported by ACR and EULAR, which weighed the different signs and symptoms of CPPD disease to increase the specificity of the classification [7]. These new criteria should be applied only if the patient ever had at least one episode of joint pain, swelling, or tenderness, and after exclusion of alternate conditions including rheumatoid arthritis, gout, psoriatic arthritis, and OA, which are less likely to explain all symptoms. A patient can immediately be classified as having CPPD disease in case of a crowned dens syndrome or a synovial fluid analysis demonstrating CPP crystals in a joint with swelling, tenderness or pain. Otherwise, a patient is classified as CPPD if the sum of specific weighted items (Table 1) exceeds 56 points. Imaging of at least one symptomatic joint is required by conventional radiography (CR), US, computerized tomography (CT), or dual-energy CT (DECT).

Typical signs and symptoms ever present during a patient’s lifetime must be considered for diagnosis of CPPD disease. The rapid development of severe joint pain, swelling and tenderness that reaches its maximum within 6–24 h, especially with overlying erythema, is highly suggestive of acute crystal inflammation, though unspecific for acute CPP crystal arthritis.

After the exclusion of more probable diagnoses, imaging of a crowned dens syndrome or synovial fluid analysis demonstrating CPP crystals in a peripheral joint with swelling, tenderness or pain can lead to a rapid diagnosis of CPPD. As CPPD disease has a predilection for knee and wrist joints, several differential diagnoses have to be considered, like gout, psoriatic arthritis and rheumatoid arthritis of the elderly. Gout, as the primary differential diagnosis of acute CPPD arthritis, classically involves joints in the feet, especially the first MTP joints. Besides, OA is common in CPPD disease, with a modestly increased rate of radiographic OA in those images with chondrocalcinosis (relative risk = 1.52) [10]. However, the proportion of radiographic OA potentially attributable to CPPD was only 4.4% [10].

As acute CPPD arthritis and sepsis may coexist, microbiological investigation should be performed as soon as infection is suspected, even if CPPD is diagnosed.

Ageing is the most prominent risk factor for CPPD disease. Another risk factor is a history of joint injury, which may predispose to CPPD disease. In a retrospective cohort study, the risk of CPPD disease in knees was described to be five times higher after meniscectomy than in the contralateral unoperated knees without surgery [11].

Besides, risk factors for CPPD include OA and metabolic conditions such as primary hyperparathyroidism, hemochromatosis, hypophosphatasia, and hypomagnesemia [2]. Also, chronic intestinal failure may be more frequent in CPPD disease of the elderly by 13.5-fold, and the use of diuretics may be a risk factor for CPPD disease by medication-induced hypomagnesemia [12]. All these risk factors should be assessed and discussed with the patients at the time of first diagnosis of CPPD disease.

In clinical practice, genetic predisposition with familial forms is rare. Familial predisposition should mainly be considered in younger patients under the age of 55 years if there is polyarticular CPPD arthritis [2]. The HFE gene mutations seem to be associated with the polyarticular disease phenotype [8] with a 6.5-fold higher frequency of CPPD in hip joints of heterozygotes for C282Y and a 4.7-fold higher risk of CPPD in hip or knee joints of patients aged < 65 years who are homozygotes for H63D [13]. Mutations in the human ANK gene (ANKH) have been shown in patients with familial CPPD, which may help to understand the aetiology of apparent sporadic CPPD [14]. Inorganic phosphate and pyrophosphate regulate the formation of CPP or hydroxyapatite crystals. The discovery of ANKH mutations in familial CPPD disease confirmed the importance of phosphate/pyrophosphate homeostasis in CPPD, with ANKH being a regulator of inorganic pyrophosphate transport [15].

Once formed, CPP crystals cannot be dissolved, and at present, there is no specific treatment to eliminate CPPD from the tissue. Therefore, the main goals of CPPD therapy are to control the acute and chronic inflammatory reactions and prevent further episodes [4].

As confirmed by a recent review, the management of CPPD disease is still based on empirical evidence and strategies derived from gout treatment [16]. A few well-designed clinical trials evaluate the treatment of CPPD disease. So far, magnesium carbonate, hydroxychloroquine and methotrexate have been assessed in randomized, double-blind controlled trials [16]. Only hydroxychloroquine and magnesium carbonate have shown some efficacy and reduction of pain intensity. Even non-steroidal antirheumatic drugs and colchicine have not been evaluated in well-designed studies. The interleukin-1 (IL-1) receptor antagonist anakinra and the IL-6 receptor-blocking antibody tocilizumab appear promising but have not been adequately assessed [17]. Also, intramuscular and intra-articular glucocorticoids and adrenocorticotropic hormones (ACTH) may help, but direct comparisons between studies were impossible due to heterogenicity. Consequently, further trials are warranted to provide evidence for clear management recommendations. Without such studies, the costs of hospitalizations caused by CPPD arthritis may further increase with the ageing population [18].

Outcome parameters provide insights into the functional status of patients and their perception of CPPD disease activity and allow comparisons of these aspects with other diseases. As for other rheumatic diseases, the role of outcome parameters should be evaluated for CPPD disease to assess and monitor disease activity during follow-up. However, there is still no internationally agreed recommendation on the optimal outcome parameters for CPPD disease.

First initiatives use outcome parameters already validated for other rheumatic diseases. For example, the pain visual analogue scale (VAS) scores during a flare of CPPD disease showed pain levels comparable with gout, although the Routine Assessment of Patient Index Data 3 (RAPID-3) scores were better in CPPD disease than in gout and similar to OA [19]. Patients with CPPD disease had worse Western Ontario and McMaster Universities Arthritis Index (WOMAC) stiffness scores than patients with mild OA but better WOMAC function scores than patients with severe OA [19].

From the laboratory perspective, C-reactive protein levels and erythrocyte sedimentation rate are undoubtedly helpful in assessing systemic inflammation. Besides, low serum magnesium and high ferritin levels were associated with CPP arthritis and may be beneficial in monitoring patients with CPPD disease [8].

For the patients, remission or low disease activity is the primary goal of any disease management, with a low rate of disease- and management-related complications. However, in line with the lack of well-designed interventional studies, patients with CPPD report more significant unmet treatment needs than patients with gout (P = 0.04) [19].

Education about CPPD disease and its treatment options is undoubtedly a big issue for patients with CPPD disease, which the treating physicians and nurses specialized in the care of inflammatory arthritis should provide, as proposed by EULAR [20]. Besides patient education, nurses will be able to focus specifically on timely access to care, efficiency of care, psychosocial support, and the promotion of self-management with early recognition of adverse effects.

A list of quality standards is proposed by the authors which was adapted from the standards developed for axial spondyloarthritis by the Assessment of SpondyloArthritis International Society (ASAS) (Table 2) [24]. Quality standards should be assessed regularly to improve healthcare quality, preferably using an appropriate software tool for the physicians’ documentation.

Concerning the few clinical trials to guide the management of CPPD disease, patients’ education is essential both on the disease and possible disease and drug-induced complications. Rapid access to care is essential, especially in case of a flare or a suspected drug-related adverse event. More well-designed studies are warranted to increase the levels of evidence for pharmaceutical approaches and efficient treatment strategies. At present, patients have to be informed about the low level of evidence from well-designed clinical studies.

Because of the lack of long-term studies assessing the efficacy and safety of emerging therapies and treatment strategies, and the complexity of CPPD arthritis, patients will certainly benefit from a multidisciplinary approach. Therefore the collaboration of rheumatologists, radiologists, physiotherapists, and other healthcare professionals in an integrated care management program for CPPD patients should be established.