© copyright annals of internal medicine, 2012 ann int med. 156 (9): itc5-1. * for best viewing:...
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© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
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© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
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© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
in the clinic
Sarcoidosis
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Who is at risk?
Varying incidence among ethnic groups
African American lifetime risk: 2.4%
White American lifetime risk: 0.85%
More common if Scandinavian, Irish, German, W. Indian descent
Relatively rare if Japanese, Spanish, Portugese descent
Family history: Familial clustering in 5%-19% of cases
Age: >80% of cases present between ages 20-40 years
Gender: marginally more common in women
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Is there a role for screening?
Screening is not recommended
Even for family members of an index case
Due to…
Variable prognosis
No evidence early diagnosis affects prognosis
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
What symptoms and clinical findings should prompt a clinician to consider sarcoidosis?
Common signs and symptoms
Cough (usually nonproductive)
Fever and weight loss
Chest pain (central substernal)
Painful ankle swelling
Painful red nodules on shins
Eye pain or blurred vision
Lung or thoracic lymph nodes almost always involved
Lofgren syndrome: common presentation (fever, bilat hilar LAD, ankle swelling, erythema nodosum)
Uveoparotid fever: hallmark presentation
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Figure 1. A patient with lupus pernio sarcoidosis
Violaceous plaques and nodules on the cheeks, bridge of nose, and nares
Lesions responded to treatment with prednisone and methotrexate
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Physical exam in suspected sarcoidosis Skin lesions: Erythema nodosum, lupus pernio, sarcoid
lesions on old scars, tattoos (“Koebner phenomenon”)
Parotid enlargement
Lymphadenopathy
Normal lung examination (usual)
Hepatosplenomegaly
Neurologic (especially VII nerve palsy): typically involves cranial neuropathies, neuroendocrine disease parenchymal brain disease, and peripheral, often small-fiber, neuropathy
Eyes (red, painful): Ocular disease; uveitis, retinal vasculitis
Cardiac: Any cardiac symptoms should raise suspicion (particularly syncope and palpitations, CHF symptoms)
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
More common in distinct ethnic groups
Symptoms Protean systemic and/or organ-specific Can affect any organ system
Characteristic presentations Fever Bihilar lymphadenopathy Ankle swelling Erythema nodosum Asymptomatic bihilar lymphadenopathy Ocular involvement: painful red eyes indicates uveitis Cutaneous symptoms: erythema nodosum, lupus pernio
CLINICAL BOTTOM LINE: Risk Factors and Clinical Features...
} Lofgren syndrome
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
How is sarcoidosis diagnosed? Do all suspected cases require biopsy?
Diagnosis of exclusion!
Diagnosis Generally Requires:
o typical noncaseating granulomata on biopsy PLUS
o exclusion of other causes of granulomatous inflammation (e.g., tuberculosis)
Confident diagnosis only at 3-6 months follow-up: if evolves in typical manner
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
How is sarcoidosis diagnosed? Do all suspected cases require biopsy?
Biopsy needed if:
Presentation atypical (r/o cancer, TB, other infection)
Systemic corticosteroids required
Clinical course doesn’t stabilize or improve in 3-6 months
Biopsy may not be needed if:
Classical Lofgren syndrome, Heerfordt syndrome, or asymptomatic BHL (high likelihood self-limited disease)
Biopsy of erythema nodosum lesions not helpful (shows panniculitis, not typical granuloma)
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
How is sarcoidosis diagnosed? Do all suspected cases require biopsy?
Biopsy easily accessible sites preferentially:
Unexplained skin lesions or peripheral LAD
Otherwise: intrathoracic LAD or lung
Transbronchial bx: yield up to 90% if radiographic infiltrates
Mediastinoscopy bx – 100% yield, but more invasive
Endobronchial endoscopic US – guided or TBNA options
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
What imaging studies should be ordered in the evaluation of a patient with sarcoidosis?
Chest x-ray
Only routine imaging recommended
Scadding staging system correlates with prognosis
Not recommended for routine use:
High-resolution CT
CT and PET scans
Consider for atypical cases + differentiate from other conditions
Monitor disease activity, progression, treatment response
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
A B
C D E
Stages of sarcoidosis
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Are pulmonary function tests useful in evaluating patients with sarcoidosis?
Results often normal, even in parenchymal lung disease
Most common abnormalities
Restrictive ventilatory defect with reduced FVC
Reduced DLCO
Airflow obstruction with FEV1/FVC <70% seen in ≈16%
Serial spirometry and measurement of DLCO can be useful for:
following response to therapy
following disease progression
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
What additional investigations should be ordered? Complete blood count: anemia and leukopenia in >20%
Renal function
Serum calcium: hypercalcemia up to 10%
24-h urine test calcium levels: hypercalciuria up to 30%
Liver function tests
Tuberculin skin test
Total immunoglobulins
ECG: indicated in all patients
Neuorosarcoidosis evaluation: if unexplained neurologic symptoms or seizures
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
What other conditions should be considered in the differential diagnosis? Infectious causes of granulomatous disease
Lymphoma, other cancers
ANCA-associated vasculitis
Coccidiomycosis (can present like Lofgren syndrome)
Alternate causes of parenchymal pulmonary infiltrates
Consider alternative diagnosis if…Age >40 yearsWeight loss >10% body weightCrackles on lung examTender lymph nodesPositive tuberculin skin testAsymmetrical BHL on chest x-ray
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
When is consultation required?
Pulmonologist: All cases of suspected disease
Ophthalmologist: All newly diagnosed cases
Cardiologist: Possible or confirmed cardiac sarcoidosis
Neurologist: Possible neurosarcoidosis
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Diagnosis of exclusion
Definitive diagnosis requires 6 months follow-up
Chest x-ray + eval for extrapulmonary involvement
Clinical Dx: typical Lofgren syndrome, asymptomatic BHL
Biopsy required? choose most accessible, least invasive site
Differential diagnosis Cancer and infection, particularly lymphoma and TB
CLINICAL BOTTOM LINE: Diagnosis...
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Which patients with pulmonary sarcoidosis require treatment? Wait on treatment if symptoms are mild
Disease often resolves or remains stable
Withhold systemic treatment 3-6 months, if possible
Use NSAIDs for EN or ankle arthralgias
Use inhaled steroids for dry cough
Treat persistent, severe or worsening pulmonary symptoms
Use oral corticosteroids
Avoid potentially toxic Rx if likely to resolve spontaneously
Controversial: whether to treat asymptomatic patients with progression of pulmonary disease on chest x-ray
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Which patients with extra-pulmonary sarcoidosis require treatment? Treat promptly: disease involving critical organ function
Active uveitis
Cranial nerve abnormalities
Pituitary or hypothalamic dysfunction
Meningitis
Seizures or other manifestations of CNS involvement
Cardiac dysfunction or dysrhythmias from granulomas
Also treat…
Symptomatic hypercalcemia or interstitial nephritis
Disfiguring facial lesions
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
What is the role of nonsystemic steroids? Pulmonary parenchymal sarcoidosis
Inhaled corticosteroids: adjunct therapy for broncho-spasm or cough
Efficacy is uncertain & routine use not recommended
Mild ophthalmologic disease Topical steroids alone
Skin lesions Topical or intralesional steroids
To reduce size and prominence, but may thin skin
Don’t use potent fluorinated steroids on face
Rhino-nasal sarcoidosis Intranasal steroids
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
What is the role of systemic steroids for the treatment of pulmonary sarcoidosis?
Immunomodulatory therapy
Effective but not FDA-approved for sarcoidosis
Oral prednisone
Consensus: start 20 – 40 mg / every other day
Evaluate response after 1 to 3 months
Continue therapy for ≥1 year (taper to lowest effective dose)
Long-term use for sarcoidosis is controversial
Use alternative if no response or intolerable SEs
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
When should nonsteroidal pharmacologic treatment be used for pulmonary sarcoidosis? Cytotoxic agent (methotrexate) or other immunosuppressant
Use long-term only if induces unequivocal improvement Folic acid reduces myelosuppression with methotrexate
Chloroquine or hydroxychloroquine Cutaneous or mucosal disease Control of hypercalcemia Those who with hyperglycemia on corticosteroids
TNF inhibition with infliximab Progressive sarcoidosis (intolerant of non-responsive to
steroids & cytotoxic agents)
Cytoxan, chlorambucil, cyclosporine Severe progressive sarcoidosis refractory to steroids and
less toxic immunosuppressive agents
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
How long should pharmacologic therapy be continued in pulmonary sarcoidosis? Initial therapy with prednisone: 9 to 12 months
Periodically attempt to taper to lowest effective dose
Frequently treatment is required for >2 years
Life-long treatment may be needed if repeated relapse
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
How should extrapulmonary sarcoidosis be treated? Myocardial sarcoidosis
Corticosteroids, tapering over months or years
Consider steroid-sparing agents
Facial nerve palsy or other neurologic disorders
Prednisone, tapering over months or years
Adding cytotoxic agent may improve response
Posterior uveitis, lacrimal, and orbital sarcoidosis
Systemic corticosteroids; IV methylprednisolone if vision threatened or changing rapidly
Hypercalciuria and hypercalcemia
Prednisone, tapering to lowest effective dose
Alternative: hydroxychloroquine
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Which patients require life-long therapy?
Patients with repeated relapse
80% relapse, often within 2 years of tapering corticosteroids
10 mg prednisone daily or every other day prevents relapse
No evidence for similar long-term, low-dose cytotoxic agents
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
What other pharmacologic therapies are available? Antimicrobial: bronchiectasis from chronic sarcoidosis
Antifungal: hemoptysis associated with aspergilloma
Vitamin D, calcium, nasal calcitonin, and bisphosphonates: osteoporosis related to steroid therapy
NSAIDs: musculoskeletal symptoms and pain from EN
Ketoconazole (600-800 mg/day): hypercalcemia
Pulmonary hypertension therapy- Rx of unproven benefit and requires expert evaluation
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
What nonpharmacologic interventions should be considered?
Rehabilitation program for advanced lung disease
Oxygen therapy for hypoxemia at rest or with exercise
Vaccination for pneumococcal pneumonia and influenza
Pacemaker or implantable defibrillator for cardiac sarcoidosis
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Which patients should be referred for organ transplantation?Patients with…
Severe functional impairment
Severe end organ damage
Progressive deterioration despite appropriate medical Rx
Ideal time for lung transplantation is imprecise
Refer before condition deteriorates to point when survival time is less than time on waiting list
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
How should sarcoidosis be monitored? Intensive longitudinal clinical surveillance for ≥ 5 years
Track organ system involvement
Regular spirometry; repeat oximetry to adjust oxygen
Consider repeat chest imaging if clinical deterioration occurs
Annual blood tests and EKG & Holter monitoringa
Target signs and symptoms that frequently occur
Those affecting pulmonary system, eyes, skin
Refer patient to opthamologist
Ocular involvement may be asymptomatic
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
When should patients with sarcoidosis be hospitalized?
Respiratory failure
Onset of cardiac symptoms (particularly syncope)
Symptomatic hypercalcemia
New or progressive neurologic disease
Acute vision loss
Acute renal failure
Severe treatment side effects
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
What is the prognosis of patients with sarcoidosis? Resolution: ≥50%
Persistent fibrosis: 25%
May cause symptoms but no progression
Chronic progressive disease: 25%
Fatal: 5% (usually pulmonary/cardiac impairment)
Predictors of good prognosis
EN; stage 1 CXR; asymptomatic presentation
Predictors of poor prognosis
Lupus pernio; cardiac, neurologic, or bone involvement; nephrolithiasis
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
What education do patients with sarcoidosis require?
Information on organ involvement
Information on symptoms to be alert for
Treatment risks and possible side effects
Measures to counteract toxicity of medications
Prognostic information
© Copyright Annals of Internal Medicine, 2012Ann Int Med. 156 (9): ITC5-1.
Observe for 3-6 months before therapy, if possible Spontaneous remission can occur 1st-line Rx, when warranted: prednisone 9-12 months
Treat promptly
Symptomatic neurologic, cardiac, or eye sarcoidosis or symptomatic hypercalcemia
Treat mild skin or eye disease with topical corticosteroids
Use alternative Rx: disease refractory or toxicity unacceptable
Methotrexate Consider infliximab if intolerable SEs or continued disease
progression
CLINICAL BOTTOM LINE: Treatment...