© Copyright Annals of Internal Medicine, 2012 Ann Int Med. 156 (9): ITC5-1. * For Best Viewing:...

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in the clinic

Sarcoidosis


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


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


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


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


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)


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


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



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)



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


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


A B

C D E

Stages of sarcoidosis


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


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


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


When is consultation required?

Pulmonologist: All cases of suspected disease

Ophthalmologist: All newly diagnosed cases

Cardiologist: Possible or confirmed cardiac sarcoidosis

Neurologist: Possible neurosarcoidosis


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...


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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...

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