SARCOIDOSIS

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

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

Etiopathogenesis

Genetic susceptibility Environmental factors

•Triggers an immune response (Th type 1)

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

Environmental agents

• 1969 Mitchell and Reese - ? Infectious agent• Non-infectious agents ? Aluminum, berrylium

etc.• Mycobacterial ?

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

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

SARCOIDOSISSARCOIDOSISSystemic InvolvementSystemic Involvement

• Lung lesions – 95%

• Thoracic lymph nodes – 50%

• Skin lesions – 30%

• Eyes – 30%

SARCOIDOSISSystemic signs

• Hilar adenopathy on chest x-ray

• Lung infiltrate

• Erythema nodosum

• Arthritis

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

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

Radiographic stages• Stage 0, no intrathoracic finding• Stage 1

– 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

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

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

• Stage I • Stage II

• Stage III • Stage IV

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

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

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

Myocardial involvement

• Myocardial involvement 5-10%– 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

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

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

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)

Ocular Involvement

Systemic steroids may be necessary in

patients with posterior segment disease where vision is threatened, especially if optic nerve is

involved

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

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

Lupus Pernio

Sarcoid Dactylitis

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.

SARCOIDOSISSystemic signs

• Facial palsy

• Salivary gland enlargement

Joint involvement

• Acute polyarthritis may be prominent– Chronic periarticular swelling and tenderness due

to osseous changes in phalanges

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

SARCOIDOSISInvestigations

• 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

SARCOIDOSISInvestigations

• 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

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

SARCOIDOSISInvestigations

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

Serum ACE• Serum ACE activity elevated in 40- 90% 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

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

Kveim-Siltzbach test

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?

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

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

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)

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)

Pathologic DDx

• Bone Marrow• TB, hystoplasmosis• Hodgkin’s and NHL• Drugs

• Other organs• TB, brucellosis• Giant cell myocarditis

Pathologic DDXSkin• 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

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

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

When to treat?Criteria for institution of glucocorticoid therapy

Disablingsymptoms

FeverArhtralgiasCoughDyspneaChest discomfortExercise limitation

Organ dysfunction

Lung Eye Heart CNS Liver

Organ derangement

Enlarged LNEnlarged spleenParotitisCutaneous lesions

Abnormal tests

HypercalcemiaProgressively elevated liver enzymes

Ancillary criteria

Elevated levels of BAL lymphocytesElevated ACEAbnormal gallium-67 scan

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

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

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

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

Treatment with Cytotoxic Drugs

• Methotrexate 10-15 mg/week; can be used solely for cutaneous and musculoskeletal symptoms.

• Systemic sarcoidosis refractory to steroids

• Cutaneous sarcoidosis after relapse

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

Alternative Regimens

• Azathioprine 50-150 mg/day +/- prednisone

• Chlorambucil +/- prednisone

• Cyclophosphamide +/- prednisone

• Hydroxychloroquine 200-400 mg/day

• Infliximab- some benefit in refractory disease

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