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Sarcoidosis

Sarcoidosis. Dr. Samir Nusair, MD Rokach Inst. for Lung Dis. & TB Prevention, Clalit Health Services Tel: 02-5017547, E-mail: SamirN@clalit.org.il. twitter.com/ samirnus. References.

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Sarcoidosis

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  1. Sarcoidosis Dr. Samir Nusair, MD Rokach Inst. for Lung Dis. & TB Prevention, Clalit Health Services Tel: 02-5017547, E-mail: SamirN@clalit.org.il twitter.com/samirnus Nusair Lect2013

  2. 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

  3. Sarcoidosis is a systemic granulomatous disorder of unknown etiology SarcoidosisDefinition Nusair Lect2013

  4. 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

  5. Non-caseating granuloma in sarcoidosis Nusair Lect 2012

  6. Non-caseating granuloma in sarcoidosis Nusair Lect2013

  7. Granuloma with caseation Mycobacterium Tuberculosis (Acid-fast stain) Nusair Lect2013

  8. 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

  9. Inflammatory response in Sarcoidosis Nusair Lect2013 AJRCCM 2011

  10. Sarcoidosis Immunopathogenesis Fibrosis may result if Th2 reaction becomes more dominant than the initial Th1 reaction leading to more prominent fibrosis NEJM 2007 Nusair Lect2013

  11. Sarcoidosis- Thoracic Manifestations • pulmonary parenchymal • lymphadenopathy (hilar, mediastinal or paratracheal) • airways and endobronchial involvement • pleural involvement • pulmonary vasculature Nusair Lect 2013

  12. 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

  13. 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

  14. Sarcoidosis – hilar adenopathy

  15. Sarcoidosis – hilar adenopathy

  16. Sarcoidosis- Lymhadeopathy & Pulmonary Parenchymal Involvement

  17. Sarcoidosis- HRCT

  18. Sarcoidosis- HRCT Miliary pattern

  19. Sarcoidosis- advanced parenchymal disease

  20. Sarcoidosis- cavitary changes

  21. Sarcoidosis follow-up at 12 yrs (bottom panes) Akira, M. et al. Chest 2005;127:185-191

  22. 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

  23. Lupus pernio Granulomata Raised plaque lesions Nusair Lect2013

  24. 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

  25. Clinical presentation • Asymptomatic radiographic findings • Cough • Dyspnea • Systemic (e.g. fever, malaise) • Other organ involvement Nusair Lect 2013

  26. 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

  27. FDG-PET A new Imaging Modality for Sarcoidosis ?

  28. FDG-PET A new Imaging Modality for Sarcoidosis ? Cardiac sarcoidosis

  29. 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

  30. 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

  31. 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

  32. Corticosteroid sparing therapy Nusair Lect 2013

  33. 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

  34. 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

  35. 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

  36. 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

  37. Anti Tumor Necrosis Factor (Anti-TNF-α) Nusair Lect 2013

  38. 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

  39. 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

  40. 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

  41. Treatment options • More than 70% of patients will not require systemic steroids Nusair Lect2013

  42. Life-span limiting complications of Sarcoidosis • Pulmonary • Fibrosis • Bronchiectasis • Mycetomas • Cardiac • Neurosarcoidosis Nusair Lect2013

  43. 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 Lect2013

  44. Treatment of SarcoidosisACUTE PRESENTATION

  45. Treatment of SarcoidosisCHRONIC PRESENTATION

  46. 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 treatment Nusair Lect2013

  47. 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 Lect2013

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