Sarcoidosis

Outline
• Introduction
• Epidemiology
• Classification
• Pathology
• Clinical features
• Investigations
• Treatment
• Complications
• Prognosis

Introduction
• Sarcoidosis is a multisystem disorder
characterized by noncaseating granulomatous
inflammation at sites of disease.
• Although any organ can be involved, the
disease most commonly affects the lungs and
intrathoracic lymph nodes
• Young adults are most frequently affected, but
the disease may affect persons of all ages.

Introduction
• The incidence, presentation & clinical course is
geographically and racially highly variable
• However, mortality rate from sarcoidosis is
uniform in the range <1% to 5%
• At present, the etiology of sarcoidosis is unknown
• However, many clinical, epidemiologic, and family
studies support the hypothesis that sarcoidosis is
triggered by exposure to ‘microbial agents’ in
individuals with a genetic susceptibility to the
disease.

Historical perceptive
• Jonathan Hutchinson was the first to describe a
case of sarcoidosis in 1887
• He called it Mortimer’s malady, after one of his
patients who presented with face and limb skin
lesions
• In 1889, Besnier described a 34-year-old man
with violaceous skin lesions of the nose, ear
lobules, and central face
• He proposed that the lesions were a variant of
lupus erythematosus leading to its designation as
“lupus pernio”

• In 1899, Caesar Boeck first described the
characteristic noncaseating granulomas in a patient
with peripheral lymphadenopathy and skin nodules
• In the early years of the 20th century, Bittorf and
Kuznitsky and Schaumann recognized that sarcoid
skin lesions, lupus pernio, and visceral lesions were
all part of the same multisystem disorder

• This important observation set the stage for the
recognition of sarcoidosis as a distinct
clinicopathologic entity
• Ansgar Kveim described the histology of tissue
lesions in patients with sarcoidosis as having a
sarcoma-like granulomas on biopsy

• Louis Siltzbach and others demonstrated in
worldwide studies that “Kveim” reaction was positive
(showed granulomas) in up to 80% of patients with
sarcoidosis and that this was highly specific for the
disease.
• Sven Lofgren in the 1940s noted that sarcoidosis
frequently begins with asymptomatic bilateral hilar
adenopathy or with acute erythema nodosum.

Epidemiology
• From global epidemiologic studies, sarcoidosis can
affect persons of every ethnic background and of both
sexes
• Data obtained by mass radiographic screening, showed
that the prevalence rates vary geographically based on
the region of the world
• Estimated age adjusted incidence rate is approximately
11 cases per 100,000 population in whites in North
America, southern Europe, and Japan
• Higher incidence rates are noted in Sweden, Denmark,
and US Blacks (34 cases per 100,000)

Epidemiology
• A US study calculated a lifetime risk “in women and
men of 2.7% and 2.1% in Blacks and 1.0% and 0.7%
in Whites, respectively”
• Sarcoidosis is rare in the preadolescent period.
• More than 80% of cases occur in persons between 20
and 50 years of age, with a second peak in women
more than 50 years of age.

Epidemiology
• African Americans and women appear to be at
higher risk for disease
• African Americans tend to present with more
severe chronic disease than their Caucasian
counterparts
• Erythema nodosum is more common among
Caucasians and relatively uncommon in blacks
and is felt to portend a better disease outcome
• Cardiac sarcoidosis is commoner in Japan and is
historically associated with a poor prognosis

Epidemiology
• Familial clustering has been reported from several
regions, suggesting that a genetic predisposition to
the development of sarcoid granulomatous
inflammation may exist
• Family clusters occur more commonly in blacks, 19%
of whom report an affected family member, in
comparison with 5% of whites

Epidemiology
• In the United States, 40% to 80% of mortality from
sarcoidosis is from advanced pulmonary disease,
with higher rates observed in blacks and women.
• In Sweden and Japan, cardiac involvement is the
leading cause of death from sarcoidosis.
• Overall, mortality rates directly related to sarcoidosis
approximate <1% to 5%

Etiology
• The etiology of sarcoidosis remains obscure despite
more than a century of intense observation and
investigation.
• However, both genetic and environmental factors
seem to play a role
• The current widely accepted hypothesis is that
sarcoidosis represents an immunologic response to
“specific environmental antigens” in genetically
predisposed persons.

Postulates on the etiology of
sarcoidosis
• Infectious disease postulate
– Mycobacterial catalase-peroxidase (mKatG)
– Mycolyl transferase antigen 85A
– Mycobacterial superoxide dismutase
– Early secreted antigen target 6
– 70% of sarcoidosis patients have lung & blood T cells
responses to mycobacterial antigens
– Overlap of peripheral blood gene expression in
individual with TB infection & sarcoidosis
– Propionibacterium acnes
– Rickettsia spp

Postulates on the etiology of
sarcoidosis
• Failure of immune regulation postulate
• Amyloid A protein
– Eliciting immune responses and triggering cytokine
release through an interaction with toll-like receptor 2
– Extensive deposition in granulomas of sarcoidosis
– Correlate with disease activity in pulmonary sarcoidosis
• Regulatory T cells (T-reg)
– expanded in peripheral blood, BAL, and granulomas
– Functionally defective or ‘‘exhausted’’
• CD1d-restricted natural killer T cells (NKT cells)
– Markedly reduced
– May allow for persistence of sarcoidosis

Genetics & Gene-Environment interaction
influence in the etiology of Sarcoidosis
• Familiar clustering of sarcoidosis occurs in 3-14% of
patients (blacks>> whites
• HLA susceptibility
– HLA-B8 (whites+++)
– HLA-DR3
– HLA-DRB1*1101 (whites & blacks)
– HLA-DRB1*1501 (whites only)
– HLA-DPB1
– HLA-DQB1
• HLA protection
– HLA-DR1
– HLA-DR4
• HLA with favourable outcomes
– HLA-DR17
– HLA-DRB1*0301
– HLA-DQB1*0201

Genetics influence in the etiology of
Sarcoidosis
• HLA with severe or chronic disease
– HLA-DRB1*1501
– HLA-DQB1*0602
• Non-HLA genes
– TNF
– ACE
– Vitamin D receptor
– BTNL2 gene (whites > blacks)
• Chromosomes loci
– 6p12.1
– 11q13.1
– 10p12.2

Etiology of Sarcoidosis
• As yet, no bacterial, fungal, or viral antigen has been
consistently isolated from sarcoidosis lesions.
• The consensus from present understanding is that
sarcoidosis is neither a malignant nor an
autoimmune disease

Pathology of Sarcoidosis
• The pathologic hallmark of sarcoidosis is the
presence of discrete noncaseating, epitheliod cell
granuloma
• The histologic features of sarcoidosis consist of
varying degrees of granulomatous inflammation and
interstitial tissue fibrosis
1. Granulomatous Inflammation
• The noncaseating epithelioid granuloma is the
characteristic lesion of sarcoidosis.

• Epitheliod cells & multinucleated giant cells
containing cytoplasmic inclusion of calcium & iron
laden Schaumann bodies, asteroid bodies &
Hamazaki-Wesenberg bodies are found at the center
of the granuloma
• These granulomas are usually not necrotic.
• When necrosis occurs, it is usually minimal and
confined to the central portions of the lesion

• At the periphery of the granuloma are CD4+ & CD8+
T cells and B lymphocytes
• The ratio of helper/inducer lymphocytes to
cytotoxic/suppressor lymphocytes (CD4+/CD8+ ratio)
in sarcoid granulomas is increased and parallels that
noted in cell profiles in bronchoalveolar lavage (BAL)
fluid

• Noncaseating granulomas may be found in any organ
in the body.
• In the lung, they tend to be peribronchial,
perivascular, interstitial, and subpleural in location.
• Although the epithelioid granuloma is the
characteristic lesion of sarcoidosis, it is probably not
the first lesion to be present in the lung

• The granulomas are preceded by, and then noted in
conjunction with, an interstitial pneumonitis
characterized by macrophages and lymphocytes, the
majority of which are T cells.
• The exact relationship between the intensity of the
interstitial pneumonitis and the density of granuloma
formation is not understood

2. Tissue Fibrosis
• The interstitial pneumonitis and granulomatous
inflammation seen in sarcoidosis results in fibroblastic
& matrix proliferation at the periphery of the
granulomas
• As a result, the granuloma is replaced in a centripetal
fashion with scar tissue with distortion of the normal
alveolar and bronchial architecture.
• Bronchiectasis and cystic parenchymal lesions can
result, and in the most severe cases, honeycombing
and pulmonary hypertension can occur.

Classification of Sarcoidosis
Based on site of disease
• Pulmonary
– Symptomatic
– Asymptomatic
• Extrapulmonary
– Symptomatic
– Asymptomatic

Classification of Sarcoidosis
Syndromic classification
• Asymptomatic in 5% of cases (2/3 of patients,
whites)
• Symptomatic
– Acute sarcoidosis with or without erythema
nodosum
– Pulmonary sarcoidosis of less than 2 years,
– Chronic pulmonary sarcoidosis of more than 2
years, and
– Dominant extrapulmonary sarcoidosis

Multisystemic involvement in Sarcoidosis

Acute sarcoidosis with or without
erythema nodosum
• It is an acute form of disease manifesting with the
acute onset of erythema nodosum associated with
bilateral hilar adenopathy, fevers, polyarthritis, and
often uveitis, known as Lofgren syndrome.
• Lofgren syndrome is more common in European and
White populations, but found in less than 5% of
Blacks with sarcoidosis

Acute sarcoidosis with or without
erythema nodosum
• Approximately 10% of patients with this syndrome
have a normal chest radiograph
• In either case, the prognosis is excellent for remission
in 70% to 80% of patients, typically within several
months.

Pulmonary Sarcoidosis
• Pulmonary involvement is a common form of
presentation in the multisystemic disease of
sarcoidosis
• Respiratory symptoms occur in 40% to 60% of patients
• Nonproductive cough with dyspnea except when
patient have fibrocystic disease with bronchiectasis
• Dull aching chest pain is a frequent complaint, possibly
caused by nerve irritation from inflammation, scarring,
or lymph node enlargement in the chest.

Pulmonary sarcoidosis
• Chest tightness and wheezing are common with
endobronchial disease or fibrocystic changes
• Physical findings are infrequent, with lung crackles
heard in less than 20% of patients; clubbing is rare
• The chest radiograph is abnormal in more than 90%
of known cases and carries prognostic information

• CXR
– Stage 0: normal, <15%
– Stage 1: bilateral hilar adenopathy, 30-50%
– Stage 2: BHL with pulmonary infiltrates, 40-60%
– Stage 3: pulmonary infiltrates only, 10-20%
– Stage 4: fibrocystic changes with cephalad hilar
retraction, 15%

• While stage IV sarcoidosis is associated with a poor
prognosis, there is a weak correlation between
stages I, II, or III chest radiographs and clinical status
• Unusual radiographic signs of sarcoidosis include
pneumothorax, mycetoma, isolated nodule or mass,
lobar atelectasis, or pleural effusions

• Pulmonary function may be normal even when the
chest radiograph demonstrates pulmonary
infiltrates
• However, characteristic resistive defect is to be
expected with reduction of lung volumes
• Isolated reduction in DLCO is highly suggestive
• Obstructive defect in advanced fibrocystic disease or
endobronchial disease

Necrotising sarcoid granulomatosis
• This is a variant of pulmonary sarcoidosis
characterized by large, confluent, noncaseating
granulomas involving both pulmonary arteries and
veins but without systemic vasculitis
• Chest radiographs typically demonstrate multiple,
usually noncavitating nodules
• Pleural disease with pleurisy or pleural effusions
occurs in the majority of patients and may be a clue
to the diagnosis.
• Most patients have spontaneous improvement or a
rapid response to corticosteroid therapy

Extrapulmonary sarcoidosis
• Many patients have manifestations of sarcoid
granulomatous inflammation in one or more organ
systems either in addition to pulmonary involvement
or without evidence of pulmonary disease

Sarcoidosis of the upper respiratory tract (SURT)
• SURT occurs in 5% to 10% of patients, usually
involving the nasal sinuses or laryngeal structures
• Chronic disease or surgical intervention may
result in destruction of the nasal septum and a
“saddle nose” deformity
• Laryngeal sarcoidosis may manifest with severe
hoarseness, stridor, or acute respiratory failure
secondary to upper airway obstruction.

Ocular sarcoidosis
• Detected in approximately 20% to 30% of patients,
more frequently in black populations
• Often associated with BHL and usually presents as
unilateral or bilateral anterior uveitis
• Optic neuritis or severe choroidoretinitis may results
in blindness

Cardiac sarcoidosis
• In USA, 10-20% of patients at diagnosis have
myocardial involvement (compare 50% in Japan)
• Arrhythmias, heart block, or sudden death may be
the initial manifestation due to involvement of the
conduction system
• Incidence rate of VT requiring ICD is reported to be
15% per year in patients with cardiac involvement

Cardiac sarcoidosis
• Myocardial inflammation can lead to dilated
cardiomyopathy and congestive heart failure,
local akinesia, or aneurysms.
• Myocardial mass, valvular dysfunction from
papillary muscle dysfunction, pericarditis, and
myocardial ischemia are rarer manifestations
• The severity of pulmonary involvement does not
appear to predict the presence or severity of
cardiac sarcoidosis

Neurosarcoidosis
• Neurologic manifestations of sarcoidosis are varied
and are estimated to occur in 10% to 20% of patients
with sarcoidosis
• Cranial neuropathies, with unilateral or bilateral
seventh nerve (Bell) palsy & lymphocytic meningitis is
the most common presentation

Neurosarcoidosis
• The more typical presentations of sarcoidosis in the
brain include a basilar meningitis or aseptic
encephalitis, sometimes associated with
hypothalamic pituitary dysfunction leading to
diabetes insipidus, hypogonadism, or
hyperprolactinemia.

Neurosarcoidosis
• Spinal cord involvement is rare and can present as a
transverse myelitis or mass-like lesion resulting in
paraparesis, hemiparesis, back and leg pains
mimicking radiculopathy.
• Peripheral neuropathies account for about 20% of
cases of neurosarcoidosis, typically presenting as
mononeuritis multiplex

Cutaneous sarcoidosis
• Chronic skin sarcoidosis is seen in approximately
25% of patients, usually manifesting as plaques or
subcutaneous nodules and is more common and
severe in blacks
• Typically, the plaques are located around the hairline,
eyelids, ears, nose, and extensor surfaces of the arms
and legs

• Lupus pernio is a disfiguring form of cutaneous
sarcoidosis of the face, with violaceous plaques and
nodules covering the nose, nasal alae, malar areas,
and areas around the eyes
• Erythema nodosum is a nongranulomatous
panniculitis seen in acute sarcoidosis

Joint & Musculoskeletal sarcoidosis
• Arthralgias /short-lived polyarthritis is typical of
acute sarcoidosis, usually associated with
erythema nodosum. Chronic joint disease is found
in less than 5% of patients
• Symptomatic myopathy with marked elevation of
serum creatinine phosphokinase, aldolase,
aspartate aminotransferase, weakness and
tenderness is uncommon.
• Typically, the myositis from sarcoidosis is
responsive to systemic immunosuppression

Exocrine gland sarcoidosis
• Granulomatous inflammation of salivary, parotid,
and lacrimal glands results in enlarged, tender
glands, and/or Sicca syndrome with dry mouth
and dry eyes in less than 5% of patients with
sarcoidosis
• The association of fever, parotid enlargement,
facial palsy, and uveitis is known as uveoparotid
fever, or Heerfordt syndrome, and is usually
accompanied by bilateral hilar adenopathy

Endocrine gland sarcoidosis
• Abnormal calcium metabolism is found in
sarcoidosis; hypercalciuria is more frequent than
hypercalcemia.
• These abnormalities are due primarily to
increased conversion of 25(OH) vitamin D
metabolites to active 1,25(OH)2 vitamin D by
tissue macrophages and epithelioid cells at sites
of granulomatous inflammation.
• Hypothalamic/pituitary insufficiency may be a
manifestation of neurosarcoidosis.

Renal Sarcoidosis
• Kidney stones are the most frequent
manifestation of renal sarcoidosis, usually related
to abnormal calcium metabolism.
• Renal failure due to nephrocalcinosis may result
from chronic, often asymptomatic hypercalcemia
or hypercalciuria.
• Granulomatous involvement of the kidneys
occurs but is rarely the cause of significant renal
dysfunction

Genitourinary sarcoidosis
• This occur in less than 1% of clinically diagnosed
cases and in 5% of autopsy cases.
• Genitourinary manifestations of sarcoidosis in
men include testicular masses and acute
epididymitis-orchiditis.
• In women, sarcoidosis may manifest with uterine
or ovarian involvement that may cause
dysmenorrhea or mimic malignancy or fibroids.

Psychosocial manifestation
• A Dutch study found the prevalence of depression
was 4% in asymptomatic patients and 30% in
symptomatic patients with sarcoidosis while the
prevalence of depression was found to be 60% in a
US study of both White and Black patients with
sarcoidosis
• Fatigue is commonly reported and may be disabling
for a subset of patients

• The prevalence of pain in sarcoidosis is unclear, but
clinical experience suggests it is common with
frequent reports of arthralgias, myalgias, headache,
and chest pain.
• The cause of pain is often multifactorial with causes
ranging from direct granulomatous inflammation of
bones, joints, muscles, or peripheral nerves to small
fiber neuropathy

• A subset of patients meets diagnostic criteria for
fibromyalgia
• In addition to its association with pain, small fiber
neuropathy may cause autonomic dysfunction with
gastrointestinal dysmotility, incontinence or
retention, sicca syndrome, flushing, sweats,
orthostatic hypotension, and sexual dysfunction.

Hepatic sarcoidosis
• Liver biopsies show granulomatous inflammation in
over 50% of patients
• Active hepatic inflammation may be associated with
fever, tender hepatomegaly, or pruritus that may
mimic primary biliary cirrhosis except that
autoimmune serologies are negative.

Hepatic sarcoidosis
• Characteristically, the serum alkaline phosphatase
and γ-glutamyltransferase are elevated
proportionately higher than the transaminases or
bilirubin
• Progressive cirrhosis occurs in a subset of patients if
not treated.

Gastrointestinal sarcoidosis
• Sarcoidosis involvement of the gastrointestinal
tract is rare
• Occasionally, direct esophageal involvement may
cause dysphagia, but more commonly this
symptom may be caused by extensive mediastinal
lymphadenopathy that impinges esophageal
motility.
• Gastric sarcoidosis may manifest as dyspepsia,
abdominal pain, or gastric nodule

Abdominal Sarcoidosis
• Involvement of the liver, spleen, and often bone
marrow with associated hypercalcemia or
abdominal lymphadenopathy and constitutional
symptoms of fever & fatigue are frequent
• This “triad” pattern may be seen with or without
pulmonary involvement; in the latter instance,
intra-abdominal malignancy must be excluded.

Hematologic sarcoidosis
• Persistent, bulky, painful, or disfiguring adenopathy is
seen in <10% of patients, most commonly involving
the cervical, supraclavicular, axillary, or epitrochlear
lymph nodes.
• Splenomegaly occurs in <10% of patients, and may
be massive and associated with hypersplenism

• Peripheral blood lymphopenia is common in
sarcoidosis.
• Granulomas in the bone marrow are found in about
20% of patients who come to autopsy but usually do
not cause symptoms.

• A known feature of sarcoidosis is the impaired
cutaneous response to common antigens that elicit
delayed-type hypersensitivity reactions, seen in >30%
of patients.
• The mechanism is unknown but may be related to
alterations in regulatory T-cell function.

Sarcoidosis and Pregnancy
• In contrast to diseases such as asthma and
systemic lupus that may progress during
pregnancy, spontaneous improvement in chronic
sarcoidosis has been reported in some patients
during pregnancy, although exacerbations often
follow several months after delivery.
• The reasons for the temporary clinical
improvement are not known but might be related
to suppressed Th1 immunity during pregnancy
associated with enhanced Treg function

Investigation of Sarcoidosis
• A diagnostic approach of sarcoidosis is based on
compatible clinical and radiologic manifestations
together with a tissue biopsy demonstrating
noncaseating granulomatous inflammation and
exclusion of other granulomatous disorders.

An approach to diagnosis of Sarcoidosis.
Lofgren syndrome
erythema nodosum skin rash,
bilateral hilar adenopathy, fever
and arthritis
Heerfordt syndrome
uveitis, parotiditis, and fever
Gallium-67 scan uptake
• Parotid and lacrimal glands
(Panda sign)
• Right paratracheal and bilateral
hilar uptake (Lambda sign)

• Once a diagnosis is established, initial evaluation
should consist of tests to evaluate the presence and
extent of pulmonary involvement and assess the
presence and severity of extrathoracic disease

• Exceptions to this approach include patients
who manifest with Lofgren syndrome in areas
with a low prevalence of histoplasmosis, which
may mimic Lofgren syndrome, in which case
most experts believe a biopsy is not necessary.
• Many experts suggest that patients with
asymptomatic bilateral hilar adenopathy with
presumptive stage I sarcoidosis do not need
biopsy unless atypical features are present

• In general, the easiest accessible biopsy site can be
approached to confirm a diagnosis of sarcoidosis.
• When a more easily accessible site is not available,
biopsy by fiberoptic bronchoscopy remains the
most common approach because of its high yield
and relative safety.

Imaging studies
CXR
• This is central to the evaluation of patients
for sarcoidosis
• BHL ± pulmonary inflitrates
• Fibrocystic changes in advanced disease
• 1-2-3 sign or Gallant sign on CXR

Imaging studies
HRCT
• Routine chest CT scanning adds little to
diagnosis.
• However, HRCT may identify active alveolitis
or fibrosis
• Gives insight to areas of involvement to
improve the yield of biopsy

Imaging studies
18F-fluorodeoxyglucose-positron emission
tomography (FDG-PET) scanning
• F(18)-Fluorodeoxyglucose PET & Gallium scanning is
occasionally used as a diagnostic test especially prior
to the current ease & availability of bronchoscopy
• May be used as an alternative to biopsy in patient
with difficult to biopsy CNS involvement
• Useful to define sites of clinically occult
granulomatous inflammation

Imaging studies
Contrast enhanced MRI scanning
• Have replaced gallium scans in the definition of
occult sites of CNS involvement
• The distribution of inflammatory loci has a
propensity for periventricular and
leptomeningeal areas, although the images are
nonspecific, and can be produced by infectious,
malignant, or occasionally demyelinating disease.
• A normal scan does not exclude neurosarcoidosis,
particularly for cranial neuropathies or in the
presence of corticosteroid therapy

Biopsy studies
Fibreoptic Bronchoscopy
• The diagnostic yield of transbronchial biopsy (TBB) is
estimated to be >40% even in patients with a stage I
chest radiograph and approaches 80% in the
presence of lung infiltrates.
• Transbronchial lung biopsy in advanced fibrocystic
sarcoidosis has a low yield, owing to extensive
fibrotic changes.

Biopsy studies
• Sampling by endobronchial mucosal biopsy (EMB)
and transbronchial needle aspiration (TBNA) of
thoracic lymph nodes provides additional sensitivity
when combined with TBB
• Some studies suggest a CD4:CD8 ratio >3.5 of BAL T
cells supports a diagnosis of sarcoidosis, but may
not differentiate some infectious or noninfectious
inflammatory lung diseases

Bronchoscopy
• CD4/CD8 ratio of >3.5 had a sensitivity of 100% and
a specificity of 81% with PPV of 81.2% to distinguish
sarcoidosis from nongranulomatous ILDs

Investigation of Sarcoidosis:
Other Biopsy sites
• For organs that are less involved in sarcoidosis,
directed biopsy of the involved tissue is often
recommended to exclude alternative causes, even
when there is documentation of a prior biopsy that
confirmed an original diagnosis of sarcoidosis.

Biopsy studies
Cardiac Biopsy
• Endomyocardial biopsy is positive in <20% of cardiac
sarcoidosis owing to sampling inefficiencies and the
infrequency of right ventricular involvement
• A diagnosis of cardiac sarcoidosis is usually
established by a noncardiac biopsy confirming
systemic sarcoidosis along with consistent myocardial
imaging studies or rhythm disturbances

Biopsy studies
Skin & Nerve Biopsy
• Specialized evaluation including skin biopsy
analysis of intraepidermal nerve fiber density
may be considered to confirm cases of small
fiber neuropathy

Nervous system involvement
• Examination of the cerebrospinal fluid is less often
performed today, but may be useful by demonstrating
characteristic lymphocytic pleocytosis and/or elevated
protein levels.
• In suspected cases of peripheral neuropathy or
myopathy, EMG or nerve conduction studies or rarely,
tissue biopsy, may help to establish a link to
sarcoidosis.
• Specialized evaluation including skin biopsy analysis of
intraepidermal nerve fiber density may be considered
to confirm cases of small fiber neuropathy

An approach to diagnosis of extrapulmonary sarcoidosis.
The diagnosis of sarcoidosis may
require histological confirmation
in a second organ

Laboratory tests
• Laboratory tests are generally not helpful in
confirming a diagnosis of sarcoidosis but may assist
in establishing an alternative diagnosis (such as
autoimmune disease etc) or the follow up of
treatment,
• A diagnostic biomarker has not been identified for
sarcoidosis.

Laboratory tests
Serology
• Elevated serum markers such as
– serum amyloid A (SAA),
– soluble interleukin-2 receptor (sIL-2R),
– lysozyme,
– angiotensin converting enzyme (ACE) &
– glycoprotein KL-6
have been reported in sarcoidosis

Laboratory tests
EUCr
• Hypercalcemia is seen in 10-13% of patients, while
hypercalciuria is 3 times more common
• Azotemia if CKD from nephrocalcinosis has developed
LFT
• Elevated alkaline phosphatase significantly correlates
to degree of fibrosis and granulomatous inflammation
of the liver
FBC
• Anaemia, lymphopenia, thrombocytopenia

Laboratory tests
Elevated Vitamin D assay
• The majority (71%) of patients with serum 1,25-
dihydroxylvitamin D levels > 51pg/ml required
long term immunosuppressive therapy
Serum ACE
• NCGs secrete ACE. Serum ACE are elevated in
60% of patients at diagnosis
• Serum ACE correlates with total body granuloma
load

Laboratory tests
Serum ACE
• Levels are increased in blood, BAL or CSF
• Serum ACE may decrease in response to treatment
• Serum ACE levels reflect the total body granuloma burden
- Sensitivity 57% - Positive predictive value 90%
- Specificity 90% - Negative predictive value 60%
 Other conditions associated with an elevated serum ACE
Disseminated tuberculosis, fungal infections, hyperthyroidism,
Gaucher disease
 It is not adequately sensitive to be useful for the diagnosis of
sarcoidosis
• Decision to treat should not be based on ACE level alone

Pulmonary function test
Pulmonary function tests
• The most common finding is isolated decrease in
DLCO
• Restrictive pattern is seen in advanced pulmonary
disease
• About 15-20% of patients have obstructive
disease
• Patients with DLCO <60% & SPO2 < 90% on 6
minute walk test have a high likelihood of
pulmonary hypertension

Evaluation of the heart
Cardio pulmonary exercise testing
• May suggest cardiac involvement that is otherwise
not evident
• Impaired heart rate recovery during the first minute
following exercise has been shown to be an
independent predictor for CVs and all-cause mortality

Evaluation of the heart
ECG
• Ventricular arrhythmias
• AV conduction blocks
• RBBB
Cardiac MRI
• Useful to identify patients with cardiac involvement

Clinical course of Sarcoidosis
• Dependent on the presentation of the patient
• The presence of extrapulmonary involvement at
presentation is a risk factor for new organ
involvement during a 2yr follow up evaluation
• Most patients who undergo remission do so within
first 2-3yrs excepting those with neurologic or
ocular involvement

Clinical course
• High rates of relapse are observed in patients
(>50%) requiring systemic immunosuppressive
medications compared with those who experience
spontaneous disease remission (<10%).
• A waxing–waning clinical course is uncommon
except for a subset of patients with neurologic or
ocular manifestations or occasionally recurrent
erythema nodosum

Decision to treat
• Treatment of sarcoidosis is usually limited to the
symptomatic patient
• About half of patients do not require long-term systemic
therapy
 Treatment decisions have to consider that patients may
have spontaneous resolution of their disease
 Limited information on how to predict who will need long-
term therapy
 Currently, a consensus recommendation is that treatment
decisions are best based on repeated clinical examinations
and direct measurement of organ function and not on
laboratory markers of disease “activity.”

Therapy for Sarcoidosis
Goal of Therapy for symptomatic sarcoidosis
• To reduce morbidity
• To prevent involvement of other organs &
complications
Options of therapy for symptomatic sarcoidosis
• The options of treatment are majorly medical
• Surgical treatment may be used in advanced stages
of disease

Therapy for Sarcoidosis
Management of asymptomatic cases
• PFT & CXR every 6-12 months
• Annual slit-lamp eye examination
• Annual ECG
Reasons
• To assess for progression or resolution
• To determine if previously uninvolved organs have
become affected
• To determine when to start treatment

NSAIDs
• NSAIDs are indicated for rheumatic complaints
especially arthralgia
• Patients with stage 1 pulmonary sarcoidosis
require only occasional treatment with NSAIDs
• NSAIDS not useful for advanced pulmonary
disease
– Naproxen
– Ibuprofen
– Ketoprofen
– Flurbiprofen
– Indomethacin

Corticosteriod therapy
• Corticosteroids remain the cornerstone of therapy for
sarcoidosis
• Controversy exists regarding the overall effectiveness
of corticosteroids in altering the long-term course of
the disease
• Corticosteroids provide prompt symptomatic relief
and reverse organ dysfunction in most patients with
the degree of reversibility dependent on the extent of
pre-existing fibrosis.

• Case series and several but not all clinical trials
support the view that corticosteroids favorably
affect disease outcome in chronic pulmonary
sarcoidosis
• British Thoracic Society found long-term improved
lung function in patients with stage II or III
pulmonary disease treated with daily
corticosteroid therapy compared with a group
treated intermittently with corticosteroids based
on symptoms

• Optimal dosing of corticosteroid therapy has not
been established by clinical trials.
• Most authorities suggest that initial treatment of
pulmonary sarcoidosis usually does not require more
than 20 to 40 mg per day of prednisone followed by a
slow taper to a maintenance dose of 5 to 15 mg per
day of prednisone

• Treatment is usually continued for a minimum of 6 to
24 months
• Inhaled steroids appear to have limited effectiveness
in chronic pulmonary sarcoidosis and are not
recommended as sole therapy.
• Overall, recurrent progressive pulmonary disease
occurs in more than 20% of patients as oral
corticosteroids are tapered or discontinued.

• In cardiac sarcoidosis patients with arrhythmias,
addition of moderate dose oral steriods 10-25mg/day
to conventional therapy showed some benefit
• High doses of oral corticosteroids or high-dose pulse
intravenous therapy are often indicated for serious
ocular or CNS disease, such as optic neuritis or
encephalitis followed by maintenance corticosteroid
or immunosuppressive therapy

Alternative agents
Nonimmunosuppressive drugs
• Hydroxychloroquine is effective in many patients
with mucocutaneous sarcoidosis, hypercalcemia and
occasionally, as a steroid-sparing agent in systemic
sarcoidosis.
• Compared to chloroquine, ocular toxicity is less with
hydroxychloroquine, and its overall safety profile
provides a rationale for an early trial

Alternative agents
• The tetracyclines, minocycline, and doxycycline,
may be effective in a subgroup of patients with
mild cutaneous sarcoidosis but rarely as a
steroid-sparing drug in systemic disease.
• These antibiotics have mild anti-inflammatory
effects, which probably account for their
mechanism of action given that other antibiotics
with similar antimicrobial activity have not been
found effective in sarcoidosis

Alternative agents
• Thalidomide was found in one study to be beneficial
in over 80% of patients with severe skin sarcoidosis
(lupus pernio unresponsive to other therapies), but
was not effective in pulmonary sarcoidosis.
• Given the drug’s well-known teratogenicity and
potential to cause peripheral neuropathy and
sedation, the drug is recommended only in patients
refractory to other treatments

Alternative agents
• Pentoxifylline is a phosphodiesterase
inhibitor with anti-inflammatory effects that
was found to be effective in early pulmonary
sarcoidosis
• Melatonin was found to be beneficial in a
small case series of patients with generally
mild disease but wider experience has not
confirmed its efficacy.

Alternative agents
Immunosuppressive drugs
• Beneficial responses are seen in up to 50% to 70% of
patients;
• Responses may take 3 to 6 months or longer
• Low-dose corticosteroid therapy is often needed for
synergistic effect to obtain adequate suppression of
granulomatous inflammation.

Alternative agents
• Methotrexate is often the first immunosuppressive
therapy used as an alternative therapy for
refractory pulmonary or systemic sarcoidosis when
corticosteroid and antimalarial therapies are
ineffective or poorly tolerated.
• Hepatic, pulmonary, and renal toxicities limit its use

Alternative agents
• Azathioprine has shown benefit in small clinical
trials and is used by some authorities as an initial
potent steroid-sparing therapy.
• Clear advantages of methotrexate or azathioprine
over low-dose corticosteroids in the routine
management of sarcoidosis have not been
established.

Alternative agents
• Other immunosuppressive agents, such as
mycophenylate mofetil, leflunomide, or
cyclophosphamide, have been found beneficial in a
small series of patients with manifestations of
sarcoidosis refractory to corticosteroids

Alternative agents
• Studies have shown that cyclosporine and FK506,
drugs known to inhibit T-cell activation, are not
effective in pulmonary or ocular sarcoidosis or in
suppressing recurrent sarcoidosis in transplants

Alternative agents
Anti-TNF therapies
• Most authorities reserve these therapies after
failure of one or more immunosuppressive drugs
• Infliximab, Etanercept, Adalimumab has shown
benefit in pulmonary sarcoidosis

Treatment algorithm for Sarcoidosis

Treatment of Sarcoidosis in Pregnancy
• Corticosteroids are the only drugs recommended for
use during pregnancy because of the potential of
other steroid-sparing drugs to cause fetal toxicity or
teratogenicity.
• Sometimes, spontaneous abatement of chronic
sarcoidosis occurs in pregnant patients, allowing a
temporary reduction in steroid dosage.
• After pregnancy, however, an exacerbation often
occurs, requiring a return to the original
maintenance dose.

Surgical treatment
Lung and Heart Transplantation
• Successful lung, heart–lung, and heart
transplantations may be performed in patients with
advanced stage IV pulmonary sarcoidosis or
cardiomyopathy
Indications
• FVC < 50% predicted
• FEV1 < 40% predicted

Morbidity of Sarcoidosis
Quality of Life
• There is need to treat depression and pain to
improve quality of life in patients with advanced
pulmonary sarcoidosis manifestations.
• The utility of nonpharmacologic treatments, such
as exercise training or pulmonary rehabilitation,
merits investigation because of the impact of
these problems in advanced pulmonary
sarcoidosis patients

Complications of Sarcoidosis
• Pulmonary hypertension
• Cor pulmonale
• Bronchiectasis
• Massive hemoptysis
• Pulmonary mycetoma
• Respiratory failure
• Depression
• Cardiac arrhythmia
• Blindness

Prognosis
• Influenced by the initial manifestations of disease.
• Patients with Löfgren syndrome have remission rates of
70% to 80%.
• Stage I chest radiograph is associated with a 60% to
90% remission rate.
• Stage II chest radiographs have a poorer outcome, with
spontaneous remission occurring 40% to 70% of the
time.
• Stage III chest radiograph is associated with remission
in only 10% to 20% of patients.
• Stage IV rarely undergo remission.

References
• Fishman’s Textbook of Pulmonary Medicine,
3rd Edition
• Google images

Sarcoidosis

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