Sarcoidosis

Dr. Samir Nusair, MD

Rokach Inst. for Lung Dis. & TB Prevention, Clalit Health Services

Tel: 02-5017547, E-mail: SamirN@clalit.org.il

Nusair Lect 2013

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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.

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SarcoidosisDefinition

Sarcoidosis is a systemic granulomatous disorder of unknown etiology

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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

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Non-caseating granuloma in sarcoidosis

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Non-caseating granuloma in sarcoidosis

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Granuloma with caseation Mycobacterium Tuberculosis (Acid-fast stain)

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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

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Inflammatory response in Sarcoidosis

AJRCCM 2011Nusair Lect 2013

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

Sarcoidosis- Thoracic Manifestations

• pulmonary parenchymal

• lymphadenopathy (hilar, mediastinal or paratracheal)

• airways and endobronchial involvement

• pleural involvement

• pulmonary vasculature

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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

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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

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Sarcoidosis – hilar adenopathy

Sarcoidosis – hilar adenopathy

Sarcoidosis- Lymhadeopathy & Pulmonary Parenchymal Involvement

Sarcoidosis- HRCT

Sarcoidosis- HRCT

Miliary pattern

Sarcoidosis- advanced parenchymal disease

Sarcoidosis- cavitary changes

Akira, M. et al. Chest 2005;127:185-191

Sarcoidosis follow-up at 12 yrs (bottom panes)

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

Lupus pernio

Granulomata

Raised plaque lesions

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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

Clinical presentation

• Asymptomatic radiographic findings

• Cough

• Dyspnea

• Systemic (e.g. fever, malaise)

• Other organ involvement

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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

FDG-PET A new Imaging Modality for Sarcoidosis ?

FDG-PET A new Imaging Modality for Sarcoidosis ?

Cardiac sarcoidosis

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)

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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

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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)

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Corticosteroid sparing therapy

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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

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)

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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

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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

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Anti Tumor Necrosis Factor (Anti-TNF-α)

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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

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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

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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

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Treatment options

• More than 70% of patients will not require systemic steroids

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Life-span limiting complications of Sarcoidosis

• Pulmonary–Fibrosis –Bronchiectasis–Mycetomas

• Cardiac• Neurosarcoidosis

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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

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Treatment of SarcoidosisACUTE PRESENTATION

Treatment of SarcoidosisCHRONIC PRESENTATION

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

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

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