Download Module5 - UMF IASI 2015

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
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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
SARCOIDOSIS
Systemic Involvement
• Lung lesions – 95%
• Thoracic lymph nodes – 50%
• Skin lesions – 30%
• Eyes – 30%
SARCOIDOSIS
Systemic signs
• Hilar adenopathy on
chest x-ray
• Lung infiltrate
• Erythema nodosum
• Arthritis
Lung involvement
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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 thallium201 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 1520%
– 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.
SARCOIDOSIS
Systemic 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
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
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
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
SARCOIDOSIS
Investigations
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
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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 DDX
Skin
• TB, atypical mycobacteriosis
• Fungal infections
• Reaction to foreign bodies: beryllium, zirconium,
tattooing, paraffin, etc.
• Rheumatoid nodules
Liver
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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
Disabling
symptoms
Organ
dysfunction
Organ
derangement
Fever
Arhtralgias
Cough
Dyspnea
Chest
discomfort
Exercise
limitation
Lung
Eye
Heart
CNS
Liver
Enlarged LN
Enlarged
spleen
Parotitis
Cutaneous
lesions
Abnormal
tests
Hypercalcemia
Progressively
elevated
liver
enzymes
Ancillary
criteria
Elevated levels
of BAL
lymphocytes
Elevated ACE
Abnormal
gallium-67
scan
To treat or not to treat...
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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
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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