A New Era for Calcium Pyrophosphate Deposition Disease Research: The First-Ever Calcium Pyrophosphate Deposition Disease Classification Criteria and Considerations for Measuring Outcomes in Calcium Pyrophosphate Deposition Disease

Round 1

Reviewer 1 Report

The paper provide an interest commentaries on the latest CPPD classification criteria. It is timely, easy to follow and should be of interest to clinicians. There are however some adjustments that I believe will further improve the manuscript.

1. I recommend writing the full name of CPPD in the paper title. This would make the manuscript more accessible for non-rheumatologists.

2. The classification criteria was intended for research rather than clinical diagnosis. This point is often overlooked by practicing clinicians. Therefore, I think it would be great if the authors could included some comments on using the classification criteria in clinical practice - whether this could be useful or appropriate?

3. On page 4, CPP crystal identification is labelled as 'silver standard'. I agree with this, but I the argument made to support this point could be improved. The fact that CPP crystals are difficult to find  microscopically should not preclude it from being a gold standard. However, I think the reason CPP crystals should be considered silver standard is that they could be found in otherwise asymptomatic joints/individuals and that the link between presence of crystal and symptoms are often questionable.

Author Response

The paper provide an interest commentaries on the latest CPPD classification criteria. It is timely, easy to follow and should be of interest to clinicians. There are however some adjustments that I believe will further improve the manuscript.

1. I recommend writing the full name of CPPD in the paper title. This would make the manuscript more accessible for non-rheumatologists.

Response: Thank you and we have made this change to the title so that it now reads, “A New Era for Calcium Pyrophosphate Deposition Disease (CPPD) Research: The First-Ever CPPD Classification Criteria and Considerations for Measuring Outcomes in CPPD”.

2. The classification criteria was intended for research rather than clinical diagnosis. This point is often overlooked by practicing clinicians. Therefore, I think it would be great if the authors could included some comments on using the classification criteria in clinical practice - whether this could be useful or appropriate?

Response: This is a helpful point, and we have added the following: “Though the classification criteria are not intended to aid in clinical diagnosis, they highlight some of the constructs that experts in CPPD disease considered most relevant. Clinicians can thus look to the CPPD disease classification criteria for elements which, if present in their patient(s), could point toward a clinical diagnosis of CPPD disease such as chondrocalcinosis, positive synovial fluid aspirate, and episodes of acute monoarthritis in the knee or wrist. However, it is not appropriate to use the scoring system to diagnose a patient with CPPD disease.” (page 2)

3. On page 4, CPP crystal identification is labelled as 'silver standard'. I agree with this, but I the argument made to support this point could be improved. The fact that CPP crystals are difficult to find  microscopically should not preclude it from being a gold standard. However, I think the reason CPP crystals should be considered silver standard is that they could be found in otherwise asymptomatic joints/individuals and that the link between presence of crystal and symptoms are often questionable.

Response: We agree that questionable relationship between crystals and symptoms is worth mentioning. The challenges with crystal identification were part of the discussion among the CPPD classification criteria working group, and we have chosen to keep this phrase with additional explanation as follows: “For this reason, absence of synovial fluid CPP crystals on one occasion received a slight negative weight rather than a large negative weight, as it is possible that synovial fluid crystal analysis could produce a false negative due to challenges with crystal identification. (By contrast, two or more synovial fluid aspirates negative for CPP crystals received a larger negative weight as the chance of two false negatives was felt to be less likely, and that two negative aspirates more likely suggests against CPPD disease.) Additionally, synovial fluid CPP crystals can be observed in joints that do not have symptoms attributable to CPPD disease.”  (page 4)

Reviewer 2 Report

In this manuscript, the authors provide an overview and perspective on the recent advances in the definition, categorization, and identification of CPPD, and the needs for establishing community-wide outcomes measures in the field.  The writing is lucid, straightforward and readable; the thinking behind it measured, important and clearly the product of someone who has spent much time and thought deeply on CPPD.  As a review—but more importantly as a guidepost—this article should help accelerate the early momentum that the new era of CPPD appears to be embarked on.  As such it provides a service to patients and physicians alike.

This reviewer has only one substantive comment. A potentially important limitation of the new classification criteria is the exclusion criterion—escape hatch if you will—that in the case of patients with more than one joint problem, physicians considering whether to classify patients as having CPPD for studies must exclude those patients whose joint problems—in their opinion—are due to other than their CPPD.  This criterion is extremely subjective, and will surely lead different physicians to make different judgements.  Given the fact that patients with CPPD frequently have other joint problems, this subjectively will surely have important implications for who gets to be a subject.  It would be helpful if the authors could include some perspective on whether, and how, this criterion might be made more objective when the next classification criteria are issued, presumably several years from now.

Minor comments:

1. Line 41—in the phrase, “validated definitions for ultrasonographic findings CPPD,” the word “in” appears to be missing between “findings” and “CPPD”.

2. Line 267—in the phrase “We are at moment when,” the word “the” appears to be missing between “at” and “moment”.

The language is fluid, readable and easy to read.

Author Response

1. This reviewer has only one substantive comment. A potentially important limitation of the new classification criteria is the exclusion criterion—escape hatch if you will—that in the case of patients with more than one joint problem, physicians considering whether to classify patients as having CPPD for studies must exclude those patients whose joint problems—in their opinion—are due to other than their CPPD.  This criterion is extremely subjective, and will surely lead different physicians to make different judgements.  Given the fact that patients with CPPD frequently have other joint problems, this subjectively will surely have important implications for who gets to be a subject.  It would be helpful if the authors could include some perspective on whether, and how, this criterion might be made more objective when the next classification criteria are issued, presumably several years from now.

Response: We agree that the application of exclusion criteria is subjective, and that attribution of symptoms is challenging in CPPD due to concurrent other forms of arthritis. We have added the following: “There is an element of subjectivity at play, as the investigator applying the classification criteria must exercise judgement as to whether all symptoms are attributable to another condition. Biomarkers (not yet identified) that distinguish between symptoms from CPPD disease and symptoms from other forms of arthritis would be quite useful to aid in ap-plying this exclusion criterion.” (page 2)

2. Line 41—in the phrase, “validated definitions for ultrasonographic findings CPPD,” the word “in” appears to be missing between “findings” and “CPPD”.

Response: We have added “in.” Thanks for noticing it.

3. Line 267—in the phrase “We are at moment when,” the word “the” appears to be missing between “at” and “moment”.

Response: We have added “the.”