2023 ACR/EULAR Classification Criteria for Calcium Pyrophosphate Deposition Disease PDF

Arthritis & Rheumatology Vol. 0, No. 0, Month 2023, pp 1–11 DOI 10.1002/art.42619 © 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. The 2023 ACR/EULAR Classiﬁcation Criteria for Calcium Pyrophosphate Deposition Disease Abhishek Abhishek,1* Sara K. Tedeschi,2* Tristan Pascart,3 Augustin Latourte,4 Nicola Dalbeth,5 6 1 7 8 4 Tuhina Neogi, Amy Fuller, Ann Rosenthal, Fabio Becce, Thomas Bardin, Hang Korng Ea,4 9 10 11 12 Georgios Filippou, John FitzGerald, AnnaMaria Iagnocco, Frédéric Lioté, Geraldine M. McCarthy,13 Roberta Ramonda,14 Pascal Richette,4 Francisca Sivera,15 Mariano Andres,16 Edoardo Cipolletta,17 1 18 19 20 Michael Doherty, Eliseo Pascual, Fernando Perez-Ruiz, Alexander So, Tim L. Jansen,21 Minna J. Kohler,22 Lisa K. Stamp,23 Janeth Yinh,22 Antonella Adinolﬁ,24 Uri Arad,25 Thanda Aung,26 Eva Benillouche,27 Alessandra Bortoluzzi,28 Jonathan Dau,29 Ernest Maningding,30 Meika A. Fang,10 Fabiana A. Figus,31 17 Emilio Filippucci, Janine Haslett,23 Matthijs Janssen,32 Marian Kaldas,33 Maryann Kimoto,33 Kelly Leamy,34 Geraldine M Navarro,35 Piercarlo Sarzi-Puttini,36 Carlo Scirè,37 Ettore Silvagni,28 Silvia Sirotti,38 13 35 35 39 John R. Stack, Linh Truong, Chen Xie, Chio Yokose, Alison M. Hendry,40 Robert Terkeltaub,41 22 22 William J. Taylor, and Hyon K. Choi This criteria set has been approved by the American College of Rheumatology (ACR) Board of Directors and the EULAR Executive Committee. This signiﬁes that the criteria set has been quantitatively validated using patient data, and it has undergone validation based on an independent data set. All ACR/EULAR-approved criteria sets are expected to undergo intermittent updates. Classiﬁcation criteria are essential in clinical and basic science research because they allow investigators to study relatively homogeneous populations of patients recruited from a single or multiple research sites. In clinical settings, diagnoses are made by health care professionals evaluating an individual patient's symptoms, signs, and results of laboratory and imaging studies in order to guide therapeutic recommendations. Patients diagnosed with a particular disease may or may not fulﬁll classiﬁcation criteria for that disease. Classiﬁcation criteria, in the hands of an experienced clinician with expertise in rheumatology, may inform a diagnostic evaluation, but improperly applied classiﬁcation criteria may lead to misdiagnosis. The ACR is an independent, professional, medical, and scientiﬁc society that does not guarantee, warrant, or endorse any commercial product or service. Objective. Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classiﬁcation criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the ﬁrst-ever validated classiﬁcation criteria for symptomatic CPPD disease. Methods. Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classiﬁcation criteria. The group generated lists of candidate items and reﬁned their deﬁnitions, collected de-identiﬁed patient proﬁles, evaluated strengths of associations between candidate items and CPPD disease, developed a classiﬁcation criteria framework, and used multi-criterion decision analysis to deﬁne criteria weights and a classiﬁcation threshold score. The criteria were validated in an independent cohort. Results. Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium 1 ABHISHEK ET AL pyrophosphate crystals in synovial ﬂuid are sufﬁcient to classify a patient as having CPPD disease. In the absence of these ﬁndings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and speciﬁcity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and speciﬁcity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). Conclusion. The 2023 ACR/EULAR CPPD disease classiﬁcation criteria have excellent performance characteristics and will facilitate research in this ﬁeld. INTRODUCTION Calcium pyrophosphate deposition (CPPD) disease is a common symptomatic arthritis characterized 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) polarized light microscopy for diagnosis, and a diversity of presentations that include acute CPP crystal arthritis, chronic This article is published simultaneously in Annals of the Rheumatic Diseases. 1 Abhishek Abhishek, MD, PhD, Amy Fuller, PhD, Michael Doherty, MD: Academic Rheumatology, University of Nottingham, Nottingham, UK; 2Sara K. Tedeschi, MD, MPH: Division of Rheumatology, Inﬂammation and Immunity, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts; 3Tristan Pascart, MD, PhD: Department of Rheumatology, Lille Catholic University, Saint-Philibert Hospital, Lille, France; 4Augustin Latourte, MD, PhD, Thomas Bardin, MD, PhD, Hang Korng Ea, MD, PhD, Pascal Richette, MD, PhD: Université de Paris, INSERM, UMR-S 1132 BIOSCAR, and Service de Rhumatologie, AP-HP, Lariboisière Hospital, Paris, France; 5Nicola Dalbeth, MBChB, MD: Department of Medicine, University of Auckland, Auckland, New Zealand; 6 Tuhina Neogi, MD, PhD: Department of Medicine, Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts; 7Ann Rosenthal, MD: Department of Medicine, Medical College of Wisconsin, Milwaukee; 8Fabio Becce, MD: Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland; 9Georgios Filippou, MD, PhD: Rheumatology Department, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 10John FitzGerald, MD, PhD, Meika A. Fang, MD: David Geffen School of Medicine, University of California, and Veterans Administration for Greater Los Angeles, Los Angeles, California; 11AnnaMaria Iagnocco, MD: Academic Rheumatology Center, Università degli Studi di Torino, Turin, Italy; 12Frédéric Lioté, MD, PhD: Université de Paris, INSERM, UMR-S 1132 BIOSCAR, Service de Rhumatologie, AP-HP, Lariboisière Hospital, and Université Paris Cité, Faculté de Santé, Paris, France; 13 Geraldine M. McCarthy, MD, John R. Stack, MD: School of Medicine and Medical Science, University College Dublin, and Mater Misericordiae University Hospital, Dublin, Ireland; 14Roberta Ramonda, MD, PhD: Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy; 15Francisca Sivera, MD, PhD: Department of Rheumatology, Hospital General Universitario Elda, Elda, Spain, and Department of Clinical Medicine, Universidad Miguel Hernandez, Elche, Spain; 16Mariano Andres, MD, PhD: Department of Medicine, Rheumatology Section, Hospital General Universitario de Alicante, Universidad ndez, Alicante, Spain; 17Edoardo Cipolletta, MD, Emilio Filippucci, Miguel Herna PhD: Rheumatology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy; 18Eliseo Pascual, MD, PhD: Rheumatology Division, Cruces University Hospital, Bilbao, Spain; 19Fernando PerezRuiz, MD, PhD: Arthritis Investigation Group, Biocruces-Bizkaia Health Research Institute, Spain, Department of Medicine, Medicine and Nursing School, University of the Basque Country, and Basque Country Rheumatology Society, Bilbao, Spain; 20Alexander So, PhD: Lausanne University Hospital, Lausanne, Switzerland; 21Tim L. Jansen, MD, PhD: VieCuri Medical Centre, Venlo, The 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 polarized light microscopy, or alternatively by research laboratory techniques that are not widely available (7). These diagnostic criteria have since been recognized 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 Netherlands, and Medical Cell BioPhysics Group, University of Twente, Enschede, The Netherlands; 22Minna J. Kohler, MD, RhMSUS, Janeth Yinh, MD, Hyon K. Choi, MD, DrPH: Department of Medicine, Rheumatology Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts; 23Lisa K. Stamp, MB, ChB, PhD, Janine Haslett, PG Dip. Health Sciences, William J. Taylor, PhD: Department of Medicine, University of Otago, Christchurch, New Zealand; 24Antonella Adinolﬁ, MD: Rheumatology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy; 25Uri Arad, MD, PhD: Department of Rheumatology, Te Whatu Ora–Health New Zealand Waikato, Hamilton, New Zealand; 26Thanda Aung, MBBS, MSc: Division of Rheumatology, University of California, Los Angeles; 27Eva Benillouche, MD: Department of Rheumatology, Lausanne University Hospital, Lausanne, Switzerland; 28Alessandra Bortoluzzi, MD, PhD, Ettore Silvagni, MD, PhD: Section of Rheumatology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy, and Azienda Ospedaliera-Universitaria di Ferrara, Cona (FE), Italy; 29Jonathan Dau, MD: Department of Medicine, Rheumatology Unit, Massachusetts General Hospital, Boston; 30Ernest Maningding, MD: Highland Hospital, Oakland, California; 31 Fabiana A. Figus, MD: Rheumatology Division, Local Health Unit (ASL), Turin-3, Collegno and Pinerolo, Italy; 32Matthijs Janssen, MD, PhD: VieCuri Medical Centre, Venlo, The Netherlands; 33Marian Kaldas, MD, Maryann Kimoto, MD: David Geffen School of Medicine, University of California, Los Angeles; 34Kelly Leamy, Masters in Nursing: Mater Misericordiae University Hospital, Dublin, Ireland; 35 Geraldine M. Navarro, MD, Linh Truong, MD, Chen Xie, MD: Division of Rheumatology, University of California, Los Angeles, California; 36Piercarlo SarziPuttini, MD, PhD: Department of Rheumatology, IRCCS Galeazzi-Sant’Ambrogio Hospital, Milan, Italy; 37Carlo Scirè, MD, PhD: Epidemiology Unit, Italian Society for Rheumatology, Milan, Italy; 38Silvia Sirotti, MD: Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy; 39 Chio Yokose, MD, MSc: Harvard Medical School, Boston, Massachusetts; 40Alison M. Hendry, PGDipHealMgt, PGDipHSc: Department of Medicine, General Medicine and Rheumatology, Middlemore Hospital, Counties Manukau Health District, New Zealand; 41Robert Terkeltaub, MD: San Diego Veterans Administration Healthcare Service, and University of California, San Diego. * Drs. Abhishek and Tedeschi are co-ﬁrst authors and contributed equally to this work. Author disclosures are available online at https://onlinelibrary.wiley.com/ doi/10.1002/art.42619. Address correspondence via email to Abhishek Abhishek, MD, PhD, at [email protected]. Submitted for publication March 8, 2023; accepted in revised form May 23, 2023. 23265205, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.42619 by Test, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2 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. METHODS Criteria development Phases 1 and 2. These classiﬁcation criteria were developed in 4 sequential phases (Figure 1) following previously established methodology (15–19). A 9-member Steering Committee oversaw the process and a 22-member Combined Expert Committee (CEC) contributed throughout. Phases 1 and 2 were described previously (20). Brieﬂy, in Phase 1 we developed a comprehensive list of potential classiﬁcation criteria items based on a scoping literature review and input from the CEC and 2 patient research partners. In Phase 2 we reduced and reﬁned the list of potential items to those considered most speciﬁc for CPPD disease. These potential items were included in the case report form (CRF) that was used to collect patient proﬁles in the derivation and validation cohorts. 3 Criteria development Phase 3. Phase 3 involved 6 steps as described below (and as outlined in Figure 1). Derivation cohort recruitment and adjudication. De-identiﬁed information on people with differing likelihood of developing CPPD disease was collected using a standardized CRF, aided by item deﬁnitions for imaging features adopted from the literature or speciﬁcally developed for this project (21–24). Data were collected retrospectively using medical record review with approval of the Health Research Authority (Research Ethics Committee reference no. 20/SC/0243) and the local Ethics Committee at each participating site. In addition to reporting clinical manifestations, risk factors for CPPD disease, and results of imaging and laboratory tests, the submitting clinicians rated their clinical impression of the likelihood that the individual had CPPD disease on a 7-point Likert scale, ranging from +3 = highly likely to −3 = highly unlikely. Each patient proﬁle was categorized as deﬁnite CPPD disease (case), deﬁnite mimicker (control), or uncertain using the submitted information. Proﬁles rated as +3 or +2 by the submitting clinician with CPP crystals conﬁrmed by SF analysis were considered deﬁnite CPPD disease. Proﬁles rated as −3 or −2 by the submitting clinician were considered deﬁnite mimickers. All other proﬁles underwent adjudication in a blinded manner by 2 independent experts from institutions that did not submit that speciﬁc patient proﬁle. After adjudication, proﬁles rated +2 or higher by both adjudicators and by the submitting clinician were considered to be deﬁnite CPPD disease, and those proﬁles rated −1 or lower by both adjudicators were considered to be deﬁnite • • Scoping literature review Patient co-investigators & Combined Expert Committee (CEC) suggestions • • • CEC meeting to discuss “difficult” items Advisory Group discussions to reduce items & refine definitions Item rating exercise by individual CEC members • • • • • • Derivation cohort recruitment & adjudication Patient profile ranking exercise Associations between potential items and CPPD disease Draft classification criteria framework Item weights via multi-criterion decision analysis exercise Threshold score determination • • Validation cohort recruitment & adjudication Sensitivity and specificity calculated Phase 1: Item generation Phase 2: Item reduction & refinement Phase 3: Item weighting & threshold score Phase 4: Validation ACR/EULAR CPPD Classification Criteria Figure 1. Overview of the ACR/EULAR classiﬁcation criteria for CPPD disease across the 4 Phases. 23265205, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.42619 by Test, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2023 ACR/EULAR CPPD DISEASE CLASSIFICATION CRITERIA mimickers (see Supplementary Table S1, available on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/ doi/10.1002/art.42619). Patient proﬁles in which both adjudicators did not provide a rating of either +2 or higher or −1 or lower and those proﬁles in which SF CPP crystals were absent and for which the submitting clinician’s rating was −1, 0, or +1 were considered uncertain. The adjudicators did not discuss the patient proﬁles among themselves. Patient proﬁle ranking by CEC. Among the derivation cohort, 30 patient proﬁles representing the full spectrum of likelihood of CPPD disease were selected. This included 7 proﬁles with a clinician rating of −2 or −3, 15 proﬁles with a clinician rating of −1, 0, or +1, and 8 proﬁles with a clinician rating of +2 or +3. These patient proﬁles were purposefully selected so that all candidate items were present in at least one of the proﬁles. CEC members then ranked the proﬁles individually from 1 to 30 according to their perceived likelihood of CPPD disease. Association between potential classiﬁcation criteria items and CPPD disease. Data from deﬁnite cases and deﬁnite mimickers (controls) in the whole derivation cohort were used to calculate the odds of CPPD disease given the presence of each of the potential classiﬁcation criteria in univariate analyses. Unadjusted logistic regression models provided estimated odds ratios (ORs) and 95% conﬁdence intervals (95% CIs) for CPPD disease. Uncertain cases were excluded since their true case/control status was unclear. Classiﬁcation criteria framework. The CEC convened 4 videoconferences to review results of the ranking exercise and the estimated ORs that were calculated for candidate items. Based on these discussions, the CEC decided to include entry criteria (required to be considered for CPPD disease classiﬁcation) as well as exclusion criteria (if present classiﬁcation as CPPD disease should not proceed), and developed the initial draft of the classiﬁcation criteria framework. The framework consisted of domains comprising similar items. The goal was to order items within each domain into mutually exclusive levels, ranging from least inﬂuential to most inﬂuential, when considering the likelihood of classifying a person as having CPPD disease. Decisions regarding domains, their levels, and the relative ordering of the levels within domains were guided by expert opinion and supported by the ORs from derivation cohort data. The Steering Committee iteratively reﬁned the classiﬁcation criteria framework between and after the CEC videoconferences. Assigning relative weights. Using a multi-criterion decision analysis (MCDA) approach, members of the CEC undertook a discrete-choice conjoint analysis exercise using 1000Minds Potentially All Pairwise RanKings of all possible Alternatives (PAPRIKA) software (http://www.1000minds.com), guided by an experienced facilitator (AH) over four 2-hour virtual meetings (for details, see Supplementary Methods at https://onlinelibrary. wiley.com/doi/10.1002/art.42619) (25). During the virtual meetings, the CEC was presented with paired CPPD disease clinical ABHISHEK ET AL scenarios that included items from 2 different domains; all other patient features were assumed to be equivalent. CEC members were asked to decide which clinical scenario was more likely to have CPPD disease: for instance, a patient with acute inﬂammatory arthritis in a peripheral joint other than the knee, wrist, or ﬁrst metatarsophalangeal (MTP) joint and evidence of calciﬁcation on imaging of 1 peripheral joint (regardless of symptoms) versus a patient with acute inﬂammatory arthritis in the ﬁrst MTP joint and evidence of calciﬁcation in 4 peripheral joints (regardless of symptoms). The facilitator encouraged discussion until consensus was reached on each pairwise decision. With the 1000Minds software, the CEC used these decisions to determine weights that were automatically scaled so that the sum across all domains ranged from 0 to 100 (see Supplementary Methods). Early in this process it became apparent that 2 of the items dominated decision-making, and therefore it was decided to make them sufﬁcient criteria, meaning that if either was present then proceeding to score the other criteria was not necessary. The CEC then re-voted on a series of pairwise decisions with those 2 items removed, to update the weights for the remaining criteria. Upon completing the MCDA exercise, some domains were re-centered to maintain the face validity of item weights. Levels in a domain with a weight difference <1% were merged, as a difference of <1% was considered unlikely to improve discrimination on a 100-point scale. Item weights were rounded to integers for consistency with published classiﬁcation criteria (15–19). These steps were undertaken by the Steering Committee and approved by the CEC. Threshold score determination. Steering Committee members were asked to individually decide whether they would feel comfortable classifying each of the 30 patient proﬁles used in the ranking exercise as CPPD disease when considering enrolling a patient into a research study. The percentage of the Steering Committee classifying each case as CPPD disease was plotted against the total additive criteria score to visualize where the threshold may fall. Classiﬁcation criteria additive scores were then calculated for the whole derivation cohort, receiver operator characteristic (ROC) curves were plotted, and tables of sensitivity and speciﬁcity were inspected to select a preliminary threshold score that maximized speciﬁcity while retaining high sensitivity. This was done ﬁrst for definite cases and deﬁnite mimickers that were eligible for scoring (i.e., those who had no exclusion criteria nor sufﬁcient criteria). Next, the sensitivity and speciﬁcity of the entire classiﬁcation criteria system – including sufﬁcient criteria and scored criteria – were calculated at the proposed threshold score among all deﬁnite cases and deﬁnite mimickers. After this, the percentage classiﬁed as CPPD disease according to the submitting clinician’s rating of likelihood of CPPD disease was examined using the entire derivation cohort. Criteria development Phase 4. In Phase 4, validation of the CPPD disease classiﬁcation criteria was conducted. An 23265205, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.42619 by Test, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 5 independent validation cohort was concurrently recruited from centers that were not contributing cases to the derivation cohort. Investigators contributing to the validation cohort were unaware of the classiﬁcation criteria framework, relative item weights, and the threshold score. Recruitment, deﬁnition of cases and mimickers (controls), and blinded case adjudication were performed as for the derivation cohort. ROC curves were developed and sensitivity and speciﬁcity of the threshold score were calculated among validation cohort deﬁnite cases eligible for scoring and deﬁnite mimickers. Then, the sensitivity and speciﬁcity of the entire classiﬁcation criteria system at the proposed threshold score were calculated among all deﬁnite cases and deﬁnite mimickers. Finally, using the entire validation cohort, we examined the distribution of the percentage classiﬁed as CPPD disease per the submitting clinician’s rating of likelihood of CPPD disease. RESULTS Patient 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 2 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). summarizes the demographic and clinical characteristics of the derivation and validation cohorts. The CEC comprised 22 experts (20 rheumatologists, 1 radiologist, and 1 methodologist). Thirteen members were from Europe, 6 from the US, and 3 from New Zealand; 41% were women. Results of the rank-ordering exercise by individual CEC members are presented in Supplementary Figure S1 (available on the Arthritis & Rheumatology website at https://onlinelibrary. wiley.com/doi/10.1002/art.42619). The CEC identiﬁed key factors important for distinguishing CPPD disease from mimickers by reviewing ranking results and ORs (see Supplementary Tables S2–S9 at https://onlinelibrary.wiley.com/doi/10.1002/art. 42619). 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 Table 1. Characteristics of the subjects in the derivation and validation cohorts by patient proﬁle Derivation cohort Symptom onset at age ≥60 years, no. (%) Female, no. (%) Inﬂammatory arthritis, no. (%)* Acute Persistent None Race/ethnicity, no. (%)† Caucasian Other‡ Regions, no. (%) US Europe New Zealand Validation cohort Deﬁnite case (n = 190) Uncertain (n = 80) Mimicker (n = 148) Deﬁnite case (n = 251) Uncertain (n = 204) Mimicker (n = 162) 144 (75.8) 113 (59.5) 63 (78.8) 48 (60.0) 76 (51.4) 88 (59.5) 201 (80.1) 141 (56.2) 147 (72.1) 104 (51.0) 81 (50.0) 63 (38.9) 175 (92.1) 44 (23.2) 9 (4.7) 56 (70.0) 29 (36.3) 14 (17.5) 116 (78.4) 66 (44.6) 19 (12.8) 244 (97.2) 51 (20.3) 5 (2.0) 161 (78.9) 53 (26.0) 31 (15.2) 138 (85.2) 50 (30.9) 9 (5.6) 164 (86.8) 25 (13.2) 72 (90.0) 8 (10.0) 136 (91.9) 12 (8.1) 175 (82.5) 37 (17.5) 139 (74.7) 47 (25.3) 124 (80.0) 31 (20.0) 50 (26.3) 131 (68.9) 9 (4.7) 19 (23.8) 54 (67.5) 7 (8.8) 43 (29.1) 91 (61.5) 14 (9.5) 120 (47.8) 117 (46.6) 14 (5.6) 113 (55.4) 76 (37.3) 15 (7.4) 54 (33.3) 92 (56.8) 16 (9.9) * Patients could have more than one presentation of inﬂammatory arthritis. † In the derivation cohort, ethnicity was recorded for 189 deﬁnite cases due to missing data for 1 subject. In the validation cohort, ethnicity was recorded for 212 deﬁnite cases, 186 uncertain cases, and 155 mimickers due to restrictions on sharing ethnicity data for the patient proﬁles of 39 deﬁnite cases, 18 uncertain cases, and 7 mimickers. ‡ Due to a number of racial/ethnic groups being identiﬁed in only a few patient proﬁles each, the race/ethnicity data are presented in aggregate for non-Caucasian categories (designated “Other”), to maintain conﬁdentiality. 23265205, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.42619 by Test, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2023 ACR/EULAR CPPD DISEASE CLASSIFICATION CRITERIA ABHISHEK ET AL 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). 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, i.e., 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 versus absent); and 4) if sufﬁcient criteria are absent, then proceed with scoring of domains. 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 upon: CDS and SF analysis demonstrating CPP crystals in a joint with swelling, Domains and categories. The ﬁnal framework included 4 clinical, 1 laboratory, and 3 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. 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 Supplementary Results and Supplementary Table S10 at https://onlinelibrary.wiley.com/doi/10.1002/art.42619). 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 Supplementary Table S10. Classiﬁcaon of paents as Calcium Pyrophosphate Deposion (CPPD) Disease CPPD Disease YES Joint pain, swelling or tenderness NO YES All symptoms more likely explained by an alternate condion NO Crowned dens syndrome or CPP crystals shown in synovial ﬂuid/biopsy YES NO YES Score > 56 points NO Not CPPD Disease Figure 2. Conceptual schematic for applying the CPPD disease classiﬁcation criteria. 23265205, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.42619 by Test, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 7 Table 2. ACR/EULAR classiﬁcation criteria for CPPD disease* Deﬁnition of criteria The CPPD disease classiﬁcation criteria should be applied in the following order: 1. Entry criterion: Ever had at least one episode of joint pain, swelling, or tenderness.† 2. Absolute exclusion criteria: All symptoms are more likely explained by an alternative condition (such as rheumatoid arthritis, gout, psoriatic arthritis, OA, etc.). 3. Sufﬁcient criteria: Presence of either crowned dens syndrome or synovial ﬂuid analysis demonstrating CPP crystals in a joint with swelling, tenderness, or pain.‡ An individual is classiﬁed as having CPPD disease if the entry criterion is met, exclusion criteria are not met, and at least one sufﬁcient criterion is fulﬁlled. If none of the sufﬁcient criteria are present, an individual is classiﬁed as having CPPD disease if the sum of the criteria is >56 points. Scoring of criteria Items can be scored if they were ever present during a patient’s lifetime. If a patient fulﬁlls >1 item in a given domain, only the highest weighted item will be scored. Imaging of at least one symptomatic joint by CR, US, CT, or DECT is required. Domains and levels A Age at onset of joint symptoms (pain, swelling, and/or tenderness) ≤60 years >60 years B Time course and symptoms of inﬂammatory arthritis§ No persistent or typical inﬂammatory arthritis Persistent inﬂammatory arthritis One typical acute arthritis episode More than one typical acute arthritis episode C Sites of typical episode(s) of inﬂammatory arthritis in peripheral joints First MTP joint No typical episode(s) Joint(s) other than wrist, knee, or ﬁrst MTP joint Wrist Knee D Related metabolic diseases¶ None Present E Synovial ﬂuid crystal analysis from a symptomatic joint# CPP crystals absent on ≥ 2 occasions CPP crystals absent on 1 occasion Not performed F OA of hand/wrist on imaging (deﬁned as present if the K/L score is ≥2) None of the below ﬁndings or no wrist/hand imaging performed OA of radiocarpal joints bilaterally ≥ 2 of the following ﬁndings: STT joint OA without ﬁrst CMC joint OA; second MCP joint OA; third MCP joint OA G Imaging evidence of CPPD in symptomatic peripheral joint(s)** None on US, CT, or DECT (and absent on CR or CR not performed) None on CR (and US, CT, DECT not performed) Present on either CR, US, CT, or DECT H Number of peripheral joints with evidence of CPPD on any imaging modality regardless of symptoms** None 1 2–3 ≥4 Points 0 4 0 9 12 16 −6 0 5 8 9 0 6 −7 −1 0 0 2 7 −4 0 16 0 16 23 25 * CR = conventional radiography; US = ultrasound; MTP = metatarsophalangeal; K/L = Kellgren/Lawrence; STT = scaphotrapeziotrapezoid; CMC = carpometacarpal; MCP = metacarpophalangeal. † Episode occurring in a peripheral joint or, in the case of crowned dens syndrome, an axial joint such as C1/C2. ‡ Crowned dens syndrome is deﬁned as presence of a) clinical features and b) imaging features. Clinical features include acute or subacute onset of severe pain localized to the upper neck with elevated inﬂammation markers, limited rotation, and often fever. Mimicking conditions such as polymyalgia rheumatica and meningitis should be excluded. Imaging features include conventional computed tomography (CT) showing calciﬁc deposits, typically linear and less dense than cortical bone, in the transverse retro-odontoid ligament (transverse ligament of the atlas), often with an appearance of 2 parallel lines in axial views. Calciﬁcations at the atlanto-axial joint, alar ligament, and/or in pannus adjacent to the tip of the dens are also characteristic. Dual-energy computed tomography (DECT) features include a dual-energy index between 0.016 and 0.036. Both the clinical features and the imaging features must be present. Sufﬁcient criteria are also met if calcium pyrophosphate (CPP) crystals are demonstrated on histopathologic analysis of the joint tissue, provided that the patient is eligible for classiﬁcation, i.e., does not already meet the exclusion criteria. For instance, articular cartilage CPP crystal deposition in patients with end-stage osteoarthritis (OA) cannot be used to classify the patient as having calcium pyrophosphate deposition (CPPD) disease when all symptoms are better explained by the presence of OA (exclusion criteria). § Persistent inﬂammatory arthritis was deﬁned as ongoing joint swelling with pain and/or warmth in ≥1 joint(s). Typical episode was deﬁned as an episode with acute onset or acute worsening of joint pain with swelling and/or warmth that resolves irrespective of treatment. ¶ Including hereditary hemochromatosis, primary hyperparathyroidism, hypomagnesemia, Gitelman syndrome, hypophosphatasia, or familial history of CPPD disease. # Synovial ﬂuid analysis should be performed by an individual trained in the use of compensated polarized light microscopy for crystal identiﬁcation. ** Imaging of at least one symptomatic peripheral joint by CR, US, CT, or DECT is required to be considered for classiﬁcation if sufﬁcient criteria are not met. Imaging evidence of CPPD refers to calciﬁcation of the ﬁbrocartilage or hyaline cartilage. Do not score calciﬁcation of the synovial membrane, joint capsule, or tendon. Imaging deﬁnitions are published elsewhere (21). Only consider involvement of peripheral joints. 23265205, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.42619 by Test, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2023 ACR/EULAR CPPD DISEASE CLASSIFICATION CRITERIA ABHISHEK ET AL 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. Color ﬁgure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.42619/abstract. 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/acrclassiﬁcation-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 versus the ﬁnal additive classiﬁcation criteria score suggested the feasibility of a score threshold between 53 and 57 (Figure 3). 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 0.93–0.98) (Figure 4). A threshold score of >56 was chosen, as this threshold maximized speciﬁcity at 87.9% while retaining a high sensitivity of 92.2% (see Supplementary Table S11 at https://onlinelibrary. wiley.com/doi/10.1002/art.42619). When the entire classiﬁcation criteria system (i.e., 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%. 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 0.96–0.99) (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 23265205, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.42619 by Test, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 9 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. Color ﬁgure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.42619/abstract. disease in both the derivation and validation cohorts (see Supplementary Table S12 at https://onlinelibrary.wiley.com/doi/10. 1002/art.42619). 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 (e.g., 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 centers in which patients’ joints are routinely imaged bilaterally. The Steering Committee considered requiring imaging of a standardized set of joints (e.g., 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 computed tomography, particularly in early CPPD disease, compared to 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 polarized light microscopy is speciﬁc but has a high false-negative rate and 23265205, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.42619 by Test, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2023 ACR/EULAR CPPD DISEASE CLASSIFICATION CRITERIA 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 ABHISHEK ET AL 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 minimize 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 2 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. ACKNOWLEDGMENTS We thank Mr. Tim Adcock, Ms. Marie Ward, and Ms. Rose Farrands-Bentley at the University of Nottingham for participating in central data entry and data management. We also thank Mr. Rocio Caño, who helped with patient recruitment in Alicante, Spain. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the ﬁnal version to be published. Dr. Abhishek had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. 23265205, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.42619 by Test, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 10 Study conception and design. Abhishek, Tedeschi, Pascart, Latourte, Dalbeth, Neogi, Rosenthal, Becce, Korng Ea, Filippou, FitzGerald, Iagnocco, McCarthy, Ramonda, Perez-Ruiz, Kohler, Stamp, Figus, Kaldas, Leamy, Hendry, Terkeltaub, Taylor, Choi. Acquisition of data. Rosenthal, Filippou, FitzGerald, Iagnocco, McCarthy, Ramonda, Andres, Cipolletta, Doherty, So, Jansen, Kohler, Stamp, Yinh, Adinolﬁ, Arad, Aung, Benillouche, Bortoluzzi, Dau, Maningding, Fang, Figus, Filippucci, Haslett, Janssen, Kaldas, Kimoto, Leamy, Navarro, Sarzi-Puttini, Scirè, Silvagni, Sirotti, Stack, Truong, Xie, Yokose, Terkeltaub, Choi. Analysis and interpretation of data. Fuller, Bardin, Korng Ea, FitzGerald, Iagnocco, Lioté, McCarthy, Ramonda, Richette, Sivera, Andres, Pascual, So, Kohler, Yinh, Janssen, Hendry, Terkeltaub, Taylor, Choi. REFERENCES 1. Zhang W, Doherty M, Bardin T, et al. European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis 2011;70:563–70. 2. Salafﬁ F, De Angelis R, Grassi W. Prevalence of musculoskeletal conditions in an Italian population sample: results of a regional community-based study. I. The MAPPING study. Clin Exp Rheumatol 2005;23:819–28. 3. 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Cipolletta E, Filippou G, Scire CA, et al. The diagnostic value of conventional radiography and musculoskeletal ultrasonography in calcium pyrophosphate deposition disease: a systematic literature review and meta-analysis. Osteoarthritis Cartilage 2021;29:619–32. 9. Lee KA, Lee SH, Kim HR. Diagnostic value of ultrasound in calcium pyrophosphate deposition disease of the knee joint. Osteoarthritis Cartilage 2019;27:781–7. 10. Sirotti S, Becce F, Sconﬁenza LM, et al. Reliability and diagnostic accuracy of radiography for the diagnosis of calcium pyrophosphate deposition: performance of the novel deﬁnitions developed by an international multidisciplinary working group. Arthritis Rheumatol 2022;75:630–8. 11. Berendsen D, Neogi T, Taylor WJ, et al. Crystal identiﬁcation of synovial ﬂuid aspiration by polarized light microscopy: an online test suggesting that our traditional rheumatologic competence needs renewed attention and training. Clin Rheumatol 2017;36:641–7. 11 14. Bernal JA, Andres M, Lopez-Salguero S, et al. Agreement among multiple observers on crystal identiﬁcation by synovial ﬂuid microscopy. Arthritis Care Research (Hoboken) 2022;75:682–8. 15. Neogi T, Jansen TL, Dalbeth N, et al. 2015 gout classiﬁcation criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol 2015;67: 2557–68. 16. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classiﬁcation criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569–81. 17. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classiﬁcation criteria for systemic lupus erythematosus. Arthritis Rheumatol 2019;71:1400–12. 18. Johnson SR, Naden RP, Fransen J,

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