Calcium pyrophosphate deposition disease (CPPD) refers to inflammatory arthritis that occurs predominantly in older adults and is caused by calcium pyrophosphate (CPP) crystals. In the articular cartilage pericellular matrix, pyrophosphate from extracellular ATP complexes with calcium to produce CPP crystals, which then stimulate inflammatory cytokines and mechanical cartilage degradation. The prevalence of CPPD, based on chondrocalcinosis found on imaging (asymptomatic CPPD) in European adults, could be between 4–7%, but this is likely an underestimate [1, 2]. Acute CPP crystal arthritis presents in one or multiple joints such as the knee or wrist as pain, erythema, and edema. It is often associated with constitutional symptoms and elevated inflammatory markers. Due to the similarity of its presentation to gout, it was formerly referred to as pseudogout. On the contrary, chronic CPP crystal arthritis presents as a polyarthritis that is like rheumatoid arthritis in distribution [1, 3]. Diagnosis of CPPD is aided by the presence of rhomboid positively birefringent crystals on polarized microscopy of synovial fluid and often chondrocalcinosis on imaging studies. Recently, there have been strides made in the development of classification criteria by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) and outcome domains that will likely greatly improve research in CPPD, as well as limited management recommendations [4–6]. However, the evidence for management recommendations continues to be scarce. Available treatment strategies for CPPD remain untargeted and many of the existing treatments are repurposed from gout, due to connections in pathophysiology. This review provides background on available therapies for CPPD, summarizes and interprets evidence up until this point, and suggests future directions for research. The published EULAR recommendations for treatment published in 2011 will serve as a frame for our discussion with reviews on other treatment options published since then [6].

The types of CPPD according to EULAR criteria which align with treatment options include (1) asymptomatic CPPD; (2) acute CPP crystal arthritis; (3) chronic CPP crystal arthritis; and (4) osteoarthritis (OA) with CPPD [7, 8]. For asymptomatic radiographic findings of CPPD, sometimes described as chondrocalcinosis, treatment is not necessary. Mere chondrocalcinosis clinically differs from other forms of CPP crystal arthritis and is associated with seronegative rheumatoid arthritis [3]. For acute CPP crystal arthritis, treatments focus on addressing symptoms secondary to the crystal-induced inflammation by using treatment strategies common to the ones for gout flares such as intra-articular glucocorticoid, non-steroidal anti-inflammatories (NSAIDs), colchicine, or systemic glucocorticoid rather than addressing crystal formation itself. Although randomized controlled studies on all of these options for CPPD have been scarce, this review highlights the progress that has been made with new studies including a recently published controlled trial in which colchicine was compared to oral prednisone and a study that compared loading dose colchicine to non-loading dose for acute CPP crystal arthritis [9, 10]. For chronic CPP crystal arthritis, which requires more long-term anti-inflammatory management, low-dose NSAIDs with gastroprotection or low-dose colchicine were recommended as initial therapy by EULAR, but low-dose glucocorticoids, methotrexate, hydroxychloroquine, and biologics have been investigated for chronic CPP crystal arthritis with data mixed regarding treatment response. Although biologics such as anakinra or tocilizumab are not mentioned by the recent EULAR recommendations, we highlight a study by Damart et al. [11] which shows biologics are currently used off-label in refractory cases of CPP crystal arthritis or cases in which all of the prior treatments are contraindicated or ineffective, drawing on evidence from one randomized controlled trial and other small studies [12, 13]. There are also other forms of CPPD such as “tophaceous pseudogout” or tumoral CPPD in which there is a deposit of CPP crystal and this can be treated surgically [14]. For patients with OA and CPPD, EULAR recommends maintaining the same therapies and objectives as if they had isolated OA [6]. Overall, in this review, we discuss updates to evidence published after the 2011 EULAR guidelines regarding all types of CPPD. We emphasize treatment challenges in the setting of comorbidities and the importance of addressing underlying conditions or potentially causative medications. Finally, we discuss the potential of future targeted treatments such as histone-deacetylase inhibitors (HDACis), which are in the early stages of research.

EULAR recommendations for CPPD are subdivided into asymptomatic CPPD, acute CPP crystal arthritis, chronic CPP crystal arthritis, and OA with CPPD. The objective in the treatment of acute CPP crystal arthritis is oriented towards rapid relief in contrast to the treatment of refractory or chronic CPP crystal arthritis which is more focused on prevention. While some treatments such as NSAIDs, colchicine, systemic glucocorticoids, and biologics are part of both acute and chronic management, intra-articular injection tends to belong to acute management and disease-modifying medications like methotrexate and hydroxychloroquine are more often used in chronic management (see Figure 1) [6]. In 2011, EULAR published recommendations that guide therapy for different manifestations of CPPD (Figure 2) [6]. Since then, additional studies have been published, which have expanded evidence for the treatment approach (see Table 1).

For the treatment of chronic CPP arthritis, the 2011 EULAR guidelines recommend in order of preference the following systemic therapies: low-dose oral non-steroidal anti-inflammatory drugs with gastroprotective treatment and/or low-dose colchicine 0.5–1.0 mg daily (if no contraindications), low-dose glucocorticoid, methotrexate, and hydroxychloroquine [6]. A retrospective cohort study by Damart et al. [11] describing 194 treatments in 129 patients included 4 main off-label treatments used in chronic CPP crystal arthritis or recurrent/refractory acute CPP crystal arthritis, which were colchicine, methotrexate, anakinra, and tocilizumab, listed in descending order of frequency, as well as lesser used treatments (long-term glucocorticoids, hydroxychloroquine, canakinumab, and sarilumab). This study was impactful because it characterized the heterogeneity of treatments currently being prescribed for chronic CPP crystal arthritis including off-label biologics. Colchicine 0.5–1.0 mg dosed 4 times daily was the most used and usually first line, with lasting efficacy in 33–50% of patients. Hydroxychloroquine was used sparingly overall as a first line. Methotrexate was second-most utilized, most often as a second line after colchicine failure and often co-prescribed with colchicine or glucocorticoids. Anakinra and tocilizumab were second or third-line and sometimes in combination with methotrexate or colchicine. Canakinumab and sarilumab were exclusively used as 3rd or 4th line. Glucocorticoids were used as an add-on therapy. Adverse events led to discontinuation most often in anakinra (31.8% due to serious infections or injection site reactions), followed by tocilizumab (20% due to effects similar to those of anakinra), then colchicine (14.1% due to diarrhea), then methotrexate (4.3%), and none of hydroxychloroquine discontinuations. Rather, the more commonly cited reasons for discontinuing most of these drugs were loss to follow-up or inefficacy, with only 34.5% of treatments still ongoing at 24 months. Median on-drug survival was highest for methotrexate (15.3 months) followed by tocilizumab (12.2 months), then anakinra (10.2 months), then colchicine (9.9 months), with 24-month retention being the highest for methotrexate and significantly higher for tocilizumab compared to anakinra. Overall, in 63.9% of follow-up visits, treatment response was assessed as good on the Likert scale (> 2/4). All outcome measures improved over time (patient global assessment, patient-reported disability level, number of episodes, and physician assessment of disease activity) for those who continued treatment [11].

In some cases of CPPD in which there is OA or deposition of tophi present, surgery may be required. Treatment of CPPD superimposed on OA has been viewed as a therapeutic challenge and it has previously been speculated whether patients with CPPD and OA have worse outcomes following joint replacement compared to patients with only OA. Results of a systematic review by Moret et al. [35] suggest that chondrocalcinosis does not significantly influence postoperative functionality after joint replacement for OA. However, the level of evidence (LOE) of the study was low (level IV) and there is a lack of randomized controlled trials to officially guide the approach to CPPD superimposed on OA. Expert opinion from EULAR as of 2011 is to treat patients with OA and CPPD as if they have OA without CPPD [4, 6].

Unlike the common articular locations for CPPD such as the knee and wrist, “Tophaceous pseudogout” is a variety of CPPD that causes deposition of CPP crystals in the TMJ, which may require surgical treatment. In one case report, the patient with tophaceous pseudogout was treated with eminectomy, condylectomy, and total TMJ reconstruction [14]. The authors of the case report made recommendations for the surgical treatment of advanced tophaceous pseudogout: (1) include tophaceous pseudogout in the differential diagnosis of lesions mimicking neoplastic processes of the TMJ or infratemporal fossa; (2) use of image-guided fine needle aspiration for tissue sampling to aid in pre-operative diagnosis; (3) consider pre-surgical embolization when dealing with a large mass in the infratemporal or peri-articular TMJ region; (4) intra-operative navigation assistance in extensive lesions may be beneficial; (5) consider single-staged alloplastic reconstruction using stock versus custom-fabricated TMJ prosthesis after resection of advanced lesions; (6) continue long-term follow up to rule out recurrence, and (7) rheumatologic referral may be indicated for thorough workup of other commonly involved joints [14]. Other case reports similarly described the reconstruction of the TMJ [36, 37]. CPP masses can occur in other areas, usually associated with repeated trauma. These might also need to be approached surgically.

The older population in which CPPD is prevalent also has a high prevalence of other conditions. As previously mentioned, CPPD superimposed on OA is a treatment challenge but can be treated as if the patient has only OA, keeping in mind there is limited data on this [6]. Treatments for OA include acetaminophen, weight loss, physical therapy, limiting the progression of joint damage, and/or joint replacement. In patients unresponsive to these therapies, NSAIDs and opioids can be used with caution unless contraindicated.

As previously discussed, in patients with CPPD and renal disease, colchicine and NSAID use are contraindicated and patients must resort to oral glucocorticoids, parenteral glucocorticoids, ACTH, or other disease-modifying agents.

Although CPPD can be idiopathic, some cases of CPPD may be associated with underlying disorders such as primary and secondary hyperparathyroidism, hypomagnesemia, hypophosphatasia, hemochromatosis, Gitelman syndrome, previous joint surgery, metabolic risk factors such as obesity and hypertension, and chronic gout [38]. It has been suggested that sudden fluctuations in calcium, such as in the post-parathyroidectomy period, can also instigate CPPD thus it has been suggested to supplement calcium following the procedure [39]. Magnesium carbonate supplementation was studied in CPPD in one small randomized controlled trial [40]. Additionally, mutations in certain genetic loci affecting the ankylosis human (ANKH) protein are associated with familial CPPD, and potential future treatment for this is discussed in another paragraph. Investigating underlying causes in patients, especially those presenting under the age of 60, is particularly important and addressing these underlying conditions should not be underestimated as a treatment option [1]. EULAR cites that treatment of underlying conditions with a LOE of Ib is a higher LOE than most other recommendations [6].

Medications may also underlie some CPPD attacks. Case reports have identified certain medications such as chemotherapies and bisphosphonates potentially associated with CPPD that may be worth avoiding in patients with CPPD. For example, Kim et al. [41] reported recurrent pseudogout a week to 10 days following infusions of nivolumab, an immune checkpoint inhibitor. There have also been reports of CPP crystal arthritis with alendronate, pamidronate, and etidronate [42–44]. Interestingly, a patient that received melanoma-associated antigen A4 (MAGE-A4) directed T-cell receptor (TCR) engineered T cells for fallopian tube cancer developed cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and acute left knee arthritis that was determined to be crystal-proven CPP crystal arthritis. The patient was administered tocilizumab and her pseudogout resolved [45].

A review by Parperis et al. [29] discussed other treatment strategies that have been investigated but not used widely, including radiation synovectomy (destruction of the synovial membrane), laser irradiation, and glycosaminoglycan or hyaluronic acid injections [46, 47]. Although these treatments reported promising results in the small and limited studies, they were not followed up by additional studies.

There is a clear need for randomized controlled trials to determine the most effective therapies for CPP crystal arthritis. Additionally, studies investigating mechanisms of crystal formation and crystal-induced inflammation are needed to identify future therapies. Recent studies linking extracellular phosphate to CPP crystal arthritis suggest that there are mechanisms of inflammation in this disease that are not yet fully understood. Specifically, researchers identified regulator proteins ectonucleotide pyrophosphatase 1 (ENPP1), ANKH, and non-specific alkaline phosphatase (TNAP) that affect levels of extracellular phosphate [48]. HDACis trichostatin A (TSA) and vorinostat (SAHA), which could be potential targeted CPPD therapies in the future, change the expression of these regulator proteins, thus lowering levels of extracellular phosphate and CPP in human primary cultured articular chondrocytes [49]. Currently, most of the clinical indications for HDACis such as SAHA are neoplastic conditions. There are no ongoing clinical trials with HDACis for CPPD in the United States. Theoretically, any substance that could decrease levels of free inorganic phosphate could decrease CPP crystals [50]. Probenecid has been considered as an option to lower free phosphate and studies have looked at nucleoside analogues, but these ideas remain in the basic research phase [51]. Investigating mechanisms of other causes of CPPD could help further elucidate whether addressing those causes would be therapeutic (for example, understanding hypomagnesemia’s role and the efficacy of magnesium supplementation). Additionally, further research could be based on the role of solubility of CPP crystals and the role of supersaturation of crystals leading to crystal deposits. It is notable that bisphosphonates, despite being inhibitors of other pathologic calcification processes, are associated with cases of CPP crystal arthritis [42]. Investigating the mechanism of these processes could lead to a better understanding of the disease and ways to treat it.

With the development and publication of the CPPD classification criteria [4], standardization of patients included in CPPD studies should improve and this could lead to more predictable outcomes of intervention studies in CPPD. In addition, increased recognition of CPPD as a common and disabling arthropathy should increase interest in studies in this area. So far, therapeutic studies in CPPD have been met with limited success. Limited data, extrapolation from gout, and expert opinion suggest that there are several standard therapies in the research of CPPD treatment. For CPP crystal arthritis, local ice application, intra-articular glucocorticoid injection, and joint aspiration for mono- or oligo-articular attacks, NSAIDs, colchicine, oral or parenteral glucocorticoids, disease-modifying medications, and off-label biologicals can be effective treatments for CPPD. Similar to glucocorticoids, biologics provide another option to patients with contraindications or lack of response to NSAIDs and colchicine. However, many of these treatments are used without the support of randomized controlled trials. Certain comorbidities, especially renal disease, may guide the choice of therapy to a degree. Although CPPD with OA may seem like a treatment challenge, expert opinion suggests OA should be treated as usual in patients with CPPD, with orthopedic surgery being an option, but this remains controversial due to the paucity of data [6]. With these therapies in mind, it should be emphasized that there may be underlying causes of CPPD that should be addressed, such as the genetic basis which is under investigation [48]. Finally, there is potential for targeted treatment of CPPD in the future but there are no trials or studies known at this time to be ongoing, which is an opportunity for future research. Although there is now at least one randomized controlled trial on colchicine and anakinra, there is a need to conduct more randomized studies on both old and new CPPD therapies.