- Email: [email protected]
Performance of diagnostic criteria in patients clinically judged to have cardiac Sarcoidosis: Is it time to regroup?
Journal Pre-proof Performance of diagnostic criteria in patients clinically judged to have cardiac Sarcoidosis: Is it time to regroup?
Manuel L. Ribeiro Neto, Christine Jellis, Rory Hachamovitch, Allison Wimer, Kristin B. Highland, Debasis Sahoo, Joseph E. Khabbaza, Aman Pande, Akhil Bindra, Brian D. Southern, Joseph Parambil, Thomas D. Callahan, Emer Joyce, Daniel A. Culver PII:
S0002-8703(20)30054-5
DOI:
https://doi.org/10.1016/j.ahj.2020.02.008
Reference:
YMHJ 6083
To appear in:
American Heart Journal
Received date:
13 November 2019
Accepted date:
6 February 2020
Please cite this article as: M.L. Ribeiro Neto, C. Jellis, R. Hachamovitch, et al., Performance of diagnostic criteria in patients clinically judged to have cardiac Sarcoidosis: Is it time to regroup?, American Heart Journal(2020), https://doi.org/10.1016/ j.ahj.2020.02.008
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier.
Journal Pre-proof
Title: Performance of Diagnostic Criteria in Patients Clinically Judged to Have Cardiac Sarcoidosis: Is It Time to Regroup?
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Short title: Diagnostic Criteria in Cardiac Sarcoidosis
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Manuel L. Ribeiro Neto, MD1, Christine Jellis, MD, PhD2, Rory Hachamovitch, MD, MSc2, Allison Wimer1, Kristin B. Highland, MD1, Debasis Sahoo, MBBS, MD1, Joseph E. Khabbaza, MD1, Aman Pande, MD1, Akhil Bindra, MD1, Brian D. Southern, MD1, Joseph Parambil, MD1, Thomas D. Callahan, MD2, Emer Joyce, MD, PhD3, Daniel A. Culver, DO1 Cleveland Clinic, Respiratory Institute, Cleveland, USA
2
Cleveland Clinic, Heart and Vascular Institute, Cleveland, USA
3
na
1
Jo
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Mater Misericordiae University Hospital, Department of Cardiology, Dublin, Ireland *Corresponding author information: Manuel L Ribeiro Neto, 9500 Euclid Avenue, A90, Cleveland, Ohio, 4415, USA, (e-mail: [email protected]).
Abstract: Background. The diagnosis of cardiac sarcoidosis (CS) is challenging. Due to the current limitations of endomyocardial biopsy as a reference standard, physicians rely on advanced cardiac imaging, multidisciplinary evaluation, and diagnostic criteria to diagnose CS. Aims. To compare the three main available diagnostic criteria in patients clinically judged to have CS. Methods. We prospectively included patients clinically judged to have cardiac sarcoidosis by a multidisciplinary sarcoidosis team from 1
Journal Pre-proof November 2016 to October 2017. We included only incident cases (diagnosis of CS within one year of inclusion). We applied retrospectively the following diagnostic criteria: the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG), the Heart Rhythm Society (HRS), and the Japanese Circulation Society (JCS) 2016 criteria. Results. We identified 69 patients. Diagnostic criteria classified patients as follows: WASOG as highly probable (1.4%), probable (52.2%), possible (0%), some criteria (40.6%), and no criteria (5.8%); HRS as histological diagnosis (1.4%), probable (52.2%), some
of
criteria (40.6%), and no criteria (5.8%); JCS as histological diagnosis (1.4%), clinical diagnosis (58%), some
ro
criteria (39.1%), and no criteria (1.4%). Concordance was high between WASOG and HRS (kappa = 1), but
-p
low between JCS and the others (kappa = 0.326). Conclusion. A high proportion of patients clinically judged to have CS are unable to be classified according to the three main diagnostic criteria. There is low
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re
concordance between JCS criteria and the other two criteria (WASOG and HRS).
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Keywords:
None
Jo
Acknowledgements:
ur
Cardiac Sarcoidosis, Cardiomyopathies, Arrhythmias
2
Journal Pre-proof Performance of Diagnostic Criteria in Patients Clinically Judged to Have Cardiac Sarcoidosis: Is It Time to Regroup? Manuel L. Ribeiro Neto, MD, Christine Jellis, MD, PhD, Rory Hachamovitch, MD, MSc, Allison Wimer, Kristin B. Highland, MD, Debasis Sahoo, MBBS, MD, Joseph E. Khabbaza, MD, Aman Pande, MD, Akhil Bindra, MD, Brian D. Southern, MD, Joseph Parambil, MD, Thomas D. Callahan, MD, Emer Joyce, MD, PhD, Daniel A. Culver, DO
of
Background
ro
The diagnosis of cardiac sarcoidosis (CS) is a very challenging process. Due to the current
-p
limitations of endomyocardial biopsy as a reference standard, physicians frequently rely on advanced cardiac imaging, multidisciplinary evaluation, and the available diagnostic criteria to diagnose or rule out
lP
criteria in patients clinically judged to have CS.
re
CS.1 In the present study, we aimed to compare the performance of the three main available diagnostic
Methods
na
We prospectively included patients clinically judged to have cardiac sarcoidosis after evaluation
ur
in a multidisciplinary sarcoidosis clinic from November 2016 to October 2017. The multidisciplinary
Jo
evaluation consisted of two key components: first, patients were seen in clinic by a pulmonologist and a heart failure specialist cardiologist, both with expertise in sarcoidosis; second, a multidisciplinary discussion was performed including other relevant subspecialties to the case (e.g. advance cardiac imaging specialist, electrophysiologist). A CS diagnosis was adjudicated after review of diagnostic data (e.g. extra-cardiac sarcoidosis diagnosis, electrocardiography, echocardiogram, advanced cardiac imaging). We included only incident cases (diagnosis of CS within one year of registry inclusion). We then reviewed the electronic medical records and applied the three main available diagnostic criteria for CS: the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG)2, the Heart Rhythm Society (HRS)3, and the Japanese Circulation Society (JCS) 2016 criteria4,5. Patients who had
3
Journal Pre-proof some criteria components but not enough to be conclusively classified (e.g. no biopsy-proven sarcoidosis for WASOG and HRS, just one major criterion for JCS) were labeled as “some criteria”. This study was reviewed and approved by the Institutional Review Board (IRB) at the Cleveland Clinic (IRB 19270). No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.
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Results
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We identified 69 patients, the majority of whom were male (60.9%) and white (81.2%) (Table 1).
-p
Most patients (58%) had biopsy proven extra-cardiac sarcoidosis, with common extra-cardiac manifestations being pulmonary (69.6%), non-thoracic lymph node (31.9%), splenic (21.7%), and hepatic
re
(14.5%) involvement. Mean (SD) age at CS diagnosis was 53 ± 9.8 years, with median time from
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symptoms to diagnosis of 7 months (IQR 22). CS was suspected based on symptoms (84.1%) or routine screening of patients with extracardiac sarcoidosis (14.5%). Common cardiac manifestations were highatrioventricular
block
(39%),
na
degree
heart
failure
(36%),
and
sustained
ventricular
ur
tachycardia/ventricular fibrillation (23%). Cardiac MRI (CMR) was performed in 68.1% (47/69), and 18F-
Jo
fluorodeoxyglucose cardiac positron emission tomography (18F-FDG cardiac PET) scan in 87% (60/69), most of them (54/60, 90%) with perfusion imaging. Isolated CS was present in 17 (26%) of patients. The prevalence of each criterion of the WASOG criteria according to the classification we used is shown in Table 2. Diagnostic criteria classified patients as follows: WASOG as highly probable (1.4%), probable (52.2%), possible (0%), some criteria (40.6%), and no criteria (5.8%); HRS as histological diagnosis (1.4%), probable (52.2%), some criteria (40.6%), and no criteria (5.8%); JCS as histological diagnosis (1.4%), clinical diagnosis (58%), some criteria (39.1%), and no criteria (1.4%). Concordance was high between WASOG and HRS (kappa = 1), but low between JCS and the others (kappa = 0.326) (Table 2).
4
Journal Pre-proof The main reason for failure to classify patients according to the WASOG and HRS criteria was the absence of biopsy confirmation of sarcoidosis (29 of 32 unclassified patients), with 53% (17/32) of them having isolated CS. Within the 17 patients with no biopsy and isolated CS, 77% (13/17) had patchy FDG uptake on 18F-FDG cardiac PET, 59% (10/17) had perfusion defects on 18F-FDG cardiac PET, and 77% (13/17) had delayed gadolinium enhancement (DE) on CMR. In patients with no biopsy-proven sarcoidosis (n = 29), the CS diagnosis was made by the JCS criteria more frequently than the
of
WASOG/HRS criteria (45% versus 0%). In patients with isolated CS, the CS diagnosis was made by the JCS
ro
criteria more frequently than the WASOG/HRS criteria (28% versus 6%).
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Conclusion
The present study demonstrates that a high proportion of patients clinically judged to have CS
re
by a multidisciplinary evaluation are unable to be classified according to the three main diagnostic
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criteria pathways. Furthermore, it shows a low concordance between the 2016 JCS criteria and the other two criteria (WASOG and HRS), with the JCS criteria more frequently classifying patients as having
na
clinical CS compared to WASOG and HRS criteria. These findings are mainly driven by a high proportion
ur
of patients with no tissue confirmation of sarcoidosis (42%) and isolated CS (26%) in our cohort. The high
topic.6
Jo
proportion of isolated CS in our cohort is similar to the one cited by a recent focused review on the
In most patients with no tissue confirmation (n = 29), biopsy was not pursued because patients had typical features of isolated CS (17/29) and no other explanation after an exhaustive evaluation. This raises an important question: how should we diagnose CS in patients with suspected isolated disease? A small prospective cohort of 31 Canadian patients suggests that the first step should be a whole-body PET scan to confirm truly isolated disease. In that study, the PET scan identified extra-cardiac disease in most patients, and the prevalence of isolated CS was only 3.2%.7 A retrospective cohort of 55 Finish patients demonstrated a specific approach to endomyocardial biopsies (EMBx) once isolated cardiac disease was
5
Journal Pre-proof suspected. Repeated sessions (up to three) of EMBx guided by advanced cardiac imaging increased the diagnostic yield from 32% to 55%, with no major complications.8 However, in many other studies the EMBx diagnostic yield is limited to 20-30%.1,9–11 The 2016 JCS criteria includes criteria for isolated CS, but since it is not derived from prospective studies its clinical applicability is uncertain. Therefore, prospective studies are needed to better define the ideal approach to diagnose isolated CS. In the remaining patients with no tissue confirmation, extra-cardiac manifestations were
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present, but no diagnostic biopsy was obtained (12/29). Some of the reasons for no biopsy included
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typical imaging findings for sarcoidosis with no evident alternative cause, history of Lofgren’s syndrome,
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and typical imaging findings with non-diagnostic biopsies. This underscores a second important question: when can CS be accurately diagnosed without tissue confirmation? This question has been
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addressed in other sarcoidosis manifestations. The classic study from Winterbauer et al demonstrated
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that asymptomatic patients with bilateral and symmetric hilar adenopathy can be safely diagnosed with sarcoidosis.12 Lofgren’s syndrome (acute onset of fever, erythema nodosum, ankle arthritis, and bilateral
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hilar adenopathy) is another circumstance where a biopsy is not necessary.13 Such evidence does not
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exist for CS. Studies are needed to address this important clinical question.
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Our study has several limitations. First and foremost, our clinical judgement could be overdiagnosing CS in our cohort, and not the diagnostic criteria missing true disease. We believe this bias is minimized by the fact that we evaluated patients in a multidisciplinary sarcoidosis clinic that includes pulmonologists alongside heart failure, cardiomyopathy, electrophysiology and advanced cardiac imaging specialist cardiologists. In addition, all patients had at least one advanced diagnostic imaging study, and most patients had both 18F-FDG cardiac PET and CMR, which has been demonstrated to have complementary value in assessing the likelihood of CS.14 A second limitation is the lack of systematic evaluation of all patients in a formal multidisciplinary meeting. Although some patients were discussed in such setting, this did not happen consistently for all patients. A third
6
Journal Pre-proof important limitation is that this is was a single center study. So clinical aspects specific to our practice could have played a role in our results (e.g. not obtaining EMBx in most patients with isolated CS). In conclusion, this study demonstrates that the main three available diagnostic criteria for CS do not encompass a high proportion of patients faced with suspected CS. Moreover, the WASOG and the HRS criteria have low concordance with the JCS criteria. These findings seem to be driven by a high proportion of patients with no tissue confirmation of sarcoidosis and isolated CS. We suggest that
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further prospective and multicentric studies are needed to better define the best approach to diagnose
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isolated CS and to identify whether cardiac sarcoidosis can be accurately diagnosed without a biopsy in
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specific situations. Disclosures: None
Cooper LT, Baughman KL, Feldman AM, et al. AHA / ACCF / ESC Scientific Statement The Role of
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References
Endomyocardial Biopsy in the Management of Cardiovascular Disease A Scientific Statement From the American Heart Association , the American College of Cardiology , and the European
2.
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Society of Cardiology. Circulation. 2007;116:2216-2233. Judson MA, Costabel U, Drent M, et al. The WASOG sarcoidosis organ assessment instrument: An
Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and
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update of a previous clinical tool. Sarcoidosis Vasc Diffus Lung Dis. 2014;31(1):19-27.
management of arrhythmias associated with cardiac sarcoidosis. Hear Rhythm. 2014;11(7):13051324. 4.
Terasaki F, Yoshinaga K. New Guidelines for Diagnosis of Cardiac Sarcoidosis in Japan. Ann Nucl Cardiol. 2017;3(1).
5.
Terasaki F, Azuma A, Anzai T, Ishizaka N, Ishida Y. Guideline on Diagnosis and Treatment of Cardiac Sarcoidosis ― Digest Version ―. Circ J. 2019;83(November):2329-2388.
6.
Okada DR, Bravo PE, Vita T, et al. Isolated cardiac sarcoidosis : A focused review of an underrecognized entity. J Nucl Cardiol. 2018;25(4):1136-1146.
7.
Juneau D, Nery P, Russo J, et al. How common is isolated cardiac sarcoidosis? Extra-cardiac and cardiac findings on clinical examination and whole-body18F–fluorodeoxyglucose positron emission tomography. Int J Cardiol. 2018;253:189-193. 7
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Kandolin R, Lehtonen J, Graner M, Schildt J, Salmenkivi K, Kivisto SM. Diagnosing isolated cardiac sarcoidosis. J Intern Med. 2011;270:461-468.
9.
Ardehali H, Howard DL, Hariri A, et al. A positive endomyocardial biopsy result for sarcoid is associated with poor prognosis in patients with initially unexplained cardiomyopathy. Am Heart J. 2005;150(3):459-463.
10.
Uemura A, Morimoto SI, Hiramitsu S, Kato Y, Ito T, Hishida H. Histologic diagnostic rate of cardiac sarcoidosis: Evaluation of endomyocardial biopsies. Am Heart J. 1999;138(2 I):299-302.
11.
Yoshida A, Ishibashi-Ueda H, Yamada N, et al. Direct comparison of the diagnostic capability of
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cardiac magnetic resonance and endomyocardial biopsy in patients with heart failure. Eur J Heart Fail. 2013;15(2):166-175.
Winterbauer RH, Belic N, Moores KD. A Clinical Interpretation of Bilateral Hilar Adenopathy. Ann
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12.
13.
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Intern Med. 1973;78:65-72.
Grunewald J, Eklund A. Sex-Specific Manifestations of Lofgren ’ s Syndrome. Am J Respir Crit Care
Vita T, Okada DR, Veillet-chowdhury M, et al. Complementary Value of Cardiac Magnetic
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Resonance Imaging and Positron Emission Tomography / Computed Tomography in the
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Assessment of Cardiac Sarcoidosis. Circ Cardiovasc Imaging. 2018;11:e007030.
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14.
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Med. 2007;175:40-44.
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Table 1. Demographics and clinical characteristics.
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Demographics and characteristics Total = 69 patients Male gender, n (%) 42 (60.9) White, n (%) 56 (81.2) Comorbidities, n (%) Hypertension 26 (37.7) Diabetes 5 (7.2) Biopsy-proven sarcoidosis, n (%) 40 (58) Organ involvement, n (%) Lungs 48 (69.6) Non-thoracic lymph nodes 22 (31.9) Spleen 15 (21.7) Liver 10 (14.5) Bone and joints 8 (11.6) Skin 7 (10.1) Eyes 4 (5.8) Parotid 3 (4.3) Hypercalcemia 2 (2.9) Neurologic 1 (1.4) Renal 1 (1.4) Age (in years) at cardiac sarcoidosis diagnosis, mean (SD) 53 (9.8) Time (in months) from symptoms to diagnosis, median (IQR) 7 (22) Presentation mode, n (%) Symptoms 58 (84.1) Screening 10 (14.5) Cardiac imaging for other reason 1 (1.4) Cardiac manifestations, n (%) High-degree atrioventricular block 27 (39.1) Heart failure (EF < 50%) 25 (36.2) Sustained ventricular tachycardia/ventricular fibrillation 16 (23.2) 18F-FDG cardiac PET scan results, n (%) Patchy FDG uptake 52 (75.4) Rb-82 perfusion abnormalities 32 (46.4) Cardiac MRI results, n (%) Delayed gadolinium enhancement 35 (50.7) T2 abnormalities 8 (11.6) Legend. EF: ejection fraction; PET: positron emission tomography scan; FDG: fludeoxyglucose; Rb-82: Rubidium-82. MRI: magnetic resonance imaging.
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Table 2. Prevalence of each criterion of the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) criteria, according to each classification we used for the present study.
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WASOG criteria (total = 69 Highly probable, Probable, Some criteria, No criteria, patients) n=1 n = 36 n = 28 n=4 Biopsy-proven sarcoidosis 1 36 0 3 Endomyocardial biopsy with granulomatous 1 0 0 0 inflammation Treatment responsive cardiomyopathy or 0 9 6 0 atrioventricular node block Reduced LVEF in the absence of other clinical 0 9 4 0 risk factors Spontaneous or inducible sustained ventricular 1 8 7 0 tachycardia with no other risk factor Mobitz type II or 3rd 0 14 13 0 degree heart block Patchy uptake on 1 29 22 0 dedicated cardiac PET Delayed enhancement on 1 16 18 0 cardiac MRI Positive gallium uptake 0 0 0 0 Defect on perfusion 0 0 0 0 scintigraphy or SPECT scan T2 prolongation on 0 4 4 0 cardiac MRI Reduced LVEF in the presence of other risk 0 5 7 0 factors (HTN, DM) Atrial dysrhythmias 0 6 8 0 Legend: LVEF: left ventricular ejection fraction; PET: positron emission tomography scan; MRI: magnetic resonance imaging; SPECT: single-photon emission computed tomography; HTN: hypertension; DM: diabetes mellitus. The columns don’t add up to 100% because one patient could have more than one criterion.
10
Journal Pre-proof
Table 3. Concordance between the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) and the 2016 Japanese Circulation Society (JCS) criteria (kappa = 0.326). WASOG Highly probable
Some criteria*
Probable
No criteria
Total
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Histological 1 0 0 0 1 diagnosis Clinical 0 27 13 0 40 JCS diagnosis Some 0 9 15 3 27 criteria No criteria 0 0 0 1 1 Total 1 36 28 4 69 Legend: *Patients who had some criteria but not enough to be properly classified (e.g. no biopsy-proven sarcoidosis for WASOG and HRS, just one major criterion for JCS) were labeled as “some criteria”.
11
Manuel L. Ribeiro Neto, Christine Jellis, Rory Hachamovitch, Allison Wimer, Kristin B. Highland, Debasis Sahoo, Joseph E. Khabbaza, Aman Pande, Akhil Bindra, Brian D. Southern, Joseph Parambil, Thomas D. Callahan, Emer Joyce, Daniel A. Culver PII:
S0002-8703(20)30054-5
DOI:
https://doi.org/10.1016/j.ahj.2020.02.008
Reference:
YMHJ 6083
To appear in:
American Heart Journal
Received date:
13 November 2019
Accepted date:
6 February 2020
Please cite this article as: M.L. Ribeiro Neto, C. Jellis, R. Hachamovitch, et al., Performance of diagnostic criteria in patients clinically judged to have cardiac Sarcoidosis: Is it time to regroup?, American Heart Journal(2020), https://doi.org/10.1016/ j.ahj.2020.02.008
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier.
Journal Pre-proof
Title: Performance of Diagnostic Criteria in Patients Clinically Judged to Have Cardiac Sarcoidosis: Is It Time to Regroup?
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Short title: Diagnostic Criteria in Cardiac Sarcoidosis
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Manuel L. Ribeiro Neto, MD1, Christine Jellis, MD, PhD2, Rory Hachamovitch, MD, MSc2, Allison Wimer1, Kristin B. Highland, MD1, Debasis Sahoo, MBBS, MD1, Joseph E. Khabbaza, MD1, Aman Pande, MD1, Akhil Bindra, MD1, Brian D. Southern, MD1, Joseph Parambil, MD1, Thomas D. Callahan, MD2, Emer Joyce, MD, PhD3, Daniel A. Culver, DO1 Cleveland Clinic, Respiratory Institute, Cleveland, USA
2
Cleveland Clinic, Heart and Vascular Institute, Cleveland, USA
3
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1
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Mater Misericordiae University Hospital, Department of Cardiology, Dublin, Ireland *Corresponding author information: Manuel L Ribeiro Neto, 9500 Euclid Avenue, A90, Cleveland, Ohio, 4415, USA, (e-mail: [email protected]).
Abstract: Background. The diagnosis of cardiac sarcoidosis (CS) is challenging. Due to the current limitations of endomyocardial biopsy as a reference standard, physicians rely on advanced cardiac imaging, multidisciplinary evaluation, and diagnostic criteria to diagnose CS. Aims. To compare the three main available diagnostic criteria in patients clinically judged to have CS. Methods. We prospectively included patients clinically judged to have cardiac sarcoidosis by a multidisciplinary sarcoidosis team from 1
Journal Pre-proof November 2016 to October 2017. We included only incident cases (diagnosis of CS within one year of inclusion). We applied retrospectively the following diagnostic criteria: the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG), the Heart Rhythm Society (HRS), and the Japanese Circulation Society (JCS) 2016 criteria. Results. We identified 69 patients. Diagnostic criteria classified patients as follows: WASOG as highly probable (1.4%), probable (52.2%), possible (0%), some criteria (40.6%), and no criteria (5.8%); HRS as histological diagnosis (1.4%), probable (52.2%), some
of
criteria (40.6%), and no criteria (5.8%); JCS as histological diagnosis (1.4%), clinical diagnosis (58%), some
ro
criteria (39.1%), and no criteria (1.4%). Concordance was high between WASOG and HRS (kappa = 1), but
-p
low between JCS and the others (kappa = 0.326). Conclusion. A high proportion of patients clinically judged to have CS are unable to be classified according to the three main diagnostic criteria. There is low
lP
re
concordance between JCS criteria and the other two criteria (WASOG and HRS).
na
Keywords:
None
Jo
Acknowledgements:
ur
Cardiac Sarcoidosis, Cardiomyopathies, Arrhythmias
2
Journal Pre-proof Performance of Diagnostic Criteria in Patients Clinically Judged to Have Cardiac Sarcoidosis: Is It Time to Regroup? Manuel L. Ribeiro Neto, MD, Christine Jellis, MD, PhD, Rory Hachamovitch, MD, MSc, Allison Wimer, Kristin B. Highland, MD, Debasis Sahoo, MBBS, MD, Joseph E. Khabbaza, MD, Aman Pande, MD, Akhil Bindra, MD, Brian D. Southern, MD, Joseph Parambil, MD, Thomas D. Callahan, MD, Emer Joyce, MD, PhD, Daniel A. Culver, DO
of
Background
ro
The diagnosis of cardiac sarcoidosis (CS) is a very challenging process. Due to the current
-p
limitations of endomyocardial biopsy as a reference standard, physicians frequently rely on advanced cardiac imaging, multidisciplinary evaluation, and the available diagnostic criteria to diagnose or rule out
lP
criteria in patients clinically judged to have CS.
re
CS.1 In the present study, we aimed to compare the performance of the three main available diagnostic
Methods
na
We prospectively included patients clinically judged to have cardiac sarcoidosis after evaluation
ur
in a multidisciplinary sarcoidosis clinic from November 2016 to October 2017. The multidisciplinary
Jo
evaluation consisted of two key components: first, patients were seen in clinic by a pulmonologist and a heart failure specialist cardiologist, both with expertise in sarcoidosis; second, a multidisciplinary discussion was performed including other relevant subspecialties to the case (e.g. advance cardiac imaging specialist, electrophysiologist). A CS diagnosis was adjudicated after review of diagnostic data (e.g. extra-cardiac sarcoidosis diagnosis, electrocardiography, echocardiogram, advanced cardiac imaging). We included only incident cases (diagnosis of CS within one year of registry inclusion). We then reviewed the electronic medical records and applied the three main available diagnostic criteria for CS: the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG)2, the Heart Rhythm Society (HRS)3, and the Japanese Circulation Society (JCS) 2016 criteria4,5. Patients who had
3
Journal Pre-proof some criteria components but not enough to be conclusively classified (e.g. no biopsy-proven sarcoidosis for WASOG and HRS, just one major criterion for JCS) were labeled as “some criteria”. This study was reviewed and approved by the Institutional Review Board (IRB) at the Cleveland Clinic (IRB 19270). No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.
of
Results
ro
We identified 69 patients, the majority of whom were male (60.9%) and white (81.2%) (Table 1).
-p
Most patients (58%) had biopsy proven extra-cardiac sarcoidosis, with common extra-cardiac manifestations being pulmonary (69.6%), non-thoracic lymph node (31.9%), splenic (21.7%), and hepatic
re
(14.5%) involvement. Mean (SD) age at CS diagnosis was 53 ± 9.8 years, with median time from
lP
symptoms to diagnosis of 7 months (IQR 22). CS was suspected based on symptoms (84.1%) or routine screening of patients with extracardiac sarcoidosis (14.5%). Common cardiac manifestations were highatrioventricular
block
(39%),
na
degree
heart
failure
(36%),
and
sustained
ventricular
ur
tachycardia/ventricular fibrillation (23%). Cardiac MRI (CMR) was performed in 68.1% (47/69), and 18F-
Jo
fluorodeoxyglucose cardiac positron emission tomography (18F-FDG cardiac PET) scan in 87% (60/69), most of them (54/60, 90%) with perfusion imaging. Isolated CS was present in 17 (26%) of patients. The prevalence of each criterion of the WASOG criteria according to the classification we used is shown in Table 2. Diagnostic criteria classified patients as follows: WASOG as highly probable (1.4%), probable (52.2%), possible (0%), some criteria (40.6%), and no criteria (5.8%); HRS as histological diagnosis (1.4%), probable (52.2%), some criteria (40.6%), and no criteria (5.8%); JCS as histological diagnosis (1.4%), clinical diagnosis (58%), some criteria (39.1%), and no criteria (1.4%). Concordance was high between WASOG and HRS (kappa = 1), but low between JCS and the others (kappa = 0.326) (Table 2).
4
Journal Pre-proof The main reason for failure to classify patients according to the WASOG and HRS criteria was the absence of biopsy confirmation of sarcoidosis (29 of 32 unclassified patients), with 53% (17/32) of them having isolated CS. Within the 17 patients with no biopsy and isolated CS, 77% (13/17) had patchy FDG uptake on 18F-FDG cardiac PET, 59% (10/17) had perfusion defects on 18F-FDG cardiac PET, and 77% (13/17) had delayed gadolinium enhancement (DE) on CMR. In patients with no biopsy-proven sarcoidosis (n = 29), the CS diagnosis was made by the JCS criteria more frequently than the
of
WASOG/HRS criteria (45% versus 0%). In patients with isolated CS, the CS diagnosis was made by the JCS
ro
criteria more frequently than the WASOG/HRS criteria (28% versus 6%).
-p
Conclusion
The present study demonstrates that a high proportion of patients clinically judged to have CS
re
by a multidisciplinary evaluation are unable to be classified according to the three main diagnostic
lP
criteria pathways. Furthermore, it shows a low concordance between the 2016 JCS criteria and the other two criteria (WASOG and HRS), with the JCS criteria more frequently classifying patients as having
na
clinical CS compared to WASOG and HRS criteria. These findings are mainly driven by a high proportion
ur
of patients with no tissue confirmation of sarcoidosis (42%) and isolated CS (26%) in our cohort. The high
topic.6
Jo
proportion of isolated CS in our cohort is similar to the one cited by a recent focused review on the
In most patients with no tissue confirmation (n = 29), biopsy was not pursued because patients had typical features of isolated CS (17/29) and no other explanation after an exhaustive evaluation. This raises an important question: how should we diagnose CS in patients with suspected isolated disease? A small prospective cohort of 31 Canadian patients suggests that the first step should be a whole-body PET scan to confirm truly isolated disease. In that study, the PET scan identified extra-cardiac disease in most patients, and the prevalence of isolated CS was only 3.2%.7 A retrospective cohort of 55 Finish patients demonstrated a specific approach to endomyocardial biopsies (EMBx) once isolated cardiac disease was
5
Journal Pre-proof suspected. Repeated sessions (up to three) of EMBx guided by advanced cardiac imaging increased the diagnostic yield from 32% to 55%, with no major complications.8 However, in many other studies the EMBx diagnostic yield is limited to 20-30%.1,9–11 The 2016 JCS criteria includes criteria for isolated CS, but since it is not derived from prospective studies its clinical applicability is uncertain. Therefore, prospective studies are needed to better define the ideal approach to diagnose isolated CS. In the remaining patients with no tissue confirmation, extra-cardiac manifestations were
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present, but no diagnostic biopsy was obtained (12/29). Some of the reasons for no biopsy included
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typical imaging findings for sarcoidosis with no evident alternative cause, history of Lofgren’s syndrome,
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and typical imaging findings with non-diagnostic biopsies. This underscores a second important question: when can CS be accurately diagnosed without tissue confirmation? This question has been
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addressed in other sarcoidosis manifestations. The classic study from Winterbauer et al demonstrated
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that asymptomatic patients with bilateral and symmetric hilar adenopathy can be safely diagnosed with sarcoidosis.12 Lofgren’s syndrome (acute onset of fever, erythema nodosum, ankle arthritis, and bilateral
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hilar adenopathy) is another circumstance where a biopsy is not necessary.13 Such evidence does not
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exist for CS. Studies are needed to address this important clinical question.
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Our study has several limitations. First and foremost, our clinical judgement could be overdiagnosing CS in our cohort, and not the diagnostic criteria missing true disease. We believe this bias is minimized by the fact that we evaluated patients in a multidisciplinary sarcoidosis clinic that includes pulmonologists alongside heart failure, cardiomyopathy, electrophysiology and advanced cardiac imaging specialist cardiologists. In addition, all patients had at least one advanced diagnostic imaging study, and most patients had both 18F-FDG cardiac PET and CMR, which has been demonstrated to have complementary value in assessing the likelihood of CS.14 A second limitation is the lack of systematic evaluation of all patients in a formal multidisciplinary meeting. Although some patients were discussed in such setting, this did not happen consistently for all patients. A third
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Journal Pre-proof important limitation is that this is was a single center study. So clinical aspects specific to our practice could have played a role in our results (e.g. not obtaining EMBx in most patients with isolated CS). In conclusion, this study demonstrates that the main three available diagnostic criteria for CS do not encompass a high proportion of patients faced with suspected CS. Moreover, the WASOG and the HRS criteria have low concordance with the JCS criteria. These findings seem to be driven by a high proportion of patients with no tissue confirmation of sarcoidosis and isolated CS. We suggest that
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further prospective and multicentric studies are needed to better define the best approach to diagnose
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isolated CS and to identify whether cardiac sarcoidosis can be accurately diagnosed without a biopsy in
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specific situations. Disclosures: None
Cooper LT, Baughman KL, Feldman AM, et al. AHA / ACCF / ESC Scientific Statement The Role of
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Table 1. Demographics and clinical characteristics.
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Demographics and characteristics Total = 69 patients Male gender, n (%) 42 (60.9) White, n (%) 56 (81.2) Comorbidities, n (%) Hypertension 26 (37.7) Diabetes 5 (7.2) Biopsy-proven sarcoidosis, n (%) 40 (58) Organ involvement, n (%) Lungs 48 (69.6) Non-thoracic lymph nodes 22 (31.9) Spleen 15 (21.7) Liver 10 (14.5) Bone and joints 8 (11.6) Skin 7 (10.1) Eyes 4 (5.8) Parotid 3 (4.3) Hypercalcemia 2 (2.9) Neurologic 1 (1.4) Renal 1 (1.4) Age (in years) at cardiac sarcoidosis diagnosis, mean (SD) 53 (9.8) Time (in months) from symptoms to diagnosis, median (IQR) 7 (22) Presentation mode, n (%) Symptoms 58 (84.1) Screening 10 (14.5) Cardiac imaging for other reason 1 (1.4) Cardiac manifestations, n (%) High-degree atrioventricular block 27 (39.1) Heart failure (EF < 50%) 25 (36.2) Sustained ventricular tachycardia/ventricular fibrillation 16 (23.2) 18F-FDG cardiac PET scan results, n (%) Patchy FDG uptake 52 (75.4) Rb-82 perfusion abnormalities 32 (46.4) Cardiac MRI results, n (%) Delayed gadolinium enhancement 35 (50.7) T2 abnormalities 8 (11.6) Legend. EF: ejection fraction; PET: positron emission tomography scan; FDG: fludeoxyglucose; Rb-82: Rubidium-82. MRI: magnetic resonance imaging.
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Table 2. Prevalence of each criterion of the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) criteria, according to each classification we used for the present study.
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WASOG criteria (total = 69 Highly probable, Probable, Some criteria, No criteria, patients) n=1 n = 36 n = 28 n=4 Biopsy-proven sarcoidosis 1 36 0 3 Endomyocardial biopsy with granulomatous 1 0 0 0 inflammation Treatment responsive cardiomyopathy or 0 9 6 0 atrioventricular node block Reduced LVEF in the absence of other clinical 0 9 4 0 risk factors Spontaneous or inducible sustained ventricular 1 8 7 0 tachycardia with no other risk factor Mobitz type II or 3rd 0 14 13 0 degree heart block Patchy uptake on 1 29 22 0 dedicated cardiac PET Delayed enhancement on 1 16 18 0 cardiac MRI Positive gallium uptake 0 0 0 0 Defect on perfusion 0 0 0 0 scintigraphy or SPECT scan T2 prolongation on 0 4 4 0 cardiac MRI Reduced LVEF in the presence of other risk 0 5 7 0 factors (HTN, DM) Atrial dysrhythmias 0 6 8 0 Legend: LVEF: left ventricular ejection fraction; PET: positron emission tomography scan; MRI: magnetic resonance imaging; SPECT: single-photon emission computed tomography; HTN: hypertension; DM: diabetes mellitus. The columns don’t add up to 100% because one patient could have more than one criterion.
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Table 3. Concordance between the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) and the 2016 Japanese Circulation Society (JCS) criteria (kappa = 0.326). WASOG Highly probable
Some criteria*
Probable
No criteria
Total
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Histological 1 0 0 0 1 diagnosis Clinical 0 27 13 0 40 JCS diagnosis Some 0 9 15 3 27 criteria No criteria 0 0 0 1 1 Total 1 36 28 4 69 Legend: *Patients who had some criteria but not enough to be properly classified (e.g. no biopsy-proven sarcoidosis for WASOG and HRS, just one major criterion for JCS) were labeled as “some criteria”.
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