1. SARCOIDOSIS

2. SARCOIDOSIS
Definition: Idiopathic systemic disorder characterized by accumulation of lymphocytes and monocytes in many organs forming noncaseating, epitheloid granuloma and subsequent conformational changes in the involved organs
Etiology: unknown
Extent of involvement : systemic
Clinical course : variable from asymptomatic disease with spontaneous resolution to progressive disease with organ system failure
Symptoms: dependent on site of involvement 1

3. Epidemiology
Common in : N. Europe (especially Scandinavia, Ireland, Great Britain),
N. America, and Japan
Low incidence: China, India, Africa, Russia
Peak age of incidence: 20’s and 30’s
Sex prevalence : women > men
In USA : blacks > whites
Worldwide: 80% of affected patients are white

4. Etiopathogenesis Genetic susceptibility Environmental factors
Triggers an immune response (Th type 1)

5. Genetic factors Prevalence in certain race Familial clustering
HLA -A1, -B8, and -DR3
HLA B22 in Italians
HLA DR-17 good prognosis in Scandinavians; protracted course with DR 15 and 16
DR5j Japanese patients have poor prognosis
Negative association: HLA B12 and -DR4

6. Environmental agents 1969 Mitchell and Reese - ? Infectious agent
Non-infectious agents ? Aluminum, berrylium etc.
Mycobacterial ?

7. Granulomatous reaction
T cells predominantly CD4 accumulate
Releases IFN-gamma, IL-2 and other cytokines
Macrophages are recruited and release its own inflammatory mediators (TNF, IL12, IL15, growth factors)
CD45RO + Th1 type lymphocyte is activated
Granuloma formation

10. Signs and Symptoms Depend on the site
Fever, fatigue, weight loss, arthralgias (1/3)
Persistent fever seen in liver involvement
Peripheral lymphadenopathy usually asymptomatic
Cough and dyspnea less often seen

11. SARCOIDOSIS Systemic Involvement
Lung lesions – 95%
Thoracic lymph nodes – 50%
Skin lesions – 30%
Eyes – 30%

12. SARCOIDOSIS Systemic signs
Hilar adenopathy on chest x-ray
Lung infiltrate
Erythema nodosum
Arthritis

13. Lung involvement In 90% - 95%of cases
Dyspnea, dry cough, and chest pain (1/3)
Primarily involves the parenchyma
Lymph node involvement, and airway lesions (larynx, trachea and bronchi) may also be involved; 20% asthma-like
Mediastinal adenopathy on routine x-ray
Bilateral hilar and right paratracheal adenopathy universally seen

14. Lung involvement
Pulmonary infiltrate may have a diffuse, fine, ground-glass appearance
Fibrosis, cystic changes, and cor pulmonale in late progressions
Uncommon manifestations include pleural effusion, pleural thickening, pneumothorax
cavity formation, lymph node (LN) calcification

15. Radiographic stages Stage 0, no intrathoracic finding Stage 1 Stage 2
Bilateral hilar adenopathy, often accompanied by paratracheal node enlargement
80% has regression of hilar nodes in 1-3 years
Stage 2
Bilateral hilar adenopathy and interstitial infiltrates (upper lung zone more than lower)
Mild to mod symptoms
can undergo spontaneous resolution
Stage 3
Interstitial disease with shrinking hilar nodes, upper lung zone interstitial opacities
Stage 4
Advanced fibrosis

16. CXR Findings Stage 1- Bilateral hilar adenopathy (80% resolution)
Stage 2- Hilar adenopathy + parenchymal infiltrates (50% resolution)
Stage 3- Parenchymal infiltrates (30% resolution)
Stage 4- Advanced fibrosis
Sarcoidosis stage 1

17. CT Scan Mediastinal and hilar adenopathy
Mid to upper lung predominance
Nodules along brochi, vessels or subpleural
Consolidation or ground glass opacity
Fibrosis with distortion of lung architecture

18. Stage I
Stage II

19. Stage III
Stage IV

20. Studies to evaluate pulmonary sarcoidosis
Imaging study with CXR, CT
Lung function tests – restrictive pattern, reduction in DLCO, endobronchial sarcoidosis presents obstructive pattern
Radiotracer scanning – staging the alveolitis in interstitial lung disease, unclear role
Broncho-alveolar lavage (BAL) – adjunctive measure to support the diagnosis.
CD4:CD8 ratio
These support the diagnosis but not confirmatory
Differ.diagnosis of pulmonary involvement – hypersensitivity pneumonitis, eosinophilic granuloma, collagen vascular disease, pneumoconiosis, chronic beryllium lung dz, infections

21. Lung Function Tests
Lung function tests show restriction, decreased compliance, and impaired diffusing capacity
Co2 retention is uncomon, but airway obstruction is common in endobronchial disease and late states with pulm. fibrosis
Serial spyrometries are important for guiding treatment

22. Perpheral Lymph Nodes Involvement
Most common : cervical, epitrochlear, axillary, and inguinal nodes
Seen in 1/3 of patients
discrete, movable and non-tender
Do not ulcerate and form draining sinuses

23. Myocardial involvement
arrhythmias, heart failure (restrictive type), conduction abnormalities
The risk of cardiac dysfunction or sudden death in these patients is low (those with positive thallium-201 imaging)
endomyocardial biopsy confirms the diagnosis
need to exclude coronary artery disease

24. Eye involvement In 15-25% of cases :
Anterior uveitis - the most common form of ocular sarcoidosis
- congestion, photophobia and ocular
discomfort
Heerfordt’s syndrome or uveoparotid fever - anterior uveitis +
parotitis, fever and facial palsy
Posterior uveitis - vitreous infiltrates, choroidal nodules,
periphlebitis, retinal hemorrhage, and
papilledema
Conjunctivitis - superficial congestion

25. Ocular Involvement Anterior segment lesions (30%)
Conjunctival granuloma
Lacrimal gland involvement/dry eye
Acute or chronic uveitis 
lesions described as ‘mutton fat’ because they are large and greasy

26. Ocular Involvement Posterior segment lesions (20%)
Patchy venous sheathing
Cellular infiltrate around vessels
Chorioretinal granulonmas
Vasculitis including occlusive causing:-
Neovascularisation
Infiltrate in vitreous (vitritis) including cell clumps (snowballs)

27. Ocular Involvement
Systemic steroids may be necessary in patients with posterior segment disease where vision is threatened, especially if optic nerve is involved

28. Skin disease In chronic sarcoidosis 15-20%
plaques, papules, subcutaneous nodules
keloid formation in atrophic scars
Nasal and conjunctival mucosal granulomas may occur
erythema nodosum (EN) with fever and arthralgias seen often in Europeans;
EN + bilateral hilar lymphadenopathy = Lofgren’s syndrome, portends a good prognosis

29. Skin disease Lupus pernio
violaceous, chronic and disfiguring lesions of the ears, nose and cheeks
Lupus pernio affecting the nose – a chronic progressive cutaneous sarcoid

30. Lupus Pernio

31. Sarcoid Dactylitis

36. Neurologic Disease In 5-10% of cases:
Unilateral facial nerve palsy - most common
Almost any structure can be involved
Hypotalamus-pituitary axis involvement can cause hyperprolactinemia and diabetes insipidus.

37. SARCOIDOSIS Systemic signs
Facial palsy
Salivary gland enlargement

38. Joint involvement Acute polyarthritis may be prominent
Chronic periarticular swelling and tenderness due to osseous changes in phalanges

39. Liver and other organs
Hepatic granulomas in biopsy in 50-80% of patients with normal liver function
Hepatomegaly in < 10%
Severe liver disease and jaundice are rare manifestations
• Myopathy, splenomegaly, lacrimal gland, parotid gland, bone involvement

40. SARCOIDOSIS Investigations
Leukopenia frequent
Serum uric acid high, but gout is rare
Alkaline phosphatasis and GGT may be high if liver involved
Hypercalcemia +/- hypercalciuria due to calcitriol from macrophages
Depression of delayed hypersensitivity is characteristic: negative (or false neg) tuberculin skin test

41. SARCOIDOSIS Investigations
Serum angiotensin-converting enzyme (ACE) – elevated in active sarcoidosis
Mantoux test – caution in patients who have had BCG vaccination. Test may be negative.
Lung function tests - restriction

42. Broncho-alveolar lavage(BAL) Gallium scanning
CD4/CD8 ratio is elevated in BAL in sarcoidosis
but reduced in hypersensitivity pneumonitis
whole-body gallium scanning is sensitive, but not specific
Symetric uptake in mediastinal and hilar nodes (lambda sign) and in lacrimal, parotid and salivary glands (panda sign)
Pathognomonic for sarcoidosis

43. SARCOIDOSIS Investigations
Gallium scan showing increased uptake in the lacrimal and parotid glands and pulmonary regions in a patient with active sarcoidosis

44. Serum ACE
Serum ACE activity elevated in % due to macrophage activity, but nonspecific since hystoplasmosis, acute milliary TB, hepatitis, and lymphomas also have this finding (5% false +)
Lacks diagnostic specificity and poor prognostic value in identifying patients with progressive disease
Tissue ACE activity is highest in sarcoid lymph nodes rather than in pulmonary tissues

45. Kveim-Siltzbach test Rarely used in practice
Intradermal injection of homogonized tissue of organs involved with sarcoidosis causes delayed cutaneous reaction in 4-6 weeks
Within granulomas are multi-nucleated giant cells called with stellate inclusions called asteroid bodies and laminated calcificcations called Schaumann’s bodies

46. Kveim-Siltzbach test
Suspension derived from a sarcoid spleen is injected intradermally. Positive rxn occurs in 4 weeks. Mechanism is unknown. The test positive 80-85%.

47. Questions
Do we need a biopsy to diagnose sarcoidosis? Where to biopsy?
What markers are available to follow disease progression of sarcoidosis?
What medications other than steroids are available for treatment?

48. Biopsy Confirmation of diagnosis Palpable lymph nodes
Subcutaneous nodule
Cutaneous lesion
Enlarged parotid
Lacrimal gland
Transbronchial lung biopsy -> recommended site for biopsy but diagnostic yield varies

49. Biopsy Tissue biopsy is essential
Biopsy almost always positive if skin, lymph nodes, conjunctiva involved
Transbronchial biopsy is best initial procedure for securing histologic evidence since granulomas can be seen regardless of chest x-ray findings
Diagnosis of pulmonary sarcoidosis relies on :
a) tight, well-formed granulomas and a rim of
lymphocytes and fibroblasts
b) perilymphatic distribution of granulomas
c) exclusion of an alternative cause

50. Pathologic DDx Lungs TB, atypical mycobacteriosis
Fungal : aspergillosis, crytptococcosis, histoplasmosis, blastomycosis, coccidiodomycosis
Mycoplasma
Pneumoconioses: berrylium, titanium, aluminum
Drug reactions
Hypersensitivity pneumonitis
Aspiration of foreign materials
Wegener’s granulomatosis
NSG (necrotizing sarcoid granulomatosis)

51. Pathologic DDx Lymph Node TB, atypical mycobacteriosis Brucellosis
Toxoplasmosis
Granulocytic histiocytic necrotizing lymphadenitis (Kikuchi’s disease)
Cat scratch disease
Carcinoma
Hodgkin’s disease
Non-Hodgkin lymphoma
GLUS (granulomatous lesions of unknown significance)

52. Pathologic DDx Bone Marrow Other organs TB, hystoplasmosis
Hodgkin’s and NHL
Drugs
Other organs
TB, brucellosis
Giant cell myocarditis

53. Pathologic DDX Skin Liver TB, atypical mycobacteriosis
Fungal infections
Reaction to foreign bodies: beryllium, zirconium,
tattooing, paraffin, etc.
Rheumatoid nodules
Liver
TB, Brucellosis
Schistosomiasis
Crohn’s disease
Hodgkin’s and NHL

54. Prognosis
About 10% will have serious disability such as ocular or respiratory
Mortality < 3%
Pulm fibrosis leading to respiratory failure is most common cause of death
Also pulmonary hemorrhage from aspergilloma

55. TREATMENT Corticosteroids Cytotoxic agents:
methotrexate, azathioprine, chlorambucil,
cyclophosphamide
Other agents : antimalarials, ketoconazole,
NSAID’s
• Infliximab

56. Criteria for institution of glucocorticoid therapy
When to treat?
Criteria for institution of glucocorticoid therapy
Ancillary
criteria
Elevated levels
of BAL
lymphocytes
Elevated ACE
Abnormal
gallium-67
scan
Disabling
symptoms
Fever
Arhtralgias
Cough
Dyspnea
Chest
discomfort
Exercise
limitation
Abnormal
tests
Hypercalcemia
Progressively
elevated
liver
enzymes
Organ
dysfunction
Lung
Eye
Heart
CNS
Liver
Organ
derangement
Enlarged LN
Enlarged
spleen
Parotitis
Cutaneous
lesions

57. To treat or not to treat... Possibility of spontaneous resolution
Variable course
Side effects of medications
Neurologic, cardiac, and intraocular involvement generally warrants early therapy
Bottomline: there is a need for serial
reevaluation

58. Use of steroids
Acutely suppress the manifestions of the disease; QUESTIONABLE IMPACT ON LONG-TERM NATURAL HISTORY
Prednisone 0.5 to 1 mg/kg/day for 4-6 weeks and then taper over 2-3 months. Treat for a minimum of 1 year using the lowest possible suppressive dose.
Repeat if the disease reactivates.
Consider alternative modalities if steroids fail
Prevent osteoporosis

59. Response to steroids
Generally used for skin lesions, iritis, uveitis, nasal polyps, or airway disease
Inhaled corticosteroids (?)
Systemic therapy: remission of granuloma, relief of respiratory symptoms, and improvement in CXR and lung function studies
Relapse after steroid withdrawal > 1/3 within 2 years

60. Indicators of Sarcoid Activity
Worsening clinical features
Worsening symptoms
Lung function deterioration
Elevated Serum Ca++
Elevated serum ACE level
Gallium scanning positivity increases
Worsening evidence of alveolitis in BAL

61. Treatment with Cytotoxic Drugs
Methotrexate mg/week; can be used solely for cutaneous and musculoskeletal symptoms.
Systemic sarcoidosis refractory to steroids
Cutaneous sarcoidosis after relapse

62. Treatment with Cytotoxic Drugs
Methotrexate toxicity:
Hypersensitivity pneumonitis and
hepatotoxicity
Appear to be limited with the use of folic or folinic acid
Avoid in patients with significant renal failure

63. Alternative Regimens Azathioprine 50-150 mg/day +/- prednisone
Chlorambucil +/- prednisone
Cyclophosphamide +/- prednisone
Hydroxychloroquine mg/day
Infliximab- some benefit in refractory disease

64. Treatment of Complications
Bronchiectasis and its complications :
- antibiotics, antifungal (aspergilloma)
- surgical resection and embolization for
hemoptysis
Osteoporosis prevention: vitamin D, calcium, nasal calcitonin, bisphosphonate
Pulmonary rehab, O2, lung transplantation