Sarcoidosis

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Sarcoidosis

• Dr.Adil Al Sulami
• KAUH

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• Sarcoidosis is a multisystem inflammatory disease
  of unknown etiology that predominantly affects
  the lungs and intrathoracic lymph nodes.

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Sarcoidosis is manifested by the presence of
noncaseating granulomas (NCGs) in affected organ
tissues.
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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.

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Epidemiology

• All racial .
• All ethnic groups.
• All ages (with the incidence peaking at 20 to 39
  years).
• M-F ratio 21.

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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.

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Pathophysiology

• T cells play a central role in the development of
  sarcoidosis, as they likely propagate an
  excessive cellular immune reaction.

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The cause of sarcoidosis is unknown. Efforts to
identify a possible infectious etiology have been
unsuccessful.
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• Genetic and environmental factors seem to play a
  role.
• As yet, no bacterial, fungal, or viral antigen
  has been consistently isolated from the
  sarcoidosis lesions.
• Sarcoidosis is neither a malignant nor an
  autoimmune disease.

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• 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 Epstein-Barr virus, have been
  unconvincingly implicated.

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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.

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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.

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Common Clinical Features
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• 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.

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• 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

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Physical finding
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• Pulmonary findings.
• Dermatological manifestations.
• Ocular manifestations .
• Cardiac manifestations
• Neurologic manifestations (rare)

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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.

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• 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.

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Stage 1
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Stage II is BHL and infiltrates
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Stage III is infiltrates alone
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• 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.

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• 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.

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• 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)

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• 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.

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• 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.

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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.

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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.

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• A diagnosis of sarcoidosis is reasonably certain
  without biopsy in patients who present with
  Löfgren's syndrome.

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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.

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• 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.

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Imaging Studies

• A chest radiograph is central to evaluation.
• Routine chest CT scan adds little.
• HRCT of the chest may be helpful.

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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.

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• The central histologic finding is the presence of
  NCGs with special stains negative for fungus and
  mycobacteria.

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• 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.

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Treatment
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• Most patients (gt75) require only symptomatic
  therapy NSAID.
• Approximately 10 of patients need treatment for
  extrapulmonary disease.
• 15 of patients require treatment for persistent
  pulmonary disease.

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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.

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• Data suggest that corticosteroid use may be
  associated with increased relapse rates.
• Occasionally, certain patients cannot tolerate or
  do not respond to corticosteroids.

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Noncorticosteroid agents

• Used more frequently.
• Common indications
• Steroid-resistant disease.
• Intolerable adverse effects.
• patient desire not to take corticosteroids.

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• 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.

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• Cyclophosphamide has been rarely used with modest
  success as a steroid-sparing treatment in
  patients with refractory sarcoidosis.
• Azathioprine is another second-line therapy,
  which is best used as a steroid-sparing agent
  rather than as a single-drug treatment for
  sarcoidosis.
• Chlorambucil is an alkylating agent that may be
  beneficial in patients with progressive disease
  unresponsive to corticosteroids or when
  corticosteroids are contraindicated.
• Cyclosporine is a fungal cyclic polypeptide with
  lymphocyte-suppressive properties that may be of
  limited benefit in skin sarcoidosis or in
  progressive sarcoid resistant to conventional
  therapy.

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• 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.

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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.

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• 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.

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• 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.

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• NSAIDs are indicated for the treatment of
  arthralgias and other rheumatic complaints.
• Patients with stage I sarcoidosis often require
  only occasional treatment with NSAIDs.

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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.

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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.

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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 lt5 of patients), but
  recurrent disease may develop at any age and in
  any organ.

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Death

• Less than 5 of patients die from sarcoidosis.
• death is usually the result of pulmonary fibrosis
  with respiratory failure or of cardiac or
  neurologic involvement.

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