#256 Sarcoidosis

February 15, 2021 | By Deb Gorth

A grand overview of granulomas with Drs. Scholand and Boltax

This grand overview of granulomas will leave you comfortable tackling an often breathtaking disease, sarcoidosis. Listen as our esteemed guests Dr. Mary Beth Scholand (University of Utah) and Dr. Jonathan Boltax (University of Utah) rheum-inate on sarcoidosis. We discuss the pathophysiology, diagnosis, and treatment of this disease, role of the primary care clinician and why sarcoidosis in the chart reminds Paul of Shakespeare. 

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Credits

• Producer: Cyrus Askin MD and Deborah Gorth
• Writer: Deborah Gorth
• Infographic and Cover art: Edison Jyang
• Hosts: Stuart Brigham MD; Matthew Watto MD, FACP; Paul Williams MD, FACP   
• Editor: Cyrus Askin MD (written materials); Clair Morgan of nodderly.com
• Guest: Drs. Mary Beth Scholand & Jonathan Boltax

Sponsor: ACP’s MKSAP18

MKSAP® is the most trusted resource for lifelong learning and Board prep for internal medicine physicians and residents. Learn more at www.acponline.org/curb2021.

Sponsor: VCU Health CE

The Curbsiders are partnering with VCU Health Continuing Education to offer FREE continuing education credits for physicians and other healthcare professionals. Visit curbsiders.vcuhealth.org and search for this episode to claim credit.

Time Stamps

• 00:00 Intro, disclaimer, guest bio, Awful(ly good?) Pun
• 03:42 Guest one-liners
• 06:28 Sponsor – ACP’s MKSAP19
• 07:40 Case from Kashlak
• 08:40 Explaining sarcoidosis
• 12:19 Possible drivers of sarcoidosis
• 13:30 Taking a sarcoidosis history
• 17:26 Suggestions for catching sarcoidosis
• 21:44 Sponsor – birchliving.com/curb
• 23:52 Sarcoidosis physical exam, Diagnosis
• 33:00 Lofgren’s and Heerfordt’s syndromes; Imaging for sarcoidosis
• 40:44 Initiating therapy for sarcoidosis; Prognosis; the Treatment team
• 51:23 Primary care considerations for sarcoidosis 
• 54:55 Diagnosing and treating a sarcoidosis exacerbation
• 61:20 Take home points and outro

Sarcoidosis Pearls

1. The characteristic noncaseating granulomas of sarcoidosis can be thought of as a callus generated by chronic inflammation, more specifically, antigen driven CD4+ T-cell activation and macrophage recruitment (Patterson et al 2017).
2. Pay close attention when patients complain of  dyspnea, and workup this complaint with sarcoidosis in your differential.
3. Consider sarcoidosis in patients who have received multiple courses of antibiotics for non-resolving pneumonia or upper-respiratory infection.
4. About two-thirds of patients who present with bilateral hilar lymphadenopathy will achieve eventual remission, while the remaining third will have chronic disease (Siltzbach et al 1974). 
5. Sarcoidosis is a multisystem systemic disease, requiring a multi-system history and evaluation to avoid missing affected organs. 
6. The central challenge of diagnosing sarcoidosis is ruling out the mimics of this disease: CVID/GLILD, tuberculosis, fungal infection, and lymphoma.
7. “The diagnosis of sarcoidosis is arbitrarily made when the statistical likelihood of alternative diagnoses becomes too small to warrant further investigation” (Baugham et al 2010).
8. Both Löfgren’s syndrome and Heerfordt’s syndrome are pathognomonic for sarcoidosis; in these instances a biopsy for diagnosis is not recommended (Crouser et al 2020). 
9. Serum ACE levels have limited diagnostic value for sarcoidosis (Ungprasert et al 2016).
10. Additional testing to evaluate systemic involvement should include: baseline eye exam, serum creatinine, alkaline phosphatase, serum calcium, 25- and 1,25-OH vitamin D, and an EKG (Crouser et al 2020). 
11. There is little correlation between radiographic findings and patients’ sarcoidosis symptoms or functional capacity (Judson et al 2008 and Karetzky and McDonough 1996).
12. The cornerstone of therapy for sarcoidosis is glucocorticoids (initial dose prednisone 20-40 mg) (Rahaghi et al 2020). 
13. If a patient isn’t responding to treatment as expected, even after the diagnosis of sarcoid, reconsider your diagnosis and reinvestigate the other sarcoidosis mimickers before considering second line therapies (biologics/immunosuppressive drugs).
14. Sarcoidosis is a high burden disease; this diagnosis has lots of uncertainty regarding progression, requires the care of multiple different providers, and has debilitating symptoms.

Sarcoidosis Notes

What is Sarcoidosis? 

Sarcoidosis is a multisystem inflammatory disease that most commonly affects the lungs. While there are still many questions regarding the exact pathophysiology of this disease, sarcoidosis is thought to be caused by a variety of factors, having both environmental and familial components. The characteristic noncaseating granulomas of sarcoidosis can be thought of as a callus generated by chronic inflammation, more specifically, antigen driven CD4+ T-cell activation and macrophage recruitment (Patterson et al 2017). The exact nature of the antigen responsible for sarcoidosis remains an area of active investigation, but both environmental exposure, including irritants like beryllium (Greaves et al 2020), and inappropriate response to commensal organisms, both P. acnes (Schupp et al 2015) and Mycobacterium (Brownell et al 2011), are implicated in disease initiation and progression. Noteworthy, a cluster of sarcoidosis cases were reported following exposures in association with the World Trade Center collapse (Izbicki et al 2007). Additionally, there is a strong familial component driving the dysregulated immune response characteristic of sarcoidosis (Rybicki et al. 2001 and Terweil and van Moorsel 2019).

Sarcoidosis Presentation

Sarcoidosis is often first identified in patients as an incidental finding of bilateral hilar lymphadenopathy on chest radiograph. This disease can range from mild asymptomatic cases to severe disease requiring hospitalization (Iannuzzi et al 2007). It is important to think about sarcoidosis in patients who have received multiple courses of antibiotics for non-resolving “pulmonary infections” and to pay close attention when patients complain of  dyspnea, further working up this complaint. While not as typical, also consider sarcoidosis in a patient presenting with multiple kidney stones, which could be caused by sarcoidosis-related elevated urine calcium. Two common (on board exams), yet rare in practice, syndromic presentations of sarcoid are:

Lofgren’s syndrome = erythema nodosum, arthritis, hilar adenopathy. 

Heerfordt syndrome =  uveitis, parotitis, and fever.

Sarcoidosis Prognosis

There is a lot of uncertainty regarding the progression of sarcoidosis. About two third of patients who present with bilateral hilar lymphadenopathy will achieve eventual remission, while the remaining third will have chronic disease. Once patients have evidence of pulmonary infiltration, half of those patients progress. Around 5% of patients diagnosed with sarcoidosis will eventually die from this disease (Siltzbach et al 1974). 

Patient History 

While pulmonary sarcoid and resulting shortness of breath or chronic cough is the most common manifestation, sarcoidosis is a multisystem systemic disease, requiring a multi-system history to avoid missing affected organs. Dr. Boltax’s typical note is summarized in our infographic and he recommends developing a templated note for sarcoidosis to avoid missing important information. In short, questions about depression, anxiety, and focal numbness could identify neurosarcoid, or asking about palpitations and syncope could help identify cardiac sarcoid. Due to the role of environmental factors, it is important to explore potential exposures (occupational, tobacco, drugs, travels, mold, pets). The history can also begin to shed light on mimikers of sarcoidosis; exposure to fungal or tuberculosis could move these infections up the differential, lifelong recurrent infections can point to common variable immune deficiency (CVID), and night sweats and weight loss could suggest lymphoma. 

Physical Exam

The physical exam for sarcoidosis should be equally as comprehensive as the history. The manifestations of sarcoidosis apparent on physical exam include: red eyes, peripheral adenopathy, crackles on lung auscultation, unexplained rashes–specifically, erythema nodosum, which are coin sized painful red subcutaneous nodules– joint synovitis, and neurological deficiencies. Patients who are suspected to have sarcoidosis should receive a full neurological exam to verify limb strength and sensation. Both the history and physical should be reassessed every visit to evaluate progression. 

Diagnosing Sarcoidosis

“The diagnosis of sarcoidosis is arbitrarily made when the statistical likelihood of alternative diagnoses becomes too small to warrant further investigation” (Baugham et al 2010).

The central challenge of diagnosing sarcoidosis is ruling out the mimics of this disease: CVID/GLILD, tuberculosis, fungal infection, and lymphoma. A definitive method of diagnosis is finding  non-caseating granulomas in a lymph node biopsy, using endobronchial ultrasound [EBUS]. Biopsy is particularly useful for ruling out lymphoma. Like everything in medicine, the decision to conduct a biopsy should be a result of shared decision making.  However, both Löfgren’s syndrome and Heerfordt’s syndrome (defined above) are pathognomonic for sarcoidosis; a biopsy for diagnosis is not recommended (Crouser et al 2020). 

Useful tests to exclude mimickers include a CBC, cytopathology, flow cytometry, and fungal and AFB cultures/stains. Depending on the patient’s risk factors, quantiferon gold, HIV, and serum quantitative immunoglobulins are useful for ruling out tuberculosis, HIV related disease or CVID respectively. 

Due to its ability to capture subtle changes in lung parenchyma, high resolution CT scan is the workhorse of interstitial lung disease and can be helpful in diagnosing sarcoidosis. A perilymphatic distribution of micronodular lesions  is typical of pulmonary sarcoid (Criado et al 2010 and Dhagat et al 2017). In many institutions, this includes prone, supine and inspiratory/expiratory imaging that can help uncover subtle manifestations of disease. 

Angiotensin-converting enzyme (ACE) levels have also been discussed as a possible diagnostic tool for sarcoidosis, because ACE is produced by the epithelioid cells of granulomas (Silverstein et al 1979).  However, serum ACE levels have limited diagnostic value.  A retrospective cohort study of Minnesota residents found that high ACE sensitivity 41.4% (95% CI 35.3-47.8 %) with a specificity of 89.9% (95% CI 88.8-91.0 %) with a resulting  PPV of 25.4 % (95 % CI 21.3-29.9 %) and a NPV of 94.9 % (95 % CI 85.0-87.4 %) (Ungprasert et al 2016). An earlier study found that 69% of patients with sarcoidosis have an ACE levels at or above mean + 1SD; unfortunately serum ACE can also be elevated in asbestosis, diabetes, hyperthyroidism, alcoholic liver disease, beryllium exposure, coccidioidomycosis, tuberculosis, silicosis, lung infection, and lung cancer (Studdy and Bird 1989). 

Following and Staging Sarcoidosis

When a diagnosis of sarcoidosis is established additional testing to evaluate systemic involvement should include: baseline eye exam, serum creatinine, alkaline phosphatase, serum calcium, 25- and 1,25-OH vitamin D, and an EKG (Crouser et al 2020). Cardiac MRI or a dedicated cardiac PET  is recommended in the case of suspected cardiac involvement (Crouser et al 2020). Dr. Boltax also recommends following high resolution CTs and PFTs on patients long term, and a full body PET scan can identify the location of disease outside of the chest (Giudicatti et al 2020).

Radiographic characterization has long been a part of sarcoidosis literature and clinical trials. However, there is little correlation between radiographic findings and patient symptoms or functional capacity (Judson et al 2008 and Karetzky and McDonough 1996) One method of sarcoidosis staging is the scadding stages (Scadding 1961):

Sarcoidosis Treatment

As a complex multisystem disease, sarcoidosis is best approached by a team of doctors, commonly lead by a pulmonologist, including colleagues from rheumatology, nephrology, ophthalmology, cardiology, dermatology,  neurology, and, importantly, pharmacy to help monitor for drug toxicity and to adjust dosages (That methotrexate dose won’t adjust itself!). Therapy for sarcoidosis should begin when there are signs of damage or danger to organs. 

Due to the heterogeneity of the sarcoidosis presentation, the therapeutic approach should be individualized and focus on adapting to patient response. The cornerstone of therapy for sarcoidosis is glucocorticoids (prednisone 20-40 mg) (Rahaghi et al 2020). Dr. Scholand likes to start with a lower dose (20 mg). After follow up in 3-6 months, tapering off of these medications could lead to remission. If the prednisone dose can be tapered to 10 mg or less without too many side effects, you can consider staying on ≤ 10 mg prednisone. If the patient responds well, but the patient does not tolerate tapering the medication, then steroid sparing agents are the second line treatments for sarcoidosis. Methotrexate is considered the first-second-line treatment for sarcoidosis, with other steroid sparing agents also being used (azathioprine, mycophenolate, leflunomide, and TNF-inhibitors) (Rahaghi et al 2020).

Long term use of glucocorticoid therapy can have a variety of side effects including hyperglycemia, cataracts, weight gain, and reduced bone density (Fardet et al 2015). Patients receiving long term (≥ 4 weeks)  high-dose (≥30mg/day prednisone) steroids should be on trimethoprim/sulfamethoxazole (TMP-SMX) as primary prophylaxis for pneumocystis pneumonia (PCP) (Park et al 2018). Also be aware of steroid withdrawal, patients could be left with adrenal insufficiency (Krasner 1999). Bisphosphonate therapy should also be considered in patients on high-dose steroids for long periods of time.

Lastly, if a patient isn’t responding to treatment as expected, even after the diagnosis of sarcoid, reconsider your diagnosis and reinvestigate the other sarcoidosis mimickers.

Sarcoidosis Flares

A sarcoidosis flare is increased activity of underlying sarcoidosis. If a patient with sarcoidosis presents with worsening symptoms, it is important to rule out other potential causes of their symptoms, including but not limited to pneumonia, heart failure, arrhythmia, and pulmonary embolism. CT angiogram can be helpful in ruling out PE and provide some evidence about the status of the lung parenchyma. These patients also should receive a cardiac evaluation, and have a low threshold for echocardiogram. 

Once other causes for increased symptoms are less likely, the therapy for a sarcoidosis flare is starting the prednisone at a higher dose. Dr. Boltax considers the severity of the flare and the rate of progression of the disease when choosing his dose, but a rule of thumb is double the outpatient therapy for months before initiating a taper. Sarcoidosis flares could indicate that it may be time to escalate therapy and add on a steroid sparing agent (methotrexate) if the lower dose steroid was unable to prevent the flare. It is important to overlap methotrexate with steroids, because it can take months to get this medication up to steady state. The steroids can be tapered while the methotrexate concentration achieves steady state. 

It is important to remember that sarcoidosis is a high burden disease; it has lots of uncertainty regarding progression, requires the care of multiple different providers, and has debilitating symptoms. 

Goal

Listeners will recognize the clinical presentation of sarcoidosis, understand its basic management, and develop a framework for managing acute exacerbations.

Learning objectives

After listening to this episode listeners will…

1. Learn the basic pathophysiology of sarcoidosis
2. Recognize common presentations of sarcoidosis and initiate a diagnostic workup
3. Appreciate the medical concerns of patients with sarcoidosis
4. Become familiar with the medical treatment of sarcoidosis and its side effects
5. Differentiate a sarcoidosis flare from other respiratory pathology
6. Learn about the management of sarcoidosis patients on the inpatient wards

Disclosures

Dr. Scholand and Dr. Boltax report no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Gorth DJ, Askin CA, Scholand MB, Boltax J, Jyang E, Williams PN, Brigham SK, Watto MF. “#256 Sarcoidosis with Dr. Scholand and Dr. Boltax”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list February 15, 2021.