Sarcoidosis
Dr.Adil Al Sulami
KAUH
Sarcoidosis is a multisystem inflammatory
disease of unknown etiology that
predominantly affects the lungs and
intrathoracic lymph nodes.
Sarcoidosis is manifested by the
presence of noncaseating
granulomas (NCGs) in affected
organ tissues.
The modern history of
sarcoidosis
 In
1899, the pioneering Norwegian dermatologist
Caesar Boeck describe skin nodules characterized by
compact, sharply defined foci of "epithelioid cells
with large pale nuclei and also a few giant cells .
 Thinking
this resembled sarcoma, he called the
condition "multiple benign sarcoid of the skin.
Epidemiology
 All
racial .
 All ethnic groups.
 All ages (with the incidence peaking at 20 to 39 years).
 M-F ratio 2:1.
The incidence
 The
highest annual incidence in northern European
countries 5 - 40 / 100,000.

In Japan, the annual incidence 1 - 2 / 100,000.
 Among
black Americans is roughly 3 times that
among white Americans (35.5 / 100,000, as
compared with 10.9 / 100,000.
Pathophysiology
T cells play a central role in the
development of sarcoidosis, as
they likely propagate an excessive
cellular immune reaction.
The cause of sarcoidosis is
unknown.
Efforts to identify a possible
infectious etiology have been
unsuccessful.
 Genetic
role.

and environmental factors seem to play a
As yet, no bacterial, fungal, or viral antigen has been
consistently isolated from the sarcoidosis lesions.
 Sarcoidosis
disease.
is neither a malignant nor an autoimmune
The following have been suggested as possible
candidates that might play a role in causing
sarcoidosis:

Mycobacteria, such as Mycobacterium tuberculosis, and atypical
pathogens have been suggested.

Fungi and viruses, particularly Mycoplasma, Chlamydia, and EpsteinBarr virus, have been unconvincingly implicated.
Environmental Causes

Some of the earliest studies of sarcoidosis reported associations with
exposures to irritants found in rural settings, such as emissions from
wood-burning stoves and tree pollen.

More recently, associations with sarcoidosis and exposure to
inorganic particles ,insecticides ,and moldy environments have been
reported.

Occupational studies have shown positive associations with service in
the U.S. Navy ,metalworking ,firefighting ,and the handling of
building supplies.
Genetic Features

Familial sarcoidosis was first reported in 1923 in two
affected sisters .

No formal twin study has been reported, but the
concordance appears to be higher in monozygotic twins
than in dizygotic twins .

In A Case-Control Study, patients with sarcoidosis stated 5
times as often as control subjects that they had siblings or
parents with sarcoidosis.
Common Clinical Features

Presentation depends on the extent and severity of the
organ involved.

Approximately 5% of cases are asymptomatic and
incidentally detected by CXR.

Systemic symptoms occur in 45% of cases such as :

Fever.
anorexia
Fatigue.
Night sweats .
Weight loss .





Pulmonary, dyspnea on exertion, cough, chest pain, and
hemoptysis (rare) occur in 50% of cases.
Löfgren's syndrome, an acute presentation consisting of:
Fever.
 Arthralgia.
 erythema nodosum.
 bilateral hilar adenopathy.
 occurs in 9 to 34% of patients .

Heerford's syndrome :
Anterior Uveitis
 Fever
 Parotid enlargment
 Facial palsy

Physical finding
 Pulmonary
findings.
 Dermatological manifestations.
 Ocular manifestations .
 Cardiac manifestations
 Neurologic manifestations (rare)
Organ Involvement
 Sarcoidal
granulomas can involve any organ, but in
more than 90% of patients, clinical sarcoidosis is
manifested as intrathoracic LN enlargement,
pulmonary involvement, skin or ocular signs and
symptoms, or some combination of these findings.
Pulmonary Involvement

dyspnea, cough, vague chest discomfort, and wheezing.

Chest radiographs in patients with sarcoidosis have been classified
into four stages:
–
–
–
–

stage 1, bilateral hilar lymphadenopathy without infiltration.
stage 2, bilateral hilar lymphadenopathy with infiltration.
stage 3, infiltration alone.
stage 4, fibrotic bands, bullae, hilar retraction, bronchiectasis,
and diaphragmatic tenting.
These so-called stages represent radiographic patterns and do not
indicate disease chronicity or correlate with changes in pulmonary
function.
Stage 1
Stage II is BHL and infiltrates
Stage III is infiltrates alone
Cutaneous Involvement
Although not life-threatening, but can be emotionally
devastating.





Erythema nodosum may occur.
Lupus pernio is the most specific associated cutaneous lesion.
Violaceous rash is often seen on the cheeks or nose.
Osseous involvement may be present.
Maculopapular plaques are possible.

Lupus pernio is more common in women than in men and is associated with
chronic disease and extrapulmonary involvement.

Erythema nodosum occurs in about 10% of patients with sarcoidosis and usually
lasts for about 3 weeks.

Biopsy specimens of erythema nodosum lesions show nonspecific septal
panniculitis, which neither confirms nor negates the diagnosis of sarcoidosis.
Liver and Spleen Involvement

10% of all patients with sarcoidosis have elevated serum
aminotransferase and alkaline phosphatase levels.

A cholestatic syndrome characterized by pruritus and jaundice,
hepatic failure, or portal hypertension can develop (liver involvement
is usually clinically silent).

Detection of hepatic and splenic lesions on CT is described in 5%
and 15% of patients.

60% of patients with hepatic manifestations of sarcoidosis have
constitutional symptoms such as fever, night sweats, anorexia, and
weight loss.

Portal hypertension with variceal bleeding, a hepatopulmonary
syndrome with refractory hypoxemia, and cirrhosis leading to liver
failure occur in only 1% of patients with sarcoidosis.
Neurologic Involvement

CNS is involved in up to 25% of patients with sarcoidosis who undergo autopsy,
but only 10% of all patients with sarcoidosis present with neurologic symptoms.

The most common problems:
–
–
–
–
–
–

cranial-nerve palsies.
Headache.
Ataxia.
cognitive dysfunction.
Weakness.
seizures.
CSF Analysis :
– nonspecific lymphocytic inflammation.
– measuring ACE levels .
– oligoclonal immunoglobulin bands in the CSF are elevated, making it difficult to
differentiate sarcoidosis from multiple sclerosis.

Magnetic resonance imaging (MRI)
Ophthalmologic Complications
The eye and adnexa are involved in 25 -80% of patients
with sarcoidosis,this necessitating routine slit-lamp and
funduscopic examination.
 Anterior or posterior granulomatous uveitis .
 Conjunctival lesions and scleral plaques may also be noted.
 Ocular involvement may lead to blindness if untreated.


Anterior uveitis
(is the most common manifestation)
chronic anterior uveitis, with insidious symptoms leading
to glaucoma and vision loss, is more common than acute
anterior uveitis.
Cardiac manifestations
 Heart
failure from cardiomyopathy rarely occurs.
 Heart block and sudden death may occur.
 Approximately 25% of patients may have NCGs at
autopsy, but fewer than 5% have clinical cardiac
disease.
 Okada et al reported on cardiac infiltration
associated with a novel heterogenous mutation
(G481D in CARD15) in early-onset sarcoidosis.
Differential Diagnosis
Hilar infiltrates:





Tuberculosis.
Lymphoma
Eosinophilic granuloma
Fungal infection
Lung cancer
NCG on a biopsy :







Berylliosis
Catscratch disease
Fungal infection
Hypersensitivity pneumonitis
Leprosy
Primary biliary cirrhosis
Tuberculosis.
Diagnosis
The diagnosis is established on the basis of :
 Clinical
finding.
 Radiologic findings.
 Supported by histologic evidence in one or more
organs of noncaseating epithelioid-cell granulomas
in the absence of organisms or particles.
A diagnosis of sarcoidosis is reasonably certain
without biopsy in patients who present with
Löfgren's syndrome.
Laboratory Studies

Routine lab evaluation often is unrevealing.

Hypercalcemia or hypercalciuria may occur (NCGs secrete 1,25
vitamin D).

Hypercalcemia is seen in about 10-13% of patients, whereas
hypercalciuria is 3 times more common.

An elevated alkaline phosphatase level suggests hepatic involvement.

Angiotensin converting enzyme (ACE) levels may be elevated.

NCGs secrete ACE, which may function as a cytokine.

Serum ACE levels are elevated in 60% of patients at the time of
diagnosis.

Levels may be increased in fluid from bronchoalveolar lavage or in
CSF.


Sensitivity and specificity as a diagnostic test is limited (60 and 70%,
respectively).
There is no clear prognostic value.

Serum ACE levels may decline in response to therapy.

Decisions on treatment should not be based on the ACE level alone.
Imaging Studies
A
chest radiograph is central to evaluation.
 Routine
chest CT scan adds little.
 HRCT
of the chest may be helpful.
Biopsy specimen
A
biopsy specimen should be obtained from the
involved organ that is most easily accessed, such as
the skin, peripheral LN, lacrimal glands, or
conjunctiva.
 If
diagnosis requires pulmonary tissue,
transbronchial biopsy by means of bronchoscopy
has a diagnostic yield of at least 85% when
multiple lung segments are sampled .
The central histologic finding is the presence of NCGs with
special stains negative for fungus and mycobacteria.

Sarcoidal granulomas have no unique histologic features to
differentiate them from other granulomas.

Special stains for acid-fast bacilli and fungi, as well as
cultures of such organisms, are essential.

If the results of lung biopsy with bronchoscopy are
negative and other organs are not obviously involved,
biopsy of intrathoracic lymph nodes, which are often
enlarged in patients with sarcoidosis ,may be necessary to
confirm the diagnosis.
Treatment
 Most
patients (>75%) require only
symptomatic therapy NSAID.

Approximately 10% of patients need
treatment for extrapulmonary disease.
 15%
of patients require treatment for
persistent pulmonary disease.
Corticosteroids are the mainstay of
therapy

prednisone given daily and then tapered over a 6-month course is
adequate for pulmonary disease.

Earlier recommendations suggested an initial dose of 1 mg/kg/d of
prednisone; however, more recent expert opinions endorse a lower
dose (eg, 40 mg/d), which is tapered to every other day long-term
therapy over several weeks.

Most patients who require long-term steroids can be treated using
10-15 mg of prednisone every other day.

High-dose inhaled corticosteroids may be an option, but conclusive
data are lacking.
 Data
suggest that corticosteroid use may be
associated with increased relapse rates.
 Occasionally,
certain patients cannot tolerate
or do not respond to corticosteroids.
Noncorticosteroid agents
Used more frequently.
Common indications :
 Steroid-resistant disease.
Intolerable adverse effects.
 patient desire not to take corticosteroids.

 Methotrexate
(MTX) has been a successful alternative
to prednisone and is a steroid-sparing agent.
 Chloroquine
and hydroxychloroquine are antimalarial
drugs with immunomodulating properties, which have been
used for cutaneous lesions, hypercalcemia, neurological
sarcoidosis, and bone lesions.
 Chloroquine has
also been shown to be efficacious for
the treatment and maintenance of chronic pulmonary
sarcoidosis.

Cyclophosphamide has been rarely used with modest success as a

Azathioprine is another second-line therapy, which is best used as a

Chlorambucil is an alkylating agent that may be beneficial in

Cyclosporine is a fungal cyclic polypeptide with lymphocyte-
steroid-sparing treatment in patients with refractory sarcoidosis.
steroid-sparing agent rather than as a single-drug treatment for
sarcoidosis.
patients with progressive disease unresponsive to corticosteroids or
when corticosteroids are contraindicated.
suppressive properties that may be of limited benefit in skin
sarcoidosis or in progressive sarcoid resistant to conventional therapy.
 Infliximab
and thalidomide have been used for
refractory sarcoidosis, particularly for cutaneous disease.

Infliximab appears to be an effective treatment for
patients with systemic manifestations such as lupus pernio,
uveitis, hepatic sarcoidosis, and neurosarcoidosis.
 Tetracyclines
have shown promise for the treatment of
cutaneous sarcoidosis.
For pulmonary disease

Asymptomatic PFT and/or CXR abnormalities are not an indication
for treatment.

In patients with minimal symptoms, serial reevaluation is prudent.

Significant respiratory symptoms associated with PFT and CXR
abnormalities likely require therapy.

For such patients, treatment is indicated if objective evidence of
recent deterioration in lung function exists.

Corticosteroids can result in small improvements in the functional
vital capacity and in the radiographic appearance in patients with
more severe stage II and III disease.
One recent study demonstrated an approach that may
minimize the use of corticosteroids without
harming the patient.
This is accomplished by

Withholding therapy unless the patient shows at least a 15% decline
in one spirometric measure associated with increasing symptoms or,

if asymptomatic, withholding therapy unless the patient shows
worsening PFTs and a change in CXR.

For extrapulmonary sarcoidosis involving such critical
organs as the heart, liver, eyes, kidneys, or central nervous
system, corticosteroid therapy is indicated.

Topical corticosteroids are effective for ocular disease.

Inhaled corticosteroids are occasionally used, in particular
in patients with endobronchial disease.
 NSAIDs
are indicated for the treatment of
arthralgias and other rheumatic complaints.
 Patients
with stage I sarcoidosis often require
only occasional treatment with NSAIDs.
Follow-up

Further Inpatient Care
– Monitor pulmonary function and CXR every 6-12 months.
– Assess for progression or resolution.
– Determine if previously uninvolved organs have become affected.

Further Outpatient Care
– Annual slit lamp eye examination and ECG are recommended.
Prognosis
Many patients do not require therapy, and their conditions
will spontaneously improve.
Markers for a poor prognosis include :
Advanced CXR stage.
 Extrapulmonary disease (predominantly cardiac and neurologic)
 Evidence of pulmonary hypertension.
 Multiple studies have demonstrated that the most
important marker for prognosis is the initial CXR stage.

Remission

2/3 of patients with sarcoidosis generally have a
remission within a decade after diagnosis, with few or no
consequences ;remission occurs for more than half of
patients within 3 years .

Unfortunately, up to 1/3 of patients have progressive
disease, leading to clinically significant organ impairment.

A recurrence after 1 or more years of remission is
uncommon (affecting <5% of patients), but recurrent
disease may develop at any age and in any organ.
Death
 Less
 death
than 5% of patients die from
sarcoidosis.
is usually the result of pulmonary
fibrosis with respiratory failure or of
cardiac or neurologic involvement .