1 Clinical Presentation: suspected CS Diagnosis of Cardiac - - PDF document

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Rheumatologic Evaluation and Treatment

• f Cardiac Sarcoidosis

Julie Zikherman Associate Professor Division of Rheumatology Department of Medicine UCSF Medical Center September 13, 2019 California HRS

Disclosures

No relevant financial relationships with commercial interests to disclose

Outline

• 1. Diagnosis and rheumatologic work-up of

cardiac sarcoidosis

• 2. Indications, options, and contra-indications for

immunosuppression

• 3. UCSF cardiac sarcoidosis cohort – response to

steroid-sparing agents

Prevalence of Cardiac Sarcoidosis

2014 HRS Expert Consensus Document on CS Rao and Dellaripa. Rheum Dis Clin North Am 2013

5% prevalence of clinically apparent CS in US sarcoid patients At least 25% prevalence of silent CS in this group by autopsy studies CS is most common cause of death in sarcoidosis (13-25% in US, 58-85% in Japan) screening for CS in sarcoidosis is recommended (symptoms review, ECG, TTE)

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Diagnosis of Cardiac Sarcoidosis

2014 HRS Expert Consensus Document on CS

Diagnosis of Cardiac Sarcoidosis

2017 Japanese criteria of CS diagnosis Terasaki et al. Ann of Nuc Card 2017 Diagnosing ‘isolated’ cardiac sarcoidosis in absence of myocardial biopsy is challenging but purely clinical criteria exist:

Clinical Presentation: suspected CS

Scenario 1– patient with biopsy-proven (usually pulmonary) sarcoidosis who is subsequently found to have findings/symptoms suggestive of CS including conduction disease and/or VT+/- ventricular dysfunction – may be symptomatic or subclinical. Scenario 2– patient without a known history of sarcoidosis who presents with findings/symptoms suggestive of CS (conduction disease and/or VT +/- unexplained cardiomyopathy). – This group of patients largely present with symptoms – e.g. heart block, VT, CHF.

specific electrophysiological features of CS covered in the next presentation

Approach to diagnosis and work-up

2017 Japanese criteria of CS diagnosis (1) Establish CS diagnosis (2) Establish extent of extra-cardiac organ involvement (3) Establish degree of active inflammation in the heart (4) Pre-screening for possible immunosuppression

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Establishing a CS diagnosis

Scenario 1– established systemic sarcoidosis found to have findings/symptoms suggestive of CS. Advanced imaging with:

• fdg-PET (ideally matched area of

fdg uptake and perfusion defect) and/or

• delayed enhancement on cMRI

are sufficient to establish the diagnosis (exclusion of other causes such as ischemic heart disease etc.) Myocardial biopsy is not required. Often these diagnoses are clear.

2014 HRS Expert Consensus Document on CS

Establishing a CS diagnosis

Scenario 2– patient presents with findings/symptoms suggestive of CS in the absence of known sarcoidosis

search for extra-cardiac sarcoidosis and (ideally) biopsy it + advanced cardiac imaging positive endomyocardial biopsy isolated cardiac sarcoidosis diagnosed clinically (2017 Japanese criteria) + advanced cardiac imaging

three routes to diagnosis

(greatest degree

• f uncertainty)

(a) (b) (c) if not if not

Establishing a CS diagnosis

Scenario 2– patient presents with findings/symptoms suggestive of CS in the absence of known sarcoidosis (a) cMRI / FDG-PET to establish plausible cardiac inflammation. If fdg-avid LAD especially in chest  pursue LN biopsy If chest CT shows evidence of sarcoidosis  bronchoscopy with EBUS bx (b) If neither, consider endomyocardial bx but low yield if area of focal fdg- uptake/DE on cMRI does not involve an accessible area. (c) If no cardiac biopsy, pursue a clinical diagnosis of isolated CS This is the group of patients that includes those in whom diagnosis is less certain.

Work-up for extra-cardiac sarcoidosis

Screen for and monitor status of extra-cardiac manifestations of sarcoidosis:

• chest imaging and PFTs at baseline, and at least q 12 mo PFTs
• baseline and annual ophthalmology exam
• skin exam
• ROS to screen for MSK, neurological symptoms
• labs to include 24hr urine ca, serum 1,25 vit D, and 25-oh vitamin D
• +/- CD4 lymphocyte counts
• +/- Ig levels to screen for underlying CVID (can cause sarcoid-like granulomatous

disease)

• other w/u determined by symptoms or lab abnormalities

e.g. CBC, LFTs, cr

Extra-cardiac/pulmonary sarcoidosis: skin, ocular, neurological, MSK, ca/d axis, renal, liver, spleen

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Pre-screening for possible immunosuppression

• hep B serologies
• hep C serologies
• HIV
• quantiferon
• baseline labs including cbc with diff, cr, LFTs

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Patients with definite or probable CS who have ‘active cardiac inflammation’ as determined by FDG uptake on PET clinical judgment is important in cases where contra-indications to immunosuppression exist (e.g. recent cancer) and/or uncertainty about the diagnosis exists (e.g. no tissue, isolated CS)

Who should be treated with immunosuppression? Immunosuppression – Why Treat?

No Randomized Data! Observational Data:

• 1. Prevent Scarring/Heart Failure
• 2. Prevent Arrhythmias
• 3. Reverse AV Block
• 4. Prolong Life?

Immunosuppression: options

No consensus on optimal approach Standard of care had been corticosteroids Emerging role for steroid-sparing agents (SSA)

• methotrexate:

can’t use with significant renal impairment or liver disease first line SSA for pulmonary sarcoidosis

• TNF blockers:

concern in heart failure, especially NYHA class 3/4 effective for ocular and neurologic sarcoidosis, but less so with pulmonary disease

• azathioprine:

screen for low metabolizer TPMT pht/gt, risk of cytopenias especially leukopenia Second line SSA for pulmonary sarcoidosis

• cellcept:

less data for sarcoidosis, but likely effective

• newer kinase inhibitors and other biologics:

Jak inhibitors? IL-6 blockade? Insufficient data so far

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Our treatment algorithm

INITIAL APPROACH Prednisone approx. 40mg/d taper over 3-4 months to <=5mg/d Simultaneously introduce SSA (first line is mtx) titrate mtx up to 20mg po weekly (or sc if GI intolerance) f/u PET once pred <=5mg/d and >= 3 months on mtx SECOND LINE If intolerant to mtx or incomplete response on PET: TNFi Adalimumab (Humira) 40mg sc q 2 weeks (+ mtx 7.5-15mg/wk) Other TNF mAbs reasonable (e.g. infliximab, certolizumab, golimumab) Etanercept (Enbrel) is a soluble TNF receptor: NOT effective and can cause sarcoidosis (rarely). If CS diagnosis isolated and uncertain: less likely to use TNFi If EF severely depressed and/or class 3-4 NYHA symptoms, avoid TNFi THIRD LINE If neither mtx nor TNFi can be used, or both fail: aza or cellcept Confirmatory PET on each new therapy to ensure response Surveillance PETs on stable therapy

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UCSF CS cohort: nearly all with clinical disease and extra-cardiac sarcoidosis

Rosenthal et al. manuscript in press, JAHA 2019

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Response of UCSF CS cohort to immunosuppression

Rosenthal et al. manuscript in press, JAHA 2019

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Response of UCSF CS cohort to immunosuppression

Rosenthal et al. manuscript in press, JAHA 2019

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Recurrence OFF immunosuppression

Rosenthal et al. manuscript in press, JAHA 2019 High rate of recurrent positive PET after discontinuing IS (16%) (89%)

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Relapse ON immunosuppression

Rosenthal et al. manuscript in press, JAHA 2019 (16%) (89%) We have seen recurrent disease ON therapy :

• subclinical progression caught on PET
• clinical disease including worsening LV dysfunction and

recurrent heart block consider surveillance PET even ON therapy

Conclusions

• Patients with systemic sarcoidosis should be screened for CS
• Increasing role for advanced cardiac imaging (cMRI, PET) in

diagnosis and monitoring of CS

• No randomized data, but immunosuppression for active disease can

prevent deterioration in EF, improve ventricular arrhythmias, and reverse complete heart block

• UCSF cohort data suggests mtx or adalimumab may be effective

SSAs

• UCSF cohort data suggests significant rate of radiographic and

clinical recurrence after IS stopped

• UCSF cohort shows some relapse ON immunosuppression so we

favor ongoing surveillance with PET scans

Active Questions in clinical diagnosis and management of CS

• Should clinically-silent CS be treated?
• What is optimal up-front IS?
• Duration of IS?
• How common is isolated CS?

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Acknowledgements

clinical research and care of UCSF sarcoidosis patients:

David Rosenthal, UCSF EP Fellow Vasanth Vedantham and colleagues, UCSF EP Van Selby, Teresa DeMarco and colleagues, UCSF cardiology Laura Koth, Nikko Arger and colleagues, UCSF Pulmonary Jeff Gelfand, UCSF Neurology