Introduction

Calcium pyrophosphate deposition (CPPD) disease is a common symptomatic arthritis characterised by the deposition of calcium pyrophosphate (CPP) crystals.1 The prevalence of radiographic chondrocalcinosis, often used as a proxy for CPPD disease, ranges from 4% to≥10% among older adults, though the prevalence of symptomatic CPPD disease remains incompletely defined.2–5 Research in CPPD disease has lagged behind other types of arthritis due, in part, to absence of validated classification criteria. Variable reliance on synovial fluid (SF) polarised light microscopy for diagnosis, and a diversity of presentations that include acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, osteoarthritis with CPPD, and crowned dens syndrome (CDS) makes it hard to compare between studies.1 The only published diagnostic criteria for CPPD disease were developed in the 1960s by Ryan and McCarty.6 For definite diagnosis, they required evidence of crystals based on the presence of both typical calcification on radiography and findings consistent with CPP crystals on SF polarised light microscopy, or alternatively by research laboratory techniques that are not widely available.7 These diagnostic criteria have since been recognised to be problematic, because conventional radiography (CR) has low sensitivity for CPPD,8–10 advanced imaging modalities such as ultrasonography and dual-energy computed tomography were not available in the 1960s, and SF analysis for CPP crystals has a high false-negative rate and high interobserver variability.11–14

To develop validated classification criteria in order to facilitate research in CPPD disease, an international collaborative working group was convened with the support of the American College of Rheumatology (ACR) and EULAR. The goal was to develop a framework enabling investigators to identify people with CPPD disease for entry into research studies, including clinical trials and observational studies. Such criteria are not intended to capture all possible cases, but rather to capture the majority of people with symptomatic CPPD disease.

RESULTSPatient profiles and cohorts

Rheumatologists from 13 sites in 6 countries submitted 418 patient profiles, forming the derivation cohort: 190 definite cases, 148 definite mimickers, and 80 uncertain (62 rated −1, 0, or+1 likelihood of CPPD disease by the submitting clinician, and 18 judged uncertain by two adjudicators). Primary diagnoses among the 148 definite mimickers included gout (n=43), rheumatoid arthritis (RA; n=38), osteoarthritis (n=27), psoriatic arthritis (PsA; n=12), other inflammatory arthritis (n=11), polymyalgia rheumatica (n=6), others (n=5), and not specified (n=6). Rheumatologists from 12 sites in 6 countries submitted 617 patient profiles, forming the validation cohort: 251 definite cases, 162 definite mimickers, and 204 uncertain. Among the 162 definite mimickers, primary diagnoses were gout (n=45), RA (n=40), osteoarthritis (n=21), PsA (n=19), other inflammatory arthritis (n=19), septic arthritis (n=5), polymyalgia rheumatica (n=1), and others (n=12) (table 1) summarises the demographic and clinical characteristics of the derivation and validation cohorts.

Table 1

Characteristics of the subjects in the derivation and validation cohorts by patient profile

The CEC comprised 22 experts (20 rheumatologists, 1 radiologist, and one methodologist). Thirteen members were from Europe, 6 from the US, and three from New Zealand; 41% were women. Results of the rank-ordering exercise by individual CEC members are presented in online supplemental figure S1. The CEC identified key factors important for distinguishing CPPD disease from mimickers by reviewing ranking results and ORs (see online supplemental tables S2–S9). These key factors were as follows: presence of CPP crystals in SF (or in biopsy tissue), presence of CDS, symptom onset after age 60 years, persistent inflammatory arthritis, typical episode(s) of acute inflammatory arthritis defined by acute onset or acute worsening of joint pain with joint swelling and/or warmth that resolves irrespective of treatment, location of typical episode(s) (knee, wrist, first MTP joint, other peripheral joints), metabolic conditions that predispose to CPPD (hereditary hemochromatosis, primary hyperparathyroidism, hypomagnesemia, Gitelman syndrome, hypophosphatasia, or familial history of CPPD disease), radiographic osteoarthritis of specific hand joints (scaphotrapeziotrapezoidal joint without first carpometacarpal joint involvement, radiocarpal joint, second metacarpophalangeal (MCP) joint, third MCP joint), and imaging evidence of CPPD (linear or punctate calcification in the hyaline cartilage or fibrocartilage) in peripheral joints. Imaging item definitions and example images were developed in parallel to this endeavour and have been previously published.21 Onset of symptoms after 60 years of age was included as a domain even though it was not associated with CPPD disease in the case-mimicker analysis. This decision was based on expert opinion and demographic characteristics of patients with CPPD disease in the published literature. Additionally, the lack of association with age was thought to be due to recruitment of potential mimickers who were older adults, that is, the age group in which CPPD disease is a possibility.

Entry, exclusion, and sufficient criteria

The CPPD disease classification framework must be applied in the following sequence (figure 2): (1) entry criteria must be fulfilled; (2) exclusion criteria must be absent; (3) sufficient criteria are evaluated (present vs absent); and (4) if sufficient criteria are absent, then proceed with scoring of domains.

Figure 2

Conceptual schematic for applying the CPPD disease classification criteria.

CEC members agreed that to be classified as CPPD disease, an individual must have had at least one episode of joint pain, swelling, or tenderness at a peripheral joint or axial joint (entry criteria). Symptomatic CPPD disease is required for classification since the intention of classification criteria is to enable enrollment into clinical trials that would focus on symptomatic individuals.

Exclusion criteria were intended to identify individuals in whom all musculoskeletal symptoms potentially attributable to CPPD disease were more likely explained by an alternate condition such as RA, gout, PsA, or osteoarthritis, to whom the classification criteria should not be further applied. The CEC noted that symptom attribution can be difficult, and if at least some symptoms are attributable to CPPD disease, then the classification criteria can be applied. It was also agreed that the classification criteria would apply to CPPD disease as a whole, and development of separate classification criteria for each clinical presentation would not be attempted within this endeavour.

Two sufficient criteria were agreed on: CDS and SF analysis demonstrating CPP crystals in a joint with swelling, tenderness, or pain (any quantity of intra- and/or extracellular crystals). In the initial MCDA exercise, presence of SF CPP crystals and CDS accounted for>40% of the weighting, and cases with SF CPP crystals or CDS had consistently been ranked most likely to have CPPD disease in the ranking exercise.

Sufficient criteria are also met if CPP crystals are demonstrated on histopathologic assessment of joint tissue, provided the patient does not meet exclusion criteria. For instance, articular cartilage CPPD disease in patients with end-stage osteoarthritis cannot be used to classify the patient as having CPPD disease when all symptoms are better explained by osteoarthritis.26

Domains and categories

The final framework included four clinical, 1 laboratory, and three imaging domains (table 2). The levels within each domain are scored based on a patient’s disease experience to date, such that if a higher and a lower weighted level were fulfilled at different points in time, the higher one is scored.

Table 2

ACR/EULAR classification criteria for CPPD disease

Assigning relative weights to domains and categories

All weights were initially zero or positive. Domain C (sites of typical episodes of inflammatory arthritis), domain E (SF CPP crystal analysis), and domain G (imaging evidence of CPPD in a symptomatic joint) were re-zeroed such that the level least likely to be present in a person with CPPD disease was assigned negative weight to maintain face validity (for details see online supplemental results and online supplemental table S10).

In domain G (imaging of a symptomatic joint), advanced imaging modalities were initially considered separately from CR; however, item weights differed by<1% so advanced imaging and CR were combined. Item weights, re-zeroing, merging of levels, and rounding-off are reported in online supplemental table S10.

The final ACR/EULAR CPPD disease classification criteria and weights are presented in table 2. The CEC agreed that imaging of at least one symptomatic peripheral joint is required for scoring when sufficient criteria are not fulfilled, given the important role of imaging when considering the likelihood of CPPD disease. A web-based calculator is accessible at https://bblinks.live/acr-classification-criteria-for-cppd-disease.

A plot of the percent agreement among Steering Committee members voting ‘yes’ for classifying patients as having CPPD disease for enrollment in a research study vs the final additive classification criteria score suggested the feasibility of a score threshold between 53 and 57 (figure 3).

Figure 3

Plot of percent agreement of Steering Committee members for classifying patient profiles as CPPD disease for inclusion in a research study (n=8 participating Steering Committee members). The patient profiles were given pseudonyms.

Classification criteria performance in the derivation and validation cohorts

Among the 190 definite cases in the derivation cohort, 130 fulfilled sufficient criteria and were ineligible for scoring. The classification criteria score separated the remaining 60 definite cases from 148 mimickers with an area under the curve (AUC) of 0.95 (95% CI 0.93 to 0.98) (figure 4). A threshold score of>56 was chosen, as this threshold maximised specificity at 87.9% while retaining a high sensitivity of 92.2% (see online supplemental table S11). When the entire classification criteria system (ie, entry, exclusion, sufficient, and scored criteria) was applied to all definite cases and definite mimickers in the derivation cohort, the threshold score of>56 had a specificity of 87.9% and sensitivity of 97.8%.

Figure 4

Receiver operating characteristic (ROC) curves in the derivation cohort (left) and validation cohort (right) for the patients who were eligible to be scored for classification of CPPD disease. In the derivation cohort, data for 60 definite cases and 148 definite mimickers were included. In the validation cohort, data for 65 definite cases and 162 definite mimickers were included.

The face validity of a threshold score of>56 was assessed. Examples of patient profiles with scores just below the threshold included the following: (1) a single typical episode of acute inflammatory arthritis involving the wrist, with symptom onset after age 60 years and chondrocalcinosis only at that wrist (score 56); (2) a single typical episode of acute inflammatory arthritis involving the knee, with symptom onset at age<60 years and chondrocalcinosis in that knee only (score 53); and (3) joint pain without inflammatory arthritis with symptom onset at age>60 years, presence of osteoarthritis in the radiocarpal joints bilaterally and second MCP joints, and chondrocalcinosis in the wrists bilaterally (score 50). The CEC reviewed these cases and agreed that they should not be classified as CPPD disease, because sufficient clinical uncertainty existed.

Among the 251 definite cases in the validation cohort, 186 fulfilled sufficient criteria and were ineligible for scoring. The threshold score of>56 separated the remaining 65 definite cases from 162 mimickers with an AUC of 0.98 (95% CI 0.96 to 0.99) (figure 4) and had a sensitivity and specificity of 96.5% and 92.5%, respectively, in this subgroup of the validation cohort. Assessment of the entire classification criteria framework (entry, exclusion, and sufficient criteria and the threshold score of>56) among the 413 definite cases and definite mimickers in the validation cohort demonstrated a sensitivity of 99.2% and specificity of 92.5%. The percentage of patient profiles classified as CPPD disease increased with the submitting clinician’s rating of CPPD disease in both the derivation and validation cohorts (see online supplemental table S12).

Discussion

These are the first-ever validated classification criteria for CPPD disease and we believe they will facilitate future observational studies and clinical trials in CPPD disease. These classification criteria were derived and validated using established methodology relying on data from 751 patient profiles and expert consensus. The classification criteria demonstrated high sensitivity and specificity in an independent validation cohort. Presence of CDS (imaging plus clinical features) or the identification of CPP crystals in SF from a symptomatic joint were sufficient for classification as CPPD disease as long as exclusion criteria were not met (eg, another condition did not explain the entire presentation). Patients without those features can be classified by scoring the remaining imaging and clinical criteria.

Among the scored criteria, imaging features and recurrent typical episodes of acute inflammatory arthritis carried the greatest weight. This reflects consensus among the multidisciplinary CEC that imaging evidence of CPP crystal deposition and acute inflammatory arthritis are central constructs in CPPD disease when laboratory evidence of SF CPP crystals is lacking. An imaging study of at least one symptomatic joint is required in patients not meeting sufficient criteria. No additional imaging is absolutely required; however, the more peripheral joints that are imaged, the greater the potential score, as may be the case for centres in which patients’ joints are routinely imaged bilaterally. The Steering Committee considered requiring imaging of a standardised set of joints (eg, bilateral knees and wrists) when considering patients for classification, but decided against this due to concerns about practical feasibility of this approach. Requiring imaging of at least one symptomatic peripheral joint was considered a reasonable compromise that would permit widespread, more equitable application of these classification criteria in all potential CPPD disease patients internationally.

The criteria highlight the importance of imaging evidence of CPP crystal deposition, as its absence prevents classification if an individual does not meet sufficient criteria. The highest levels of 2 imaging domains account for nearly half of the weighting, comprising evidence of CPP crystals in a symptomatic joint, and evidence of CPP crystals in≥4 peripheral joints. While imaging features alone in a patient with joint pain would not be sufficient for classification, they were weighted heavily in the MCDA exercise such that they became a necessary component in the scored criteria. The CEC discussed at length the high sensitivity of ultrasound and CT, particularly in early CPPD disease, compared with CR.10 27 This higher sensitivity is reflected in negative points assigned if no evidence of CPPD disease is found on advanced imaging. Because advanced techniques demonstrate high, yet imperfect specificity for CPPD disease, the group did not reach agreement with regard to evidence of CPPD on advanced imaging as being sufficient to confer a classification of CPPD disease. Imaging evidence of CPPD on advanced imaging modalities and evidence on CR received nearly equal weight (<1% difference), given the high specificity associated with both modalities, resulting in their being grouped together and reflecting expert consensus that imaging evidence of CPPD on any modality is equally convincing.

A practical gold standard for CPPD disease does not exist in clinical settings, as SF CPP crystal positivity on polarised light microscopy is specific but has a high false-negative rate and significant interobserver variability.11–14 Challenges of CPP crystal identification include small crystal size and absent or weak positive birefringence.11 Furthermore, feasibility of CPP crystal identification may be limited by the difficulty of joint aspiration, particularly from small joints. Thus, although the CEC determined that presence of any quantity of CPP crystals in a symptomatic joint can lead to classifying an individual as having CPPD disease, requiring presence of SF CPP crystals in all cases is not practical for classification. To that end, the proposed criteria are intended to enable accurate classification of CPPD disease, regardless of whether joint aspiration was performed. Nevertheless, joint aspiration remains important to clinically diagnose CPPD disease in practice and to exclude mimicking conditions including gout and septic arthritis.

Attribution of symptoms to CPPD disease can be challenging, particularly in patients with osteoarthritis or in those with RA, as these diseases can coexist with CPPD disease and/or be misdiagnosed initially.28–30 These CPPD disease classification criteria acknowledge the frequent coexistence of CPPD disease with other rheumatic and musculoskeletal diseases (RMDs), by excluding from classification only those patients for whom all symptoms are better explained by another condition, and allowing investigators to attempt classification if they suspect that at least some symptoms are due to CPPD disease. Distinguishing between CPP crystal deposition and basic calcium phosphate deposition on imaging can be challenging, although imaging definitions for CPPD disease developed as part of this project may mitigate this issue.21

The current endeavour has strengths. First, the criteria establish the clinical picture of CPPD disease as an inflammatory arthritis among older adults, typically manifesting with acute inflammatory features (and occasionally with chronic inflammation) and a predilection for knee and wrist joints. Discussions about the threshold made clear that requiring joint inflammation provided superior specificity for CPPD disease classification while maintaining>90% sensitivity in patients who lack evidence of CDS or SF CPP crystals. Inflammatory arthritis is not absolutely required; individuals with osteoarthritis and SF CPP crystals could be classified by sufficient criteria if not all symptoms are explained by osteoarthritis. Critically, the classification criteria must be applied in the order presented in figure 2 and table 2 so that individuals whose symptoms are attributable to osteoarthritis and who have SF CPP crystals would not be classified as having CPPD disease. Second, patient profiles in the derivation and validation cohorts were collected from a large international pool, supporting generalizability of the findings. Nevertheless, further testing of the criteria in other populations would be valuable. Third, we followed well-established methodology for classification criteria development, supporting the validity of the process and final product. Fourth, the criteria allow people with CPPD disease and another RMD to be classified as having CPPD disease.

Several limitations warrant a mention. Given the absence of a pathologic gold standard for CPPD disease diagnosis, expert opinion was used to label cases and mimickers. We excluded a significant number of uncertain patient profiles from ROC analyses and sensitivity/specificity calculations, as their true case/control status could not be reliably determined. The heterogeneous nature of CPPD disease can lead to differences in clinical opinion about whether particular features are attributable to CPPD disease, reflected in the clinician’s rating of −1 to +1 for likelihood of CPPD disease and/or lack of agreement among adjudicators. Together with its heterogeneous nature, different rheumatologists’ perceptions of the clinical phenotype that may be attributed to CPPD disease vary substantially. To minimise the possibility that differences in opinion would affect threshold determination, we adopted stringent case and mimicker definitions – often requiring unequivocal evidence of CPPD disease or agreement between the submitting clinician and two experts. The inclusion of only definite cases and definite mimickers may have contributed to the classification criteria’s high sensitivity and specificity in our validation cohort. Nevertheless, the proportion of individuals classified as having CPPD disease increased progressively across the submitting clinician’s rating, including among cases deemed uncertain (rated −1, 0, or+1 by the submitting clinician), further supporting the internal validity of this approach. Even so, we recommend that the performance of these criteria be evaluated in other cohorts. Despite challenges with attribution, the CPPD disease classification criteria enable identification of a relatively homogeneous group of patients with a preponderance of evidence for CPP crystal deposition and characteristic clinical symptoms, in whom all features are not better explained by another disease. We did not address asymptomatic CPPD, since the purpose of classification criteria is to identify individuals with symptomatic disease to be included in clinical studies. The current criteria represent an endeavour to identify patients with symptomatic CPPD disease with maximal sensitivity and specificity for inclusion in prospective studies, including clinical trials and observational studies.

In conclusion, the 2023 ACR/EULAR classification criteria for CPPD disease represent the first validated criteria set for the condition, with robustly validated performance characteristics. Future studies of CPPD disease may employ these as inclusion criteria for participant screening and enrollment.