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Sarcoidosis
Dr. Samir Nusair, MD
Rokach Inst. for Lung Dis. & TB Prevention, Clalit Health Services
Tel: 02-5017547, E-mail: [email protected]
Nusair Lect 2013
twitter.com/samirnus
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References
• Baughman RP, Culver DA, Judson MA. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med 2011;183:573-81.
• Beegle SH, Barba K, Gobunsuy R, Judson MA. Current and emerging pharmacological treatments for sarcoidosis: a review. Drug Des Devel Ther 2013 ;7:325-38.
Nusair Lect 2013
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SarcoidosisDefinition
Sarcoidosis is a systemic granulomatous disorder of unknown etiology
Nusair Lect 2013
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SarcoidosisPathology
• Granulomatous inflammation– epithelioid granuloma– non-caseating– multinucleated giant cells – T lymphocytes (CD4>CD8 cells)
• Encroachment on anatomic structures rather than destruction
Nusair Lect 2013
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Non-caseating granuloma in sarcoidosis
Nusair Lect 2012
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Non-caseating granuloma in sarcoidosis
Nusair Lect 2013
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Granuloma with caseation Mycobacterium Tuberculosis (Acid-fast stain)
Nusair Lect 2013
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Sarcoidosis – Pathogenesis
• Hypothesis: sarcoidosis results from exposure of genetically susceptible hosts to specific environmental agents– epidemiologic clustering– activated (CD4+) T lymphocytes and macrophages
with Th1 cytokine pattern– restricted TCR usage (specific antigen triggering)– presence of foreign antigens in tissue (e.g.,
mycobacterial catalase-peroxidase (mKatG)
• Compartmentalization of the immune system
Nusair Lect 2013
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Inflammatory response in Sarcoidosis
AJRCCM 2011Nusair Lect 2013
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Sarcoidosis Immunopathogenesis
Fibrosis may result if Th2 reaction becomes more dominant than the initial Th1 reaction leading to more prominent fibrosis
NEJM 2007 Nusair Lect 2013
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Sarcoidosis- Thoracic Manifestations
• pulmonary parenchymal
• lymphadenopathy (hilar, mediastinal or paratracheal)
• airways and endobronchial involvement
• pleural involvement
• pulmonary vasculature
Nusair Lect 2013
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Thoracic lymph node involvement in Sarcoidosis
• bilateral-hilar• paratracheal (71% of patients, Rt. > Lt.) • subcarinal adenopathy
• Very uncommon: – isolated anterior mediastinal adenopathy – isolated posterior mediastinal adenopathy – unilateral hilar adenopathy
Nusair Lect 2013
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Pulmonary parenchymal involvement in Sarcoidosis
• Evident on HRCT
• most commonly symmetric
• diffuse, reticular, nodular
• upper & middle lung zones predominance
• rarely, unilateral lesions, multiple large nodules, and solitary nodules
Nusair Lect 2013
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Sarcoidosis – hilar adenopathy
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Sarcoidosis – hilar adenopathy
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Sarcoidosis- Lymhadeopathy & Pulmonary Parenchymal Involvement
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Sarcoidosis- HRCT
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Sarcoidosis- HRCT
Miliary pattern
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Sarcoidosis- advanced parenchymal disease
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Sarcoidosis- cavitary changes
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Akira, M. et al. Chest 2005;127:185-191
Sarcoidosis follow-up at 12 yrs (bottom panes)
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Extra-pulmonary involvement in Sarcoidosis (1)
• Extrathoracic lymphadenopathy• Skin
– Erythema nodosum– Plaques, maculopapular eruptions, subcutaneous
nodules, lupus pernio• Eye
– Uveitis (75% anterior, 25% posterior)– Conjuctival nodules– Keratoconjuctivitis sicca– Optic Neuritis (rare, sudden loss of vision or color
vision)Nusair Lect 2013
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Lupus pernio
Granulomata
Raised plaque lesions
Nusair Lect 2013
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Extra-pulmonary involvement in Sarcoidosis (2)
• Spleen• Liver
– LFT abnorm., elevated Alk Phosph, rarely cirrhosis• Kidney
– Hypercalciuria, hypercalcemia (increased 1,25 Vit D)• Nervous system• Musculoskeletal system• Heart• Endocrine & exocrine (parotid) glands
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Clinical presentation
• Asymptomatic radiographic findings
• Cough
• Dyspnea
• Systemic (e.g. fever, malaise)
• Other organ involvement
Nusair Lect 2013
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Laboratory testing in Sarcoidosis
• PFT: FVC, TLCO
• Chest imaging• Liver enzymes, calcium, urinary calcium clearance• ACE• BAL and transbronchial biopsy or other organ biopsy• Gallium-67 scan
“Panda” sign
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FDG-PET A new Imaging Modality for Sarcoidosis ?
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FDG-PET A new Imaging Modality for Sarcoidosis ?
Cardiac sarcoidosis
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Treatment options• Non-steroidal anti-inflammatory • Corticosteroids
– systemic
– inhaled (for cough and/or obstructive dis.)
• Steroid sparing therapy– Cytotoxic
• Methotrexate • Leflunomide• (Azathioprine?)
– Other• Hydroxychloroquine• Thalidomide (for cutaneous sarcoidosis)• Mycophenolate?
• Steroid refractory sarcoidosis– Anti Tumor Necrosis Factor (infliximab, adalimumab)
Nusair Lect 2013
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Corticosteroids (CS) in Pulmonary Sarcoidosis
• Corticosteroids do not influence Survival• Recurrence of clinical symptoms may occur
at a prolonged time interval after CS discontinuation
• Initial dose of prednisone not more than 40mg/d
• Aim for Maintenance dose of prednisone not higher than 10mg/d
Nusair Lect 2013
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Corticosteroid sparing therapy
• Recurrence of symptoms after corticosteroid (CS) therapy dosage reduction
• Reduces the required systemic CS dosage• Allow therapy when there are severe side
effects of CS• Prevent cumulative toxicity of corticosteroids
(i.e., osteoporosis) in chronic persistent sarcoidosis
• May be indicated when there is either no response (usually neurosarcoidosis)
Nusair Lect 2013
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Corticosteroid sparing therapy
Nusair Lect 2013
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Methotrexate
• Serves as steroid-sparing agent• Effect evident by 12 months (steroid dose reduction)• Folic acid analogue, inhibition of pyridine metabolism
in which folate is cofactor• Effect mediated by elevation of adenosine in
extracellular space, inhibition of inflammatory cytokines
• Effective in most forms of sarcoidosis (incl. lung, eye, skin, and neurologic involvement)
• Usual dose 10-25mg/week
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Antimalarials
• Chloroquine and hydroxychloroquine (plaquenil)• Mechanism: reduces release of several cytokines
and impaired antigen presentation by monocytes, macrophages, and dendritic cells to CD4+ T-helper cells
• Effective in cutaneous sarcoidosis and arthritis• Time interval is long until effect- therefore given with
steroids initially • Major side effect Retinopathy- therefore, baseline
testing and every 6-12 months (much less in hydroxychloroquine)
Nusair Lect 2013
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Leflunomide
• Analogue of Methotrexate (MTX)• Inhibits cyclooxygenase-2 • Inhibits de no vo synthesis of pyrimidines• Prevents lymphocyte proliferation,
suppresses TNF-α signaling • Similar to MTX in effect and could be an
alternative when MTX intolerance develops
Nusair Lect 2013
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Anti Tumor Necrosis Factor (Anti-TNF-α)
• TNF-α has unique role in granuloma formation • Modality unique for steroid refractory sarcoidosis
patients• Infliximab useful in pulmonary sarcoidosis,
neurosarcoidosis, Lupus pernio • Effect evident within few weeks• Infliximab: intravenous, risk of TB reactivation, worsens
heart failure, antibody formation thus reducing effect• Adalimumab: some effect, slower than infliximab• Etanercept: Not effective in sarcoidosis
Nusair Lect 2013
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Anti Tumor Necrosis Factor (Anti-TNF-α)
Nusair Lect 2013
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Azathioprine
• A purine analog, acts to inhibit purine synthesis necessary for the proliferation of cells, especially B and T lymphocytes
• Reports of usefulness based on open label case series
• Steroid sparing to reduce required CS dose
Nusair Lect 2013
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Cyclophosphamide
• An alkylating agent that prevents cell division by cross-linking DNA strands and decreasing DNA synthesis
• Decrease in lymphocyte number and function• Severe toxicity, myelosuppressive, affects
spermatogenesis • Urologic neoplasia and Inflamm. may be reduced by IV
rather than PO route• Neurosarcoidosis, Cardiac sarcoid unresponsive to
corticosteroids and other modalities
Nusair Lect 2013
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Mycophenolate
• A reversible inhibitor of inosine monophosphate dehydrogenase in purine biosynthesis that is necessary for the growth of T cells and B cells
• May be useful for Neurosarcoidosis • Not much data available• Should be considered a third-line CS sparing
drug
Nusair Lect 2013
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Treatment options
• More than 70% of patients will not require systemic steroids
Nusair Lect 2013
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Life-span limiting complications of Sarcoidosis
• Pulmonary–Fibrosis –Bronchiectasis–Mycetomas
• Cardiac• Neurosarcoidosis
Nusair Lect 2013
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Treatment of Pulmonary Sarcoidosis
• Lymphadenopathy– Observation
• Parenchymal disease– Observe unless FVC or TLCO < 65% of
predicted – if FVC or TLCO deteriorate >15% of baseline
within 3-6 months then treat
Nusair Lect 2013
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Treatment of SarcoidosisACUTE PRESENTATION
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Treatment of SarcoidosisCHRONIC PRESENTATION
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Indications for treating extra-pulmonary Sarcoidosis with systemic corticosteroids
• posterior uveitis• CNS involvement• Cardiac: Arrhythmias, conduction defects, cardiomyopathy• Hypercalciuria & hypercalcemia unresponsive to hydration
and dietary restriction• Massive splenomegaly with cytopenia• Cholestatic hepatitis• Arthritis unresponsive to NSAIDs• Skin: lupus pernio and skin infiltrate unresponsive to
topical treatmentNusair Lect 2013
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Lung Transplantation for Pulmonary Sarcoidosis
• Less than 2% of patients will require Lung Tx• Contraindicated in the presence of mycetomas• Contraindicated in the presence of
neurosarcoidosis • Combined Heart-Lung Tx may be appropriate in
the presence of cardiac sarcoidosis• Sarcoidosis may recur in the transplanted
allograft but clinically insignificant
Nusair Lect 2013