Optimizing Care in Pulmonary Sarcoidosis

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Hello, Good evening, everyone.

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Nice to see everybody on the call.

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Thanks for joining us tonight with this program with Doctor Daniel Vis.

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My name is Lee Fidler and I'm a respirologist at Sunnybrook Health

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Sciences Center in the University Health Network in Toronto.

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And it's my pleasure to moderate this evening's program and introduce you to

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tonight's speaker.

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Doctor Daniel Vis is a respirologist and assistant professor at the University of

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Calgary.

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He's the medical director of the Pulmonary Sarcoidosis Clinic,

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a recognized sarcoidosis clinic by the World Association of Sarcoidosis and

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Other Granulomatous Disorders.

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His clinical and research work focuses on advanced pulmonary sarcoidosis and

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bronchoscopy and he collaborates with colleagues in nearly all medical

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subspecialities.

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He's currently leading population level and translational research studies in

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sarcoidosis.

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We hope that you find value in today's unaccredited medical education

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presentation.

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Now, before we start, 
we need to cover a few housekeeping items.

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And to ensure the evening's program is fair and balanced,

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The faculty has been fully responsible for developing the content in this

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learning activity.

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In the spirit of balance and integrity, here are the faculty's disclosure slides.

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And now with without further ado, I'll hand it over to Doctor Daniel Vis.

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Awesome.

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Thanks for that kind introduction, Dr.

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Fidler.

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It's a real pleasure to have the opportunity to speak in front of everyone

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today about, you know, my favorite disease.

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Building the Sarcoidosis Clinic has been a very rewarding experience.

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The patients are fun to take care of and I think that a clinic dedicated to

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sarcoidosis has, you know, 
been an unmet need in many centers and

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certainly ours.

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I look to take those learnings gathered from the last six years of running the

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pulmonary sarcoidosis clinic to explore a few things

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today. 
Our learning objectives will include

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exploring latest insights into clinical presentation of pulmonary sarcoidosis,

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reviewing current treatment strategies and approaches for managing pulmonary

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sarcoidosis.

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We'll place an emphasis on those with refractory disease and then as a kind of

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a fun way to finish, 
try to identify some practical strategies

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to overcome common challenges in diagnosis and management.

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I'd like to give some acknowledgements as I get started.

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The two photos at the top, 
the the gentleman was my primary mentor

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at the Royal Brompton Hospital in the UK.

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His name is Vasilis Kouranos, 
he's an expert clinician scientist and a

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really level headed sarcoidosis clinician.

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Really gave me my framework and understanding for approaching these

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complex patients.

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Beside is our clinical nurse specialist who makes our clinic run.

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You know, 
it wouldn't be possible without her

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support and then we're supported by the University of Calgary,

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the Snyder Institute for Chronic Diseases, which helps with translational research

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and good association with basic scientists.

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And then many, 
many thanks to the Canadian Sarcoidosis

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Organization.

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For anyone not familiar, 
they should look into the Canadian

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Sarcoidosis Organization.

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They're a really grassroots body that's donated quite a bit and very generously

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to to my sarcoidosis research and they look to continue fundraising every year

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for sarcoidosis research initiatives.

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Oh, sorry about that guys.

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And we'll start with reviewing the clinical presentation.

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Now, 
I won't spend too much time delving into

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the clinical presentation.

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Most of this will be fairly familiar to you guys.

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We'll try to get into the some of them, maybe the more interesting or nuanced

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things, 
but always good to set set the table with

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some clinical background.

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Sarcoidosis is currently understood to occur because of a combination of an

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environmentally triggered immune mediated phenomenon plus a genetically predisposed

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host.

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That's a very interesting disease that can vary widely with its symptoms and

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disease course.

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It's also fun to treat because there's 
less clearly defined management algorithm

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than we have with, you know, 
asthma or COPD and the treatment regimens

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can be associated with significant side effects and complications.

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The figure to the right is reviewing some of the histopathologic findings

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classically associated with sarcoidosis as well as some, you know,

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very classic X-rays and CT findings, you know,

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with bilateral hilar and mediastinal adenopathy, nice doughnut sign.

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And then, you know, 
significant thoracic lymphadenopathy and

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some perilymphatic nodularity.

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I won't spend too much time delving into this,

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but this is a little figure I made for myself to help remind me the

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pathophysiology of sarcoidosis.

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Remember there's an antigen that comes to an antigen presenting cell,

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either a macrophage or a dendritic cell.

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This starts a CD4 mediated phenomenon by Th1 and Th17 cells.

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A variety of cytokines, 
you know common ones make TNF alpha,

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IL-6 circulate to form a granuloma and that granuloma is persistent usually

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because of a Th17 to Th1 imbalance with addition T regulatory cells and B cells

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also contributing to maintenance of persistent granulomas.

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This figure will come up again later as we talk about therapeutic mechanisms.

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This poor gentleman is a Microsoft stock image who we're going to give a horrible

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case of sarcoidosis.

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We'll start by giving him pulmonary sarcoidosis.

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Remember that 90% of patients with sarcoidosis have some pulmonary

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involvement, whether that's adenopathy, nodules, PMF, UIP,

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or pulmonary hypertension.

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And the progressive fibrotic variant is important to recognize as it's [a]

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meaningful driver of mortality.

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Here's a gentleman with the progressive fibrocystic variant.

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He's a 68 year old gentleman from my practice who is on chronic oxygen.

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He's quite unwell.

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Cardiac sarcoidosis is very important to recognize as it disproportionately drives

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morbidity and mortality.

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Depending on the study you read, somewhere around 10% of patients have

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sarcoidosis with clinically apparent phenomenon,

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but up to 1/3 have cardiac sarcoidosis on a biopsy.

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There's two major types of cardiac disease,

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conduction disease and cardiomyopathy.

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Treatment should be considered in all patients with evidence of active

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inflammation on FDG-PET.

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But many of the treatments for cardiac sarcoidosis will not surround

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immunosuppression.

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It will be things like heart failure management, ICD placement,

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pacemaker therapies, 
and these will generally be ...

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these decisions will be made in conjunction with our colleagues in

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cardiology.

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This is a fun case vignette. 
A 30 year old gentleman who was referred

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to me for shortness of breath and some faint pulmonary nodules.

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I don't know how well it's projecting but you can see he's got some some visual

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nodularity here.

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I took him for the bronchoscopy.

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He had an abnormal rhythm strip and so 
did an ECG on him which confirmed a right

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bundle branch block.

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Uncommon for a 30 year old gentleman.

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Ended up presenting a few weeks afterwards and with a perfusing VT in the

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hospital.

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Was admitted to the Foothills Medical Center or Cardiology Center and had a PET

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scan performed with, you know, dramatic avidity.

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Shortly after.

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He had a pacemaker placed and he's [done fantastic] since.

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Hepatic sarcoidosis is common and important to recognize.

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Up to 50 to 60% of people on a biopsy or on autopsy will have hepatic involvement

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of their sarcoidosis.

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The severity is quite, 
can range quite widely from mild liver

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enzyme abnormalities all the way to cirrhosis and portal hypertension.

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Asymptomatic liver enzyme elevation is extremely common and should be followed

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without, you know, worrying too much about it.

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You know, 
an isolated alkaline phosphatase

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elevation, you know, 
between 120 and 300 is very common.

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You know, I, you know, 
somewhere between 25 and 50% of patients

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will carry that.

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And you know, 
when you're working up an

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undifferentiated patient, 
I find this isolated cholestatic liver

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enzyme elevation is, is, 
is is something that raises my pre-test

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probability for sarcoidosis.

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Indications for treatment include Cholestasis.

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And so if the patient has bilirubinemia, that's probably an indication for

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treatment or impaired synthetic dysfunction.

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And then they should at least see a hepatologist to help with some treatment

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decisions if the ALP is greater than 
three times upper limit normal or there's

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persistent ALP abnormalities.

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Renal sarcoidosis is is fairly common as well.

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10 to 15% will have some renal involvement.

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2 major categories of renal disease, interstitial nephritis and then

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nephrolithiasis and calcium issues.

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They're often managed a bit differently.

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Patients with reduced GFR, 
we're typically aiming to treat them.

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And so if their reduced GFR is from renal inflammation directly,

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then corticosteroids.

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If their reduced GFR is from hypercalcemia,

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corticosteroids could also be useful.

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But there's a few other treatments that can be useful for this category of

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patients as well, 
including hydroxychloroquine and

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ketoconazole, 
which are generally felt to be less

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effective for interstitial nephritis and ketoconazole would not be effective for

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interstitial nephritis.

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We have dermatologic sarcoidosis.

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Macular papular sarcoidosis is the classic one we think about.

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It can look like almost anything.

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And so don't rule out any manifestations too early.

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You know, 
get your friendly colleagues from

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dermatology to, you know, 
become involved or or perhaps perform a

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skin biopsy.

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Non-immunosuppressive therapies are often considered first, right?

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Topical therapies, laser therapies, some immunomodular therapies like,

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you know, Minocycline, hydroxychloroquine. Erythema nodosum is another dermatologic

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manifestation typically associated with the Lofgren's syndrome variant.

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But some patients with sarcoidosis have erythema nodosum outside of Lofgren's

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syndrome.

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Usually about 85% of the erythema nodosum will be self-resolving in two years.

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The most important dermatologic manifestation to be to appreciate is

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lupus pernio, which is, 
you know fairly treatment refractory.

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Many times it's cosmetically disfiguring and generally requires systemic treatment

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over and above hydroxychloroquine.

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Calcium abnormalities are common in sarcoidosis, ranging from 6 to 18%.

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One of the biggest things that I that I 
took home managing a lot of hypercalcemia

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is to always check the PTH.

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You know that's an important - and we remember that from our internal medicine

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days.

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But about 10% of patients with hypercalcemia with sarcoidosis have it

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because of primary hyperparathyroidism.

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And so the primary hyperparathyroidism is is not so rare that it, you know,

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can't really coexist with sarcoidosis.

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And if you treat enough sarcoidosis, you will catch multiple cases of primary

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hyperparathyroidism, 
probably have about 5 patients with

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primary hyperparathyroidism in my practice that we've identified as a

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result of checking the PTH for hypercalcemia.

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About 50% of those patients with hypercalcemia will go on to develop renal

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dysfunction if left untreated.

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And so hypercalcemia is an indication for treatment on its own.

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On the other hand, 
treatment of asymptomatic hypercalciuria

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to prevent stone formation is generally not indicated.

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You focus on dietary changes first, so avoiding excessive vitamin D or

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calcium supplementation.

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You want to augment fluid intake and so at least 2 liters of water every day.

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Addition of some ascorbic acid via lemon juice or something can be helpful as well.

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You want to avoid thiazide diuretics, which I'm sure they reduce hypercalciuria

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but can worsen hypercalcemia, 
and you want to make sure that patient is

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compliant with the reduced oxalate diet.

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To cover briefly some of the common syndromes we have, the Lofgren's syndrome,

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which is the more common of the two, presents with a combination of fever,

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erythema nodosum, ankle arthritis, and hilar and mediastinal adenopathy,

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has an excellent prognosis with spontaneous resolution in 80 to 90% by

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two years, 
and treatment beyond NSAIDs is rarely

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required.

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Heerfordt-Waldenstrom syndrome or uveoparotid fever is the other commonly

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described sarcoidosis syndrome with fever, perititis, uveitis,

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and unilateral facial nerve palsy.

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Many people present with kind of a 
partial Heerfordt-Waldenstrom syndrome as

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well.

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If the patient has, you know, meaningful nerve palsy,

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they should generally receive treatment.

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Otherwise the manifestations are generally self resolving in one to three

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years.

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Hey, 
here's just an image of some patients

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that I saw with Lofgren's syndrome.

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You can see on the X-ray there is a pylon and the CT scan greatly shows mediastinal

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adenopathy.

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And here we have the ocular, neurologic, laryngeal, sino-nasal,

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osseus and bone marrow manifestations kind of broadly captured under other

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ocular is fairly common.

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And 10%, you know, 
depending on the study you read,

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5 to 25% of people will have it.

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About 5% of people who present with sarcoidosis present with ocular as their

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primary manifestation, 
neurologic sarcoidosis as a major driver

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of morbidity and mortality.

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And it's important to recognize not 10% don't have CNS disease,

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but this accounts people who have peripheral or small fiber neuropathy as

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well.

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Laryngeal, 
sino-nasal sarcoidosis are rare,

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but sino-nasal sarcoidosis can be quite - can carry meaningful morbidity.

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Osseus sarcoidosis often less so, but can be fairly uncomfortable for

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patients. 
And cytopenia is associated with bone

00:15:26.693 --> 00:15:29.974 
marrow sarcoidosis are difficult to quantify the frequency,

00:15:29.974 --> 00:15:32.435 
but cytopenias with bone marrow involvement,

00:15:32.435 --> 00:15:34.240 
you know are not uncommonly seen.

00:15:36.840 --> 00:15:42.534 
Spend a bit of time discussing the diagnostics now and so the diagnostic

00:15:42.534 --> 00:15:43.080 
workup.

00:15:43.240 --> 00:15:47.385 
This comes in, you know, 2 broad parts, but first you want to establish the

00:15:47.385 --> 00:15:50.821 
diagnosis and note that this does not always require a biopsy,

00:15:50.821 --> 00:15:52.839 
but frequently does require a biopsy.

00:15:54.000 --> 00:15:57.529 
Pre-test probability can be high enough in specific clinical and radiographic

00:15:57.529 --> 00:15:59.520 
situations, 
so we'll discuss a bit further.

00:16:01.720 --> 00:16:07.180 
Once you've solidified the diagnosis via a biopsy or a pathognomonic clinical

00:16:07.180 --> 00:16:11.030 
radiographic presentation, then you want to assess for

00:16:11.030 --> 00:16:13.200 
extra-pulmonary manifestations.

00:16:13.600 --> 00:16:15.473 
Generally, 
break this down into a few broad

00:16:15.473 --> 00:16:17.559 
categories, 
but you know you're going to want to

00:16:17.559 --> 00:16:20.326 
screen for cardiac disease, 
which for with - for everyone should

00:16:20.326 --> 00:16:22.199 
include an ECG as well as a symptom screen.

00:16:23.080 --> 00:16:25.841 
Based on the ECG, 
I have a low threshold to pursue

00:16:25.841 --> 00:16:29.360 
echocardiogram and also a low threshold to pursue a cardiac MRI.

00:16:29.360 --> 00:16:30.640 
If there's any abnormalities.

00:16:32.240 --> 00:16:35.807 
You want to screen for calcium abnormalities with serum and urine

00:16:35.807 --> 00:16:36.240 
calcium.

00:16:37.200 --> 00:16:40.090 
In general, 
I'll screen the patients on one occasion

00:16:40.090 --> 00:16:44.397 
with a 24 hour urine calcium at outset. That does not need to be repeated on a

00:16:44.397 --> 00:16:47.451 
regular basis, 
provided that you know the rest of their

00:16:47.451 --> 00:16:48.759 
clinical disease courses

00:16:49.280 --> 00:16:52.252 
uncomplicated, 
but it is useful to check on at least one

00:16:52.252 --> 00:16:55.120 
occasion to help inform potential dietary suggestions.

00:16:55.320 --> 00:16:58.480 
Prevention of even 1 renal stone can prevent a lot of pain and suffering.

00:17:00.160 --> 00:17:04.138 
Hepatic sarcoidosis you want to screen for the ALT, ALP and bilirubin.

00:17:04.138 --> 00:17:06.604 
Renal sarcoidosis, 
the standard creatinine.

00:17:06.604 --> 00:17:10.974 
Ophthalmologic sarcoidosis or ocular sarcoidosis you're only going to be able

00:17:10.974 --> 00:17:12.880 
to find with the help of a friend.

00:17:12.960 --> 00:17:16.634 
And so I refer all these patients to ophthalmology and then dermatologic and

00:17:16.634 --> 00:17:19.880 
neurologic sarcoidosis will be discovered with the symptoms screen.

00:17:19.880 --> 00:17:23.800 
There's no, you know, 
routine MRIs or routine EMGs.

00:17:28.880 --> 00:17:32.240 
And so the most common way to confirm the diagnosis is via bronchoscopy.

00:17:32.800 --> 00:17:35.617 
Bronchoscopy is a relatively accessible procedure,

00:17:35.617 --> 00:17:38.600 
combined safety and a high sensitivity for diagnosis.

00:17:39.880 --> 00:17:42.632 
Most cases should be considered for biopsy confirmation,

00:17:42.632 --> 00:17:43.840 
but there are exceptions.

00:17:44.000 --> 00:17:47.760 
And so Lofgren's syndrome is a classically defined exception.

00:17:48.080 --> 00:17:52.265 
Asymptomatic stage 1 sarcoidosis in the right patient population is also

00:17:52.265 --> 00:17:56.795 
generally thought to not need biopsy confirmation and I'll review a little bit

00:17:56.795 --> 00:17:59.720 
of the literature around that in a moment as well.

00:17:59.720 --> 00:18:04.663 
Select parenchymal disease behavior and patterns are also are not strictly

00:18:04.663 --> 00:18:09.935 
necessary in the recent diagnosis and detection of sarcoidosis ATS document and

00:18:09.935 --> 00:18:14.746 
in 2020 they do discuss that you know patients with long standing highly

00:18:14.746 --> 00:18:20.216 
characteristic parenchymal lung findings that have not changed for years can often

00:18:20.216 --> 00:18:25.160 
be followed as if they have sarcoidosis without, without further biopsies.

00:18:25.360 --> 00:18:30.945 
But if those patients have progressive disease or dynamic changes on their CT or

00:18:30.945 --> 00:18:36.186 
features that are not strictly in keeping, then biopsy is likely necessary.

00:18:36.186 --> 00:18:41.358 
These two studies are, you know, 
just good - a good review of why it's not

00:18:41.358 --> 00:18:46.600 
necessary to do a biopsy in everyone with asymptomatic stage 1 sarcoidosis.

00:18:46.920 --> 00:18:51.430 
The study on the right was just kind of a 
proof of concept study done with a

00:18:51.430 --> 00:18:56.175 
literature review where the author Jerome Reich took the fraction of patients in

00:18:56.175 --> 00:19:00.979 
the population that have sarcoidosis and then the fraction of those patients that

00:19:00.979 --> 00:19:03.439 
present with an asymptomatic presentation.

00:19:03.840 --> 00:19:08.221 
And then took the frequency in the population of the alternative important

00:19:08.221 --> 00:19:12.076 
diagnoses, namely lymphomas, 
Hodgkin and non-Hodgkin lymphoma and

00:19:12.076 --> 00:19:14.938 
tuberculosis, 
took the prevalence of them in the

00:19:14.938 --> 00:19:19.320 
population and also the fraction of those patients that were asymptomatic.

00:19:19.720 --> 00:19:24.908 
And so the fraction of patients that are asymptomatic with stage 1 sarcoidosis in

00:19:24.908 --> 00:19:29.337 
the general population is so, so, 
so much higher than the fraction of

00:19:29.337 --> 00:19:33.577 
patients that have these important alternative conditions that are

00:19:33.577 --> 00:19:34.400 
asymptomatic.

00:19:34.840 --> 00:19:40.103 
And so he estimated based on a ratio of these populations that you would have to

00:19:40.103 --> 00:19:44.586 
perform 10,000 bronchoscopies or 10, 
000 biopsies to confirm stage 1

00:19:44.586 --> 00:19:48.160 
sarcoidosis to find 5 alternative important diagnosis.

00:19:48.800 --> 00:19:50.040 
So .05%

00:19:51.880 --> 00:19:58.600 
The real seminal study where this concept was first elucidated was back in 1973.

00:19:59.320 --> 00:20:03.640 
A hundred patients underwent mediastinoscopy for all indications.

00:20:04.160 --> 00:20:08.589 
They looked back at the - at the diagnosis reached and in patients that

00:20:08.589 --> 00:20:12.895 
had a normal physical exam and were asymptomatic at the time of their

00:20:12.895 --> 00:20:13.880 
mediastinoscopy,

00:20:14.600 --> 00:20:19.557 
Every patient ended up having sarcoidosis, and so the author concluded that an a

00:20:19.557 --> 00:20:23.963 
priori diagnosis could be made in patients who were asymptomatic with a

00:20:23.963 --> 00:20:27.880 
normal physical exam with stage 1, stage 1 sarcoidosis changes.

00:20:34.200 --> 00:20:38.219 
When you're performing bronchoscopy, there are a few situations with stage 1

00:20:38.219 --> 00:20:42.291 
sarcoidosis where you should consider bronchoscopy and that would be atypical

00:20:42.291 --> 00:20:43.440 
radiographic patterns.

00:20:43.440 --> 00:20:47.880 
So let's say asymmetric adenopathy greater on one side than the other.

00:20:48.320 --> 00:20:51.372 
The patient has a concurrent or recent malignancy,

00:20:51.372 --> 00:20:56.041 
a high risk or suspicion of an active infection perhaps from a [ TB ] endemic

00:20:56.041 --> 00:20:56.519 
country.

00:20:56.520 --> 00:21:00.972 
Sometimes there is suspicion for clinically relevant extrapulmonary

00:21:00.972 --> 00:21:05.031 
sarcoidosis and so the patient has brain lesions or you know,

00:21:05.031 --> 00:21:08.960 
optic nerve swelling without other accessible biopsy sites.

00:21:09.440 --> 00:21:13.006 
In that case, if there's adenopathy, this is a great way to confirm a

00:21:13.006 --> 00:21:14.280 
diagnosis of sarcoidosis.

00:21:14.680 --> 00:21:19.763 
And then also at the stage 1 sarcoidosis patient just isn't really - the disease

00:21:19.763 --> 00:21:22.400 
behavior isn't isn't what we would expect.

00:21:22.600 --> 00:21:25.400 
I had a patient with, you know, long standing stage 1 pulmonary

00:21:25.400 --> 00:21:26.800 
sarcoidosis, stable lymph nodes.

00:21:27.040 --> 00:21:30.921 
And then one year his lymph nodes doubled in size and I took him to bronchoscopy

00:21:30.921 --> 00:21:31.880 
and he had lymphoma.

00:21:32.080 --> 00:21:36.020 
And so, you know, 
disease behavior out of keeping would be

00:21:36.020 --> 00:21:39.560 
an indication for - for biopsy and stage 1 patients.

00:21:40.000 --> 00:21:44.040 
Generally care should be given to the least invasive biopsy site.

00:21:44.080 --> 00:21:46.353 
And so if a patient has active dermatologic lesions,

00:21:46.353 --> 00:21:47.640 
that's a great place to start.

00:21:47.720 --> 00:21:49.640 
If they don't, you know, maybe bronchoscopy.

00:21:49.920 --> 00:21:54.202 
If they don't, you know, maybe you know, endomyocardial, liver, etcetera, you know,

00:21:54.202 --> 00:21:55.120 
a targeted biopsy.

00:22:00.800 --> 00:22:04.764 
The utility of different techniques varies on rate based on radiographic

00:22:04.764 --> 00:22:06.720 
stage as well as mucosal appearance.

00:22:08.200 --> 00:22:08.960 
EBUS-TBNA

00:22:08.960 --> 00:22:13.760 
Depending on the study you read, the yield is between 57% and 94%.

00:22:14.920 --> 00:22:18.660 
The - That yield ranges so much because it depends what stage you do,

00:22:18.660 --> 00:22:22.240 
and for patients with stage 1 disease the yield is extremely high.

00:22:22.480 --> 00:22:26.120 
As you increase the stage, the yield drops reliably.

00:22:27.040 --> 00:22:30.738 
In transbronchial lung biopsy, 
the yield is somewhere between 50% and

00:22:30.738 --> 00:22:34.066 
82% and it's higher in patients with stage 2 lung involvement.

00:22:34.066 --> 00:22:38.240 
Endobronchial biopsy performs a little bit worse, but not insignificantly bad.

00:22:38.240 --> 00:22:40.160 
The yield is still 39% to 62%.

00:22:40.600 --> 00:22:45.247 
It's higher actually if patients have abnormal appearing mucosa or are of

00:22:45.247 --> 00:22:46.880 
African American ancestry.

00:22:47.400 --> 00:22:48.560 
We can see in this picture here.

00:22:48.560 --> 00:22:52.160 
It's a great, 
it's a great airway for sarcoidosis.

00:22:52.160 --> 00:22:54.909 
You know, this is clear gobblestoning, OK, You know,

00:22:54.909 --> 00:22:58.800 
quite a significant and quite a 
significant presentation of cobblestoning.

00:22:59.000 --> 00:23:03.200 
And so in these cases the endobronchial biopsy scores quite well.

00:23:06.160 --> 00:23:09.235 
This table, 
and that will come up here is from a

00:23:09.235 --> 00:23:13.440 
study that myself and colleagues did at the University of Calgary.

00:23:13.880 --> 00:23:17.984 
We were looking into different endobronchial biopsy techniques but also

00:23:17.984 --> 00:23:18.840 
performed EBUS.

00:23:19.640 --> 00:23:23.008 
This study was not aimed at describing these things, but this,

00:23:23.008 --> 00:23:24.720 
this is a big table nonetheless.

00:23:26.040 --> 00:23:30.760 
You can see they're classified by chest X-ray stage one, two, three and four.

00:23:31.000 --> 00:23:34.740 
And below in the red box you have endobronchial biopsy positivity versus

00:23:34.740 --> 00:23:35.560 
EBUS positivity.

00:23:36.320 --> 00:23:40.680 
And you can see in chest X-ray stage 1, endobronchial biopsy does not perform

00:23:40.680 --> 00:23:41.240 
very well.

00:23:41.240 --> 00:23:45.320 
Only about 22% of biopsies were positive. EBUS,

00:23:45.320 --> 00:23:48.720 
On the other hand, 
all 41 patients had a positive EBUS.

00:23:48.720 --> 00:23:52.771 
So in our study, 
you know the yield actually for stage 1

00:23:52.771 --> 00:23:56.680 
sarcoidosis patients was 100% and we have 41 patients.

00:23:56.680 --> 00:23:59.360 
So you know, a meaningful, meaningful cohort.

00:24:00.160 --> 00:24:05.628 
Stage 2 sarcoidosis on the other hand, you see a clear step up in endobronchial

00:24:05.628 --> 00:24:10.960 
biopsy positivity up to 51% with a clear drop in EBUS positivity down to 71%.

00:24:11.720 --> 00:24:15.040 
As you go into stage 3, 
the numbers start to really fall.

00:24:15.040 --> 00:24:18.966 
Our cohort was not enriched with as many stage 3 or stage 4 patients,

00:24:18.966 --> 00:24:23.453 
but you can see the endo bronchial biopsy still performs fairly well in stage 3

00:24:23.453 --> 00:24:25.360 
disease and stage 4 disease. EBUS,

00:24:25.360 --> 00:24:28.434 
On the other hand for stage 3 disease, it performed,

00:24:28.434 --> 00:24:33.074 
quite poorly despite the limited - taking into account the limited size of this

00:24:33.074 --> 00:24:33.480 
cohort.

00:24:33.760 --> 00:24:36.840 
We did were able to get positivity in stage 4 sarcoidosis.

00:24:36.840 --> 00:24:40.947 
But overall you see a trend of improved performance in earlier stage disease with

00:24:40.947 --> 00:24:44.904 
reduced performance later and then a kind of good performance of endobronchial

00:24:44.904 --> 00:24:47.960 
biopsy as the lungs become more involved with the condition.

00:24:51.960 --> 00:24:55.902 
And so this will take us to our first poll and so I'll provide a bit of

00:24:55.902 --> 00:24:58.640 
background and then Lorenzo will launch the poll.

00:24:59.200 --> 00:25:01.865 
And so, you know, 
you're under- you're performing a

00:25:01.865 --> 00:25:05.454 
bronchoscopy for this patient, 
a 42-year-old gentleman with cough and

00:25:05.454 --> 00:25:06.480 
shortness of breath.

00:25:06.600 --> 00:25:10.520 
His X-ray shows stage 2/3 radiographic 
changes.

00:25:11.160 --> 00:25:13.886 
His CT has shown mildly enlarged lymph nodes, you know,

00:25:13.886 --> 00:25:16.760 
between 1 and 2 cm and some early internal calcifications.

00:25:17.200 --> 00:25:20.520 
His mucosa appears inflamed with nodules and cobblestoning.

00:25:20.840 --> 00:25:23.000 
How would you approach this bronchoscopy?

00:25:26.920 --> 00:25:30.729 
We have the option of EBUS, 
EBUS-TBNA plus endobronchial biopsies,

00:25:30.729 --> 00:25:35.278 
EBUS-TBNA plus transbronchial biopsies or forgoing the EBUS-TBNA and proceeding

00:25:35.278 --> 00:25:38.520 
directly with endobronchial and transbronchial biopsies.

00:25:56.280 --> 00:26:01.080 
We'll give maybe 10 or 15 more seconds and then I will close the poll.

00:26:25.680 --> 00:26:25.960 
Awesome.

00:26:25.960 --> 00:26:28.640 
And so well the poll has ended.

00:26:28.640 --> 00:26:29.200 
Perfect.

00:26:30.040 --> 00:26:32.424 
And so yeah, 
we'll get Lorenzo to share the results

00:26:32.424 --> 00:26:33.800 
here so everyone can see them.

00:26:34.120 --> 00:26:39.448 
But the 55% of the audience gave the answer I was looking for EBUS-TBNA plus

00:26:39.448 --> 00:26:41.040 
endobronchial biopsies.

00:26:41.520 --> 00:26:44.695 
And so the, you know, 
EBUS-TBNA alone is likely to be

00:26:44.695 --> 00:26:48.400 
frustrating in a patient like this, especially with, you know,

00:26:48.400 --> 00:26:52.400 
only mildly enlarged lymph nodes and early internal calcifications.

00:26:53.320 --> 00:26:56.458 
Oftentimes the- the nodes can feel quite firm or, you know,

00:26:56.458 --> 00:26:59.440 
almost like a pencil eraser, and it gives scanty yields.

00:27:00.440 --> 00:27:05.160 
And so EBUS alone is unlikely to be enough in this person.

00:27:05.160 --> 00:27:09.708 
And so if we could add something that had incremental diagnostic yield without risk

00:27:09.708 --> 00:27:13.120 
or with minimal risk, 
that would really augment the EBUS-TBNA.

00:27:13.440 --> 00:27:16.680 
And I believe the audience selected the the correct answer,

00:27:16.680 --> 00:27:20.840 
which is EBUS-TBNA plus endobronchial biopsy. endobronchial - EBUS-TBNA plus

00:27:20.840 --> 00:27:24.240 
Transbronchial biopsy is not strictly incorrect.

00:27:24.960 --> 00:27:28.080 
However, 
because transbronchial lung biopsy

00:27:28.080 --> 00:27:33.257 
carries a higher risk of significant bleeding and also pneumothorax and,

00:27:33.257 --> 00:27:39.214 
and because the patient has cobblestoning that suggests the endobronchial biopsy is

00:27:39.214 --> 00:27:41.200 
likely to give us an answer.

00:27:41.600 --> 00:27:46.742 
Endobronchial biopsy is - would be - would add more diagnostic yield for less

00:27:46.742 --> 00:27:51.752 
risk And so is a better - a better 
procedure to pair with EBUS TBNA in this

00:27:51.752 --> 00:27:52.280 
context.

00:27:52.800 --> 00:27:57.397 
And so I would perform a EBUS-TBNA. 
Get my samples and then go back with

00:27:57.397 --> 00:28:02.120 
standard bronchoscope to obtain endobronchial biopsies from targeted area.

00:28:02.640 --> 00:28:06.612 
I mean this is a common strategy that I use in patients with a higher stage

00:28:06.612 --> 00:28:07.240 
sarcoidosis.

00:28:08.480 --> 00:28:12.864 
If the patient didn't have a nodular or inflamed mucosa with cobblestoning,

00:28:12.864 --> 00:28:17.536 
then -then I would select transbronchial lung biopsies because the endobronchial

00:28:17.536 --> 00:28:22.266 
biopsy is - the yield really drops if you don't have an abnormal appearing mucosa

00:28:22.266 --> 00:28:26.535 
and a transbronchial biopsy is more likely to add yield in the setting of

00:28:26.535 --> 00:28:27.920 
normal appearing mucosa.

00:28:31.040 --> 00:28:31.200 
Awesome.

00:28:31.400 --> 00:28:32.080 
Thanks, Lorenzo.

00:28:44.860 --> 00:28:50.365 
So now we'll talk a little bit about management in general as an approach to

00:28:50.365 --> 00:28:51.080 
treatment.

00:28:51.080 --> 00:28:53.358 
Major organ involvement requires treatment,

00:28:53.358 --> 00:28:57.603 
but defining major organ involvement can be difficult and even the most difficult

00:28:57.603 --> 00:29:00.710 
for pulmonary disease, 
which is common and has probably the

00:29:00.710 --> 00:29:02.160 
widest spectrum of severity.

00:29:03.240 --> 00:29:06.279 
Risk stratification for sarcoidosis patients historically been quite

00:29:06.279 --> 00:29:06.720 
difficult.

00:29:07.920 --> 00:29:11.428 
Unacceptable loss of quality of life 
should be addressed and should attempt to

00:29:11.428 --> 00:29:13.960 
be remediated with the safest and lowest dose treatment.

00:29:14.400 --> 00:29:17.309 
And so you kind of have two major headings to consider treatment,

00:29:17.309 --> 00:29:20.440 
major organ involvement and then unacceptable loss of quality of life.

00:29:22.880 --> 00:29:25.680 
There's also kind of two ways to think 
about treatments for these patients.

00:29:25.680 --> 00:29:28.684 
You know, one, 
can we treat their granulomas with

00:29:28.684 --> 00:29:31.749 
immunomodulating treatment, But on the other hand,

00:29:31.749 --> 00:29:36.257 
you never forget that treatments for the non-inflammatory complications of

00:29:36.257 --> 00:29:38.120 
sarcoidosis can also add value.

00:29:38.320 --> 00:29:42.435 
And so making sure their sleep apnea is appropriately managed for their fatigue,

00:29:42.435 --> 00:29:45.889 
making sure that they have good, good energy management strategies.

00:29:45.889 --> 00:29:48.429 
Making sure that if they have pulmonary fibrosis,

00:29:48.429 --> 00:29:51.325 
that they're being considered for drugs like nintedanib,

00:29:51.325 --> 00:29:55.237 
making sure that if they have sarcoidosis associated pulmonary hypertension,

00:29:55.237 --> 00:29:59.199 
that they're seen and considered for for treatments directed at vasodilation.

00:29:59.560 --> 00:30:02.954 
And so the anti-granuloma therapy is, 
it's valuable,

00:30:02.954 --> 00:30:07.438 
but there's only so far the 
anti-granuloma therapy could take you for

00:30:07.438 --> 00:30:09.680 
the non-inflammatory complications.

00:30:12.280 --> 00:30:15.040 
And so here's a little bit of a busy figure, but I'll take you guys through it.

00:30:15.120 --> 00:30:18.177 
And this is a nice paper that I liked from Current Opinion in Pulmonary

00:30:18.177 --> 00:30:18.560 
Medicine.

00:30:19.800 --> 00:30:22.400 
And so I stole the figure from it, referenced down below.

00:30:23.160 --> 00:30:25.010 
In general, 
you have sarcoidosis and you're asking

00:30:25.010 --> 00:30:26.680 
yourself, 
do you have an indication to treat?

00:30:28.000 --> 00:30:30.628 
You have asymptomatic patients, patients in danger,

00:30:30.628 --> 00:30:32.600 
patients with impaired quality of life.

00:30:32.600 --> 00:30:36.419 
As your 3 broad heading, 
they define what is danger here and what

00:30:36.419 --> 00:30:38.040 
is impaired quality of life.

00:30:38.400 --> 00:30:41.023 
To cover those briefly in pulmonary sarcoidosis,

00:30:41.023 --> 00:30:44.716 
that would be pulmonary fibrosis, hypoxemia, pulmonary hypertension,

00:30:44.716 --> 00:30:47.607 
severe impairment in PFTs, rapid changes in the PFTs,

00:30:47.607 --> 00:30:51.729 
cardiac disease, neurologic disease, ocular disease, renal disease, calcium,

00:30:51.729 --> 00:30:55.744 
significant hepatic dysfunction, 
all the things we covered in the clinical

00:30:55.744 --> 00:30:58.689 
diagnosis or sorry, 
the clinical presentation section.

00:30:58.689 --> 00:30:59.760 
For quality of life,

00:31:01.280 --> 00:31:04.015 
The patients with significant respiratory symptoms,

00:31:04.015 --> 00:31:08.225 
we know those patients with cough and shortness of breath, it's quite limiting,

00:31:08.225 --> 00:31:10.960 
you know, 
despite not having severe derangements in

00:31:10.960 --> 00:31:13.802 
their PFTs, 
patients with cosmetically important skin

00:31:13.802 --> 00:31:17.221 
lesions, Lupus Pernio, 
it kind of is on the border of danger and

00:31:17.221 --> 00:31:19.800 
quality of life because it's fairly disfiguring.

00:31:20.000 --> 00:31:23.275 
But other maculopapular sarcoidosis can be cosmetically important as well,

00:31:23.275 --> 00:31:24.280 
especially on the face.

00:31:25.040 --> 00:31:28.600 
And then pain or systemic issues are also in the quality of life category.

00:31:28.600 --> 00:31:32.671 
So things like small fiber neuropathy, fatigue, osseus disease, arthritis,

00:31:32.671 --> 00:31:33.160 
etcetera.

00:31:33.840 --> 00:31:37.601 
And so this flow chart is, is is nice, but if the patient is asymptomatic,

00:31:37.601 --> 00:31:40.160 
no anti-inflammatory treatment, follow them along.

00:31:40.720 --> 00:31:43.199 
If the patient is symptomatic, but they don't have danger,

00:31:43.199 --> 00:31:44.880 
they just have impaired quality of life.

00:31:45.680 --> 00:31:48.680 
Is there impaired quality of life related to organ dysfunction?

00:31:48.720 --> 00:31:49.960 
Well then maybe they are in danger.

00:31:49.960 --> 00:31:51.360 
You got to question your diagnosis.

00:31:51.680 --> 00:31:55.940 
But if their impaired quality of life is 
not related to organ dysfunction and they

00:31:55.940 --> 00:32:00.047 
don't have active disease and so let's say this is like obstructive sleep apnea

00:32:00.047 --> 00:32:04.205 
or fatigue and this - and the patient has coexistent obstructive sleep apnea but

00:32:04.205 --> 00:32:07.799 
without active sarcoidosis, 
you're going to want no anti-inflammatory

00:32:07.799 --> 00:32:10.519 
treatment, 
but organ and symptom targeted treatment.

00:32:11.320 --> 00:32:15.127 
If the patient has impaired quality of life and it's not related to organ

00:32:15.127 --> 00:32:17.596 
dysfunction, 
but they do have disease activity,

00:32:17.596 --> 00:32:20.580 
you're going to have to make a decision with the patient.

00:32:20.580 --> 00:32:24.747 
A risk/benefit discussion about the- the pros and cons of immunosuppression or -

00:32:24.747 --> 00:32:26.239 
or anti-granuloma treatments.

00:32:27.240 --> 00:32:29.840 
Most interesting is under the danger - danger category and so on.

00:32:29.840 --> 00:32:33.400 
Patients that are in danger, 
do they have disease activity?

00:32:33.520 --> 00:32:36.669 
And so you know, 
that could be assessed for in a variety

00:32:36.669 --> 00:32:38.880 
of ways, beyond the topic of this slide.

00:32:39.640 --> 00:32:44.404 
But if that - if they don't have disease activity but are in danger, for example,

00:32:44.404 --> 00:32:48.065 
pulmonary hypertension, 
then you're going to want to use organ

00:32:48.065 --> 00:32:50.680 
targeted and symptomatic targeted therapies.

00:32:51.120 --> 00:32:54.550 
On the other hand, 
if they're in danger and they have active

00:32:54.550 --> 00:32:59.049 
disease because they have hypoxemia, pulmonary fibrosis, rapid decline of PFTs,

00:32:59.049 --> 00:33:03.379 
well then you're going to want to talk about anti-inflammatory treatment and

00:33:03.379 --> 00:33:07.709 
maintain a good risk balance throughout the whole follow up as you treat the

00:33:07.709 --> 00:33:10.408 
patient or as their, their body changes, their,

00:33:10.408 --> 00:33:14.119 
the risks and benefits of various treatments will change as well.

00:33:24.670 --> 00:33:27.678 
And so I won't, 
I won't spend too much time on this,

00:33:27.678 --> 00:33:28.870 
this flow chart here.

00:33:29.390 --> 00:33:31.854 
It's a get it becoming a little bit 
outdated with some of the new literature

00:33:31.854 --> 00:33:32.430 
that's coming out.

00:33:32.430 --> 00:33:35.762 
But it's just a nice flow chart that comes from our most recent clinical

00:33:35.762 --> 00:33:36.630 
practice guideline.

00:33:38.000 --> 00:33:41.503 
There has been a new trial that came out in New England Journal of Medicine

00:33:41.503 --> 00:33:43.440 
earlier in 2025 called the PREDMETH trial.

00:33:43.760 --> 00:33:46.170 
That is, you know, 
maybe change the way how we approach some

00:33:46.170 --> 00:33:47.000 
of these early steps.

00:33:47.240 --> 00:33:49.433 
But in overall, 
I think this is still a nice,

00:33:49.433 --> 00:33:50.960 
nice flow chart to take through.

00:33:52.480 --> 00:33:55.524 
You have a patient with pulmonary sarcoidosis and you're going to assess

00:33:55.524 --> 00:33:58.694 
the need for treatment largely with the flow chart that was outlined on the

00:33:58.694 --> 00:33:59.320 
previous slide.

00:33:59.760 --> 00:34:02.745 
If the patient's at low risk, OK, you'll observe.

00:34:02.745 --> 00:34:05.491 
If they have a lot of quality of life issues,

00:34:05.491 --> 00:34:07.760 
then they can receive glucocorticoids.

00:34:08.160 --> 00:34:09.880 
If the patients at intermediate risk,

00:34:10.080 --> 00:34:15.667 
And so these are patients that have, 
you know, nephrolithiasis or you know,

00:34:15.667 --> 00:34:20.665 
cosmetically apparent skin lesions and patients that are high risk,

00:34:20.665 --> 00:34:24.488 
they follow a similar, follow a similar flow chart,

00:34:24.488 --> 00:34:26.400 
but patients at high risk.

00:34:26.400 --> 00:34:30.356 
So this is again patients with severe pulmonary involvement, cardiac disease,

00:34:30.356 --> 00:34:31.320 
neurologic disease.

00:34:31.960 --> 00:34:34.252 
This flow chart is just for pulmonary sarcoidosis,

00:34:34.252 --> 00:34:37.400 
but it looks the same for the other high risk manifestations as well.

00:34:37.920 --> 00:34:41.976 
You're going to want to start with glucocorticoids and then attempt to taper

00:34:41.976 --> 00:34:42.240 
them.

00:34:42.600 --> 00:34:45.387 
If you're unable to successfully taper them,

00:34:45.387 --> 00:34:47.680 
you'll move to a second line therapy.

00:34:48.800 --> 00:34:52.623 
In general for high risk patients, 
we do find methotrexate to be the most

00:34:52.623 --> 00:34:56.240 
effective of the of the second line agents and the most well studied.

00:34:56.840 --> 00:35:01.508 
But for patients without as high of risk, you know the treatment can be made more

00:35:01.508 --> 00:35:06.120 
based on side effects or more based on comorbidities or medication interactions.

00:35:06.600 --> 00:35:11.070 
And so you know other patients in the intermediate risk category might start on

00:35:11.070 --> 00:35:14.200 
MMF because of intolerances or issues with methotrexate

00:35:14.200 --> 00:35:16.909 
for instance. 
If patients are unable to reach an

00:35:16.909 --> 00:35:21.444 
appropriate dose of corticosteroids with addition of second line agent and you're

00:35:21.444 --> 00:35:24.596 
going to want to talk about talk about adding, you know,

00:35:24.596 --> 00:35:28.080 
our more definitive third line agents. For high risk patients,

00:35:28.080 --> 00:35:31.512 
The science supports infliximab more for pulmonary disease,

00:35:31.512 --> 00:35:34.945 
but for patients with -without high risk pulmonary disease,

00:35:34.945 --> 00:35:37.919 
there's less distinction between the two molecules.

00:35:39.480 --> 00:35:43.408 
Again, you know, when you start these two, you're generally going to have to make a

00:35:43.408 --> 00:35:45.560 
change to what you're doing in this category.

00:35:45.880 --> 00:35:47.960 
And so we'll talk about that a little bit more later.

00:35:48.240 --> 00:35:51.040 
Many of the agents you know you'll - you might want to stop all together.

00:35:51.080 --> 00:35:55.060 
Other agents you might want to continue at a reduced dose for augmentation or

00:35:55.060 --> 00:35:58.480 
sarcoidosis therapy and also prevention of autoantibody formation.

00:35:59.920 --> 00:36:03.080 
This bottom row here is kind of what I would call fourth line therapies.

00:36:03.080 --> 00:36:06.200 
And so, you know, 
these should not be thought of as

00:36:06.200 --> 00:36:09.980 
stronger or you know, 
the best treatment that we're saving for

00:36:09.980 --> 00:36:10.280 
last.

00:36:10.560 --> 00:36:15.600 
I would consider this to be, you know, kind of more - less evidence based.

00:36:15.640 --> 00:36:19.446 
And so hence they're not in category 3, but there is, you know,

00:36:19.446 --> 00:36:22.896 
some- some science surrounding respiratory corticotropin,

00:36:22.896 --> 00:36:26.999 
JAK inhibitors and rituximab for select cases of refractory disease.

00:36:31.840 --> 00:36:34.520 
This this picture I love quite a bit as well.

00:36:34.640 --> 00:36:38.045 
And it's also from Current Opinion Pulmonary Medicine.

00:36:38.045 --> 00:36:42.750 
Talks a little bit about how to break down pulmonary sarcoidosis in general

00:36:42.750 --> 00:36:46.279 
into who to treat, 
who not to treat and what's variable.

00:36:47.080 --> 00:36:48.360 
This is - these are a little bit wordy.

00:36:48.360 --> 00:36:50.840 
And so I'll give you a chance to kind of read through them.

00:36:50.840 --> 00:36:55.340 
But these are specific phenotypes that aren't really teased out in some of the

00:36:55.340 --> 00:36:56.480 
guideline documents.

00:36:57.800 --> 00:37:01.580 
No treatment is generally recommended for asymptomatic type 1 - or stage 1 -

00:37:01.580 --> 00:37:05.360 
Lofgren's syndrome or asymptomatic patients even with mild PFT derangements.

00:37:06.240 --> 00:37:09.591 
Treatment however, 
is recommended for stage 2 and 3

00:37:09.591 --> 00:37:14.231 
sarcoidosis patients with symptoms like dyspnea and PFT derangements or

00:37:14.231 --> 00:37:16.680 
associated radiographic abnormalities.

00:37:17.160 --> 00:37:20.593 
It's also generally recommended for patients with extrinsic bronchial

00:37:20.593 --> 00:37:22.360 
compression by enlarged lymph nodes.

00:37:22.640 --> 00:37:26.331 
And we've, 
we've all seen those people who have very,

00:37:26.331 --> 00:37:31.800 
very pathological lymphadenopathy with associated symptomatology or wheezing or

00:37:31.800 --> 00:37:35.492 
airflow obstruction. 
Patients with meaningful airflow

00:37:35.492 --> 00:37:39.526 
limitation or endobronchial stenosis as a result of their,

00:37:39.526 --> 00:37:44.653 
their granulomatous involvement. 
In patients with stage 4 sarcoidosis with

00:37:44.653 --> 00:37:47.320 
shortness of breath and active disease.

00:37:47.800 --> 00:37:51.155 
And so if the patient has stage 4 sarcoidosis, they have symptoms,

00:37:51.155 --> 00:37:53.560 
abnormal PFTs and there's still active disease.

00:37:53.920 --> 00:37:56.411 
You know, 
kind of regardless of how the degree of

00:37:56.411 --> 00:37:58.903 
the abnormality of PFTs or degree of the dyspnea,

00:37:58.903 --> 00:38:02.641 
that residual granulomatous activity in stage 4 patients that generally be

00:38:02.641 --> 00:38:03.040 
treated.

00:38:04.600 --> 00:38:08.038 
It's controversial whether or not we should treat patients who have abnormal

00:38:08.038 --> 00:38:09.200 
PFTs but are asymptomatic.

00:38:09.800 --> 00:38:11.928 
In general, 
it's felt not to be worth the side

00:38:11.928 --> 00:38:12.880 
effects of treatment.

00:38:13.280 --> 00:38:18.188 
And then pulmonary hypertension is a little bit of a gray area because many of

00:38:18.188 --> 00:38:23.096 
the effective treatments are pulmonary vasodilator therapies with less benefit

00:38:23.096 --> 00:38:24.960 
from anti-granuloma therapies.

00:38:25.280 --> 00:38:29.128 
But in patients that do have active inflammation from sarcoidosis,

00:38:29.128 --> 00:38:33.724 
it's generally felt that the treatment 
with anti granuloma therapy is indicated

00:38:33.724 --> 00:38:36.080 
in these pulmonary hypertension patients.

00:38:37.120 --> 00:38:40.644 
You should remember though that there are no clear guidelines around when and how

00:38:40.644 --> 00:38:42.880 
treatment should be initiated in pulmonary disease.

00:38:43.320 --> 00:38:47.749 
And in general a period of watchful waiting after initial diagnosis is often

00:38:47.749 --> 00:38:49.360 
reasonable for new diagnosis

00:38:49.360 --> 00:38:53.776 
patients that have without fibrosis or a lot of calcification on their X-ray,

00:38:53.776 --> 00:38:56.890 
most you know, 
many will have spontaneous remission in

00:38:56.890 --> 00:38:58.080 
the first six months.

00:39:03.000 --> 00:39:04.920 
And so here, brings us to our second poll.

00:39:07.600 --> 00:39:08.800 
And so we have a few patients here,

00:39:08.800 --> 00:39:13.520 
one's a 35 year old female with arthritis and fatigue diagnosed 4 months ago.

00:39:13.560 --> 00:39:18.295 
Biopsy confirmed she has ALP of 280, bilirubin of 10, CRP of 18,

00:39:18.295 --> 00:39:22.520 
mild leukopenia, thrombocytopenia on CBC, normal imaging,

00:39:22.520 --> 00:39:24.560 
normal PFTs and chest X-ray.

00:39:25.360 --> 00:39:28.920 
Second patient's a 42 year old gentleman, asymptomatic, diagnosed a year ago.

00:39:28.920 --> 00:39:32.741 
Biopsy confirmed. 
ECG has a new left bundle branch block.

00:39:32.741 --> 00:39:33.400 
Cardiac MR

00:39:33.400 --> 00:39:38.160 
has late gadolinium enhancement and his cardiac PET has active inflammation.

00:39:39.160 --> 00:39:43.500 
You have a 62 year old female with arthritis and fatigue also diagnosed four

00:39:43.500 --> 00:39:44.120 
months ago.

00:39:44.120 --> 00:39:48.720 
Biopsy confirmed with hypercalcemia 2.95, mild real insufficiency.

00:39:48.720 --> 00:39:52.800 
PTH is suppressed, 
normal PFT and chest X-ray, normal ECG.

00:39:52.800 --> 00:39:56.800 
And then you have a 28 year old male with cough and dyspnea diagnosed 16 months ago.

00:39:57.160 --> 00:40:01.464 
Again, biopsy confirmed. 
PFT is showing a decline of FVC and FEV1

00:40:01.464 --> 00:40:04.400 
by about 10% or 15% since initial diagnosis.

00:40:04.760 --> 00:40:07.360 
There's been progressive radiographic changes on the chest X-ray.

00:40:07.600 --> 00:40:09.400 
He has the symptoms of cough and shortness of breath.

00:40:09.920 --> 00:40:12.567 
Of these four patients, 
which 4 is appropriate for watchful

00:40:12.567 --> 00:40:12.920 
waiting?

00:40:40.240 --> 00:40:41.680 
Yeah, we'll give it about 10 more seconds.

00:41:04.870 --> 00:41:05.230 
Awesome.

00:41:05.790 --> 00:41:06.950 
We'll have Lorenzo share the results.

00:41:06.950 --> 00:41:07.750 
We'll just talk through them.

00:41:09.750 --> 00:41:13.670 
And so the vast majority of the group got the answer that I was looking for.

00:41:14.070 --> 00:41:17.230 
The appropriate patient for watchful waiting is the 35 year old with arthritis

00:41:17.230 --> 00:41:17.710 
and fatigue.

00:41:18.600 --> 00:41:21.360 
They have ALP elevation but it's below 3 times upper limit normal.

00:41:21.360 --> 00:41:23.600 
Their CRP is elevated but that's not an indication for treatment

00:41:23.600 --> 00:41:26.160 
by its own. 
Mild leukopenia and thromocytopenia

00:41:26.160 --> 00:41:30.241 
can be observed and so this patient would be appropriate to watch without

00:41:30.241 --> 00:41:31.400 
initiating treatment.

00:41:31.840 --> 00:41:35.127 
The second patient has cardiac inflammation on their PET scan with a new

00:41:35.127 --> 00:41:38.280 
conduction abnormality and so would have an indication for treatment.

00:41:38.680 --> 00:41:42.285 
The 62 year old had a calcium of 2. 
95 with associated renal dysfunction and

00:41:42.285 --> 00:41:44.440 
so that would be an indication for treatment.

00:41:44.920 --> 00:41:48.301 
And the 28 year old male, 
and this is the kind of the most

00:41:48.301 --> 00:41:51.109 
borderline, 
but the patient did have progressive

00:41:51.109 --> 00:41:54.318 
imaging changes, 
progressive PFT changes and associated

00:41:54.318 --> 00:41:58.157 
symptomatology. In general, 
that would be considered an indication

00:41:58.157 --> 00:41:58.960 
for treatment.

00:41:59.280 --> 00:42:00.560 
So thanks guys.

00:42:01.320 --> 00:42:02.120 
We'll close the poll.

00:42:19.320 --> 00:42:24.560 
And so and next we'll cover approach to biologics.

00:42:27.840 --> 00:42:28.240 
Here we go.

00:42:28.640 --> 00:42:31.440 
The slides popping up a bit funny, but I think it's good now.

00:42:32.200 --> 00:42:35.360 
And so first we'll talk about infliximab.

00:42:35.360 --> 00:42:39.040 
Infliximab binds to circulating and membrane bound TNF.

00:42:39.040 --> 00:42:42.360 
So it affects this part of our inflammatory cascade.

00:42:43.200 --> 00:42:47.698 
Infliximab is that chimeric antibody targeting circulating membrane bound

00:42:47.698 --> 00:42:49.400 
anti-TNF or sorry TNF-alpha.

00:42:50.120 --> 00:42:52.000 
It's the most widely used third line agent.

00:42:52.320 --> 00:42:53.640 
It's preferred in Delphi studies.

00:42:53.640 --> 00:42:57.894 
There's two early randomized control trials performed with the drug and there

00:42:57.894 --> 00:43:01.876 
has been studies that show improvement in spirometry, DLCO, chest X-ray,

00:43:01.876 --> 00:43:03.840 
quality of life, 6 minute walk test.

00:43:04.120 --> 00:43:06.600 
And so there's good evidence behind the molecule.

00:43:08.600 --> 00:43:12.359 
It's also useful for non-pulmonary manifestations and so you can see the

00:43:12.359 --> 00:43:15.140 
list there, cutaneous, neurologic etcetera, etcetera.

00:43:15.140 --> 00:43:16.480 
for non-pulmonary disease,

00:43:16.480 --> 00:43:18.880 
None of these are high quality randomized control trials.

00:43:20.360 --> 00:43:24.513 
Also important to note is that many studies show high risk of relapse when

00:43:24.513 --> 00:43:29.166 
the anti-TNF was withdrawn up to 80% with most of the relapse happening within 4 to

00:43:29.166 --> 00:43:29.720 
11 months.

00:43:30.680 --> 00:43:33.000 
It should be - and a

00:43:33.000 --> 00:43:35.783 
Caveat here is that the longer the patient is on anti TNF therapy,

00:43:35.783 --> 00:43:37.320 
the less likely they are to withdraw.

00:43:37.640 --> 00:43:42.314 
And so many of the patients that had high relapse rates were completing a year or

00:43:42.314 --> 00:43:45.107 
less of anti-TNF therapy before discontinuation,

00:43:45.107 --> 00:43:46.760 
hence the high relapse rates.

00:43:47.840 --> 00:43:50.480 
Predictors of response include active inflammation.

00:43:50.480 --> 00:43:52.440 
You can prove that by a variety of parameters.

00:43:52.440 --> 00:43:55.520 
Nodular lung changes predict response to treatment.

00:43:56.080 --> 00:44:00.191 
Neurologic disease, lupus pernio, uveitis, advanced pulmonary disease are all the

00:44:00.191 --> 00:44:03.400 
types of sarcoidosis that generally respond well to infliximab.

00:44:03.680 --> 00:44:07.000 
There's also some genetic markers that portend a good prognosis.

00:44:07.200 --> 00:44:10.440 
They're not a genetic marker that I have access to in Calgary.

00:44:10.560 --> 00:44:13.040 
I'm not sure about colleagues in other places.

00:44:14.040 --> 00:44:15.960 
Next molecule we'll talk about is adalimumab.

00:44:16.200 --> 00:44:20.760 
And so it also binds to circulating and membrane bound

00:44:21.080 --> 00:44:25.600 
TNF, 
it's non-chimeric as opposed to chimeric.

00:44:25.880 --> 00:44:30.884 
That's important because infliximab more readily develops auto antibodies against

00:44:30.884 --> 00:44:31.800 
the adalimumab,

00:44:31.800 --> 00:44:36.407 
because of its chimeric nature, adalimumab is less likely to cause

00:44:36.407 --> 00:44:37.920 
autoantibody formation

00:44:37.920 --> 00:44:40.667 
because of that. 
it's been less well studied than

00:44:40.667 --> 00:44:43.360 
infliximab, 
particularly in refractory pulmonary

00:44:43.360 --> 00:44:43.800 
disease.

00:44:44.000 --> 00:44:49.241 
But there has been a number of case reports and studies that show that for

00:44:49.241 --> 00:44:54.832 
patients who end up failing infliximab that switching to adalimumab can salvage

00:44:54.832 --> 00:44:56.160 
their presentation.

00:44:56.360 --> 00:45:01.577 
And I've seen that in clinical practice, patients develop either serious adverse

00:45:01.577 --> 00:45:06.666 
effects from the infliximab infusions, or they develop autoantibodies and lose

00:45:06.666 --> 00:45:11.176 
efficacy and then when switched to adalimumab obtain a more prolonged

00:45:11.176 --> 00:45:12.399 
treatment response.

00:45:12.680 --> 00:45:17.000 
I've also seen patients that haven't responded as well to switching molecules.

00:45:17.000 --> 00:45:20.739 
But I have a handful of cases that have done quite well switching even within the

00:45:20.739 --> 00:45:21.560 
anti-TNF category.

00:45:22.680 --> 00:45:27.567 
There's no head-to-head studies comparing adalimumab to infliximab. In general,

00:45:27.567 --> 00:45:32.454 
you know you should think about favoring infliximab if the patient has advanced

00:45:32.454 --> 00:45:36.119 
pulmonary disease because it's been supported by more RCTs.

00:45:36.120 --> 00:45:37.760 
It's what the Delphi studies suggest.

00:45:38.720 --> 00:45:43.868 
You should favor adalimumab if you're worried about severe allergic reactions

00:45:43.868 --> 00:45:46.640 
and and the drug is just less immunogenic.

00:45:47.560 --> 00:45:50.040 
For patients with cutaneous sarcoidosis or uveitis.

00:45:50.040 --> 00:45:54.122 
There isn't really a clear favorable molecule and so kind of pick your

00:45:54.122 --> 00:45:54.640 
favorite.

00:45:57.960 --> 00:46:04.800 
And so the next poll and I'll go through here and then we'll have Lorenzo launch

00:46:04.800 --> 00:46:05.560 
it again.

00:46:06.160 --> 00:46:08.862 
And so in this case, 
you have a 50 year old female,

00:46:08.862 --> 00:46:12.240 
ongoing cough and shortness of breath, chest pain and arthritis.

00:46:13.000 --> 00:46:17.664 
They're on Prednisone 10 milligrams daily, methotrexate 20 milligrams injected

00:46:17.664 --> 00:46:20.440 
subcutaneously every week, also on folic acid.

00:46:20.720 --> 00:46:25.047 
They have progressive adenopathy, progressive parenchymal changes,

00:46:25.047 --> 00:46:28.600 
and some coalescing nodules with early PMF developing.

00:46:29.640 --> 00:46:33.960 
PFT is showing FVC of 85% predicted, FEV1 62% predicted.

00:46:33.960 --> 00:46:37.240 
Both have declined in the last year, DLCO 78% predicted.

00:46:37.720 --> 00:46:41.551 
For a patient like this with ongoing symptoms, relatively young age,

00:46:41.551 --> 00:46:44.161 
and progressive imaging and PFT abnormalities,

00:46:44.161 --> 00:46:48.160 
Would we elect to increase the prednisone to 20 milligrams daily alone?

00:46:48.680 --> 00:46:52.115 
Substitute the methotrexate with mycophenolate mofetil,

00:46:52.115 --> 00:46:56.226 
add an anti-TNF molecule, 
reduce the methotrexate and maintain the

00:46:56.226 --> 00:46:57.760 
prednisone where it's at.

00:46:58.360 --> 00:47:01.213 
Or add an anti-TNF molecule, increase the methotrexate to 25

00:47:01.213 --> 00:47:04.160 
milligrams and increase the prednisone to 15 milligrams daily.

00:47:35.560 --> 00:47:35.720 
Awesome.

00:47:35.720 --> 00:47:38.000 
And so I'll close the poll in next 10 seconds here.

00:47:46.910 --> 00:47:47.150 
Awesome.

00:47:50.110 --> 00:47:51.630 
So I'll get Lorenzo to share the results.

00:47:51.630 --> 00:47:53.590 
But the audience did fantastic.

00:47:53.790 --> 00:47:57.876 
And so in a case like this where there's nothing explosive happening, like,

00:47:57.876 --> 00:48:00.994 
you know, new, you know, 
new VTAC from cardiac disease or

00:48:00.994 --> 00:48:04.112 
something, you know, 
we're going to augment the patient's

00:48:04.112 --> 00:48:07.070 
therapy without necessarily increasing the prednisone.

00:48:07.230 --> 00:48:09.670 
This is a great moment to add anti-TNF therapy.

00:48:10.640 --> 00:48:14.721 
The way I use anti-TNF in this context is I would look to start infliximab on the

00:48:14.721 --> 00:48:15.120 
patient.

00:48:15.480 --> 00:48:19.155 
I would keep their prednisone at the same dose and then I would reduce the

00:48:19.155 --> 00:48:20.920 
methotrexate to 10 milligrams weekly

00:48:21.320 --> 00:48:25.905 
Oral or subcutaneous is okay, 
but in general I always keep the patients

00:48:25.905 --> 00:48:29.598 
on low dose of methotrexate coexisting with the anti-TNF.

00:48:29.598 --> 00:48:34.566 
One because it provides some anti-sarcoid or anti-granuloma therapy through a

00:48:34.566 --> 00:48:35.840 
different mechanism.

00:48:36.000 --> 00:48:39.195 
But more than that, 
it's proved to be synergistic with

00:48:39.195 --> 00:48:43.030 
infliximab and many other autoimmune conditions, Crohn's disease,

00:48:43.030 --> 00:48:46.574 
rheumatoid arthritis too. 
Namely by preventing or mitigating

00:48:46.574 --> 00:48:48.840 
autoantibody formation to the molecule.

00:48:48.840 --> 00:48:51.840 
So um extending duration of effectiveness.

00:48:53.840 --> 00:48:54.480 
So thanks guys.

00:48:55.520 --> 00:48:58.752 
Kind of a couple of slides left and we'll get through over the next few minutes and

00:48:58.752 --> 00:49:00.600 
then we'll leave time for questions at the end.

00:49:00.600 --> 00:49:14.300 
Here we go.

00:49:14.740 --> 00:49:20.665 
And so the last few slides, 
we'll just cover some basically common

00:49:20.665 --> 00:49:27.564 
practical challenges to - my slide deck got frozen - practical strategies for

00:49:27.564 --> 00:49:28.980 
common problems.

00:49:30.700 --> 00:49:31.900 
So my deck is frozen here.

00:49:31.900 --> 00:49:34.100 
So practical strategies for common challenges.

00:49:34.400 --> 00:49:38.788 
The first common challenge would be kind of mild disease, hypercalciuria,

00:49:38.788 --> 00:49:41.280 
mild hypercalcemia, arthritis and fatigue.

00:49:41.800 --> 00:49:44.200 
I find hydroxychloroquine to be a really useful drug.

00:49:44.400 --> 00:49:47.231 
You know, 
hydroxychloroquine works in a wide

00:49:47.231 --> 00:49:51.006 
variety of ways, 
including mitigating antigen presentation,

00:49:51.006 --> 00:49:55.536 
inhibiting T and B cell activation, balancing the Th17 and T regulatory

00:49:55.536 --> 00:49:56.040 
balance.

00:49:57.080 --> 00:49:58.800 
And it's quite well tolerated.

00:49:58.880 --> 00:50:01.652 
Yeah, there's very minimal side effects, especially, you know,

00:50:01.652 --> 00:50:04.600 
the ocular issues don't develop generally for at least five years.

00:50:04.880 --> 00:50:08.885 
And so a low threshold to use hydroxychloroquine for arthritis, fatigue,

00:50:08.885 --> 00:50:13.440 
dermatological manifestations or calcium issues is a - is a useful clinical Pearl.

00:50:13.440 --> 00:50:14.600 
I've had a lot of success with it.

00:50:17.400 --> 00:50:21.324 
I wanted to talk just briefly about PET scan and sarcoidosis,

00:50:21.324 --> 00:50:23.920 
which is becoming more and more in vogue.

00:50:24.280 --> 00:50:27.524 
It's a highly useful investigation, especially for patients with cardiac

00:50:27.524 --> 00:50:27.880 
disease.

00:50:28.320 --> 00:50:32.757 
Everyone with cardiac disease needs cardiac PETs at least at some point in

00:50:32.757 --> 00:50:34.000 
their disease course.

00:50:34.800 --> 00:50:38.593 
For advanced pulmonary disease to- to assess response to treatment.

00:50:38.593 --> 00:50:42.834 
It can be helpful to find a biopsy site, especially if the bronchoscopy was

00:50:42.834 --> 00:50:46.516 
negative or they don't have significant pulmonary manifestations,

00:50:46.516 --> 00:50:49.919 
and to determine disease activity and response to treatment.

00:50:49.920 --> 00:50:53.868 
For some of our other manifestations without biomarkers, so for example,

00:50:53.868 --> 00:50:56.734 
arthritis, 
it wouldn't be terribly commonly used for

00:50:56.734 --> 00:50:57.600 
this indication.

00:50:57.600 --> 00:51:01.819 
But for patients that have a lot of osseous pain in addition to the arthritis

00:51:01.819 --> 00:51:05.661 
pain or bone marrow involvement, sometimes the PET scan can be useful,

00:51:05.661 --> 00:51:10.043 
especially if you're making a decision about potentially escalating this patient

00:51:10.043 --> 00:51:12.640 
to biologic molecules to treat their condition.

00:51:15.280 --> 00:51:17.720 
What do we do when we lose a biologic effectiveness?

00:51:17.720 --> 00:51:20.218 
Well, 
you can rotate between your anti-TNF

00:51:20.218 --> 00:51:20.800 
molecules.

00:51:20.800 --> 00:51:25.720 
So go from adalimumab to infliximab or 
vice versa. As described earlier,

00:51:25.720 --> 00:51:30.017 
I use low dose cytotoxics like methotrexate to mitigate autoantibody

00:51:30.017 --> 00:51:30.640 
formation.

00:51:30.840 --> 00:51:33.840 
There's also a bit of literature 
supporting low dose azathioprine for this

00:51:33.840 --> 00:51:34.480 
context as well.

00:51:34.760 --> 00:51:36.120 
Methotrexate is more well studied.

00:51:36.640 --> 00:51:41.932 
There's also some evolving evidence for JAK inhibitors and anti-IL6 and there's

00:51:41.932 --> 00:51:46.960 
ongoing clinical trials right now the Efzofitimod trial has been completed.

00:51:47.480 --> 00:51:54.262 
The other trials are currently recruiting. There was one case report on IL-6 they

00:51:54.262 --> 00:51:56.000 
had 4 patients in it.

00:51:56.000 --> 00:52:00.240 
All these patients had disease refractory to anti-TNF molecules.

00:52:01.440 --> 00:52:03.360 
All the patients had some pulmonary involvement.

00:52:03.640 --> 00:52:05.520 
The drug seemed to work fairly well.

00:52:05.800 --> 00:52:09.958 
All patients had reduction in the prednisone dose, had improved symptoms,

00:52:09.958 --> 00:52:12.600 
and you know, 
generally favorable PFT changes.

00:52:12.880 --> 00:52:15.348 
Admittedly, 
this is a very small case series with all

00:52:15.348 --> 00:52:17.954 
the all the problems, 
the methodology problems that come

00:52:17.954 --> 00:52:20.560 
alongside that, 
but it's nice to potentially have backup

00:52:20.560 --> 00:52:22.160 
plans if an anti-TNF isn't working.

00:52:22.920 --> 00:52:27.225 
The other category of medications that's proving to be interesting is the JAK-STAT

00:52:27.225 --> 00:52:27.640 
pathway.

00:52:27.960 --> 00:52:31.176 
And so there's, you know, 
more studies coming out all the time and

00:52:31.176 --> 00:52:34.344 
tofacitinib in this context. 
Here is kind of the proof-of-concept

00:52:34.344 --> 00:52:37.800 
study that demonstrated it was effective 
with a really nice graph here.

00:52:38.080 --> 00:52:42.058 
They had five patients initially and they were determining, you know,

00:52:42.058 --> 00:52:44.673 
not just response to spirometry and symptoms,

00:52:44.673 --> 00:52:47.800 
but also what what would happen with their prednisone.

00:52:48.160 --> 00:52:50.640 
2 of the patients were lost to follow up quite early.

00:52:51.200 --> 00:52:53.882 
One of them was lost to follow up, but one of them developed

00:52:53.882 --> 00:52:57.356 
neurosarcoidosis and so he just needed more prednisone and different treatment

00:52:57.356 --> 00:52:57.840 
strategies.

00:52:58.160 --> 00:53:00.877 
But the three patients that proceeded normally had, you know,

00:53:00.877 --> 00:53:03.814 
dramatic reductions in their prednisone over the first six months,

00:53:03.814 --> 00:53:06.399 
with many patients coming off their prednisone altogether.

00:53:06.760 --> 00:53:10.907 
All these patients had improvement in 
their symptoms despite drops in the

00:53:10.907 --> 00:53:15.110 
prednisone and preservation of - of spirometry or even some improvement in

00:53:15.110 --> 00:53:17.800 
spirometry despite the drop in prednisone dose.

00:53:17.800 --> 00:53:20.800 
And so quite a promising molecule

00:53:21.080 --> 00:53:22.760 
It's fairly well tolerated in my experience.

00:53:31.440 --> 00:53:34.040 
And so that, that concludes my program.

00:53:34.280 --> 00:53:37.640 
And pulmonary sarcoidosis is clearly heterogeneous.

00:53:37.640 --> 00:53:39.400 
Management should be individualized.

00:53:39.840 --> 00:53:43.030 
Challenges frequently occur and they require a prudent and experienced

00:53:43.030 --> 00:53:43.480 
clinician.

00:53:43.800 --> 00:53:47.255 
And then in, in, in practice, 
there's a wide variety of interesting

00:53:47.255 --> 00:53:47.560 
cases.

00:53:48.160 --> 00:53:50.160 
I'm happy to discuss with colleagues at any time.

00:53:50.280 --> 00:53:52.743 
And so, you know, 
hopefully you have my name and contact

00:53:52.743 --> 00:53:55.640 
information and I'm always happy to get a phone call or an e-mail.

00:53:56.080 --> 00:53:57.520 
It's been a pleasure speaking with you guys today.

00:53:58.000 --> 00:53:58.400 
Thank you.