Sarcoidosis

I. What every physician needs to know.

Sarcoidosis, also known as Boeck’s disease, or Besnier-Boeck-Schaumann disease, is a multisystem granulomatous disease that can affect any organ. Its cause is unknown. Sarcoidosis is typically a chronic disease but an acute form known as Lofgren’s syndrome (bilateral hilar adenopathy, erythema nodosum and non-inflammatory arthritis of the ankles) can occur.

The lungs and lymph nodes are affected in more than 90% of the cases. The diagnosis is usually made by obtaining a biopsy of affected tissues revealing noncaseating granulomas. The disease course is characterized by spontaneous remissions and recurrences. Treatment is not always necessary, but the mainstay of therapy are systemic corticosteroids.

II. Diagnostic Confirmation: Are you sure your patient has sarcoidosis?

The diagnosis of sarcoidosis is based on a combination of typical clinicoradiologic findings, histologic confirmation and exclusion of other causes of granulomatous inflammation. Histologic findings of granulomatous inflammation alone is inadequate to make the diagnosis as other disease processes can lead to granulomas formation. Generally, if a patient is suspected of having sarcoidosis, the initial diagnostic effort must be to:

1. Demonstrate that 2 or more organs are involved.

2. Ensure histologic confirmation of epithelioid noncaseating granulomas.

3. Exclude other conditions, most commonly tuberculosis, lymphoma, histoplasmosis, and berylliosis.

Biopsy may not be required in the acute form (Lofgren’s syndrome) when a patient presents acutely with bilateral hilar adenopathy, erythema nodosum and arthritis involving both ankles.

A. History Part I: Pattern Recognition:

A typical patient with sarcoidosis will present with:

1. Asymptomatic bilateral hilar adenopathy

2. Dry cough, wheezing, shortness of breath and abnormal chest X-ray (CXR) as in 1.

3. Erythema nodosum

4. Lymphadenopathy

Remember that sarcoidosis can affect almost any organ, including the eyes (uveitis), central nervous system (CNS) (aseptic meningitis, cranial nerve palsies, transverse myelitis), heart (heart failure, arrhythmias, heart block), liver (abnormal transaminases), adrenals, skin, etc.

B. History Part 2: Prevalence:

The prevalence of sarcoidosis is 10-20 per 100,000 persons. The prevalence is higher in the Scandinavian population. African-Americans tend to have more severe disease. Women are affected more often than men with ratio of ~ 2:1. There appear to be two peaks of age of onset: 20-29 years and 60-65 years. Sarcoidosis is rare before adulthood.

C. History Part 3: Competing diagnoses that can mimic sarcoidosis.

Other conditions that can mimic sarcoidosis and can cause granulomas frequently have to be ruled out.

Tuberculosis – history of exposure to tuberculosis, positive PPD, HIV, unilateral hilar adenopathy with lung cavitation, positive smear or culture for M. tuberculosis, biopsy showing caseating granulomas.
Lymphoma – extrathoracic lymph node involvement more common; biopsy consistent with lymphoma
Histoplasmosis – history of having been in an endemic area (Ohio and Mississippi river valleys, central and southeastern states); CXR showing pulmonary nodularity; positive urinary histoplasma antigen; isolation from a biopsy sample.
Berylliosis – ask for occupational exposure like beryllium mining and manufacturing of fluorescent bulbs.

D. Physical Examination Findings.

Findings depend on the organ involved.

Lungs

Lung exam may range from normal in the early stages to wheezing and dry crackles in the advanced stages when pulmonary fibrosis occurs.

Skin

Lupus pernio – violaceous, dark indurations on nose, cheeks, lips, and ears. Can be disfiguring. It is more common in African American patients and is a predictor of poor prognosis and resistance to therapy.
Erythema nodosum – painful panniculitis (inflammation of the subcutaneous fatty tissue) on the shins, self-limiting over 3 weeks, predicts good prognosis.
Papules, macules and plaques on neck and back that can be either hyper- or hypopigmented.
Nontender cervical and submandibular lymphadenopathy.

Eye

Uveitis:
Most common manifestation of ocular sarcoidosis.

Anterior uveitis: Typically presents acutely with photophobia, lacrimation, and redness.

Posterior uveitis and optic neuritis can occur.
Keratitis
Sicca syndrome
Nodules on conjunctivae

Parotid glands

Bilateral non-tender enlargement

Cardiac

Sarcoidosis can cause an infiltrative cardiomyopathy leading to heart failure (both systolic and diastolic), conduction abnormalities, and arrhythmias.

Nervous system

Peripheral facial nerve palsy, can be bilateral
Optic neuropathy
Aseptic meningitis
Transverse myelitis
Peripheral neuropathy
Seizures

Liver

Hepatomegaly, jaundice, and elevated transaminases can be seen in the setting of granulomatous infiltration of the liver.

E. What diagnostic tests should be performed?

As sarcoidosis is a multi-systemic disease, there are no pathognomonic physical findings. Erythema nodosum, especially when accompanied by acute bilateral arthritis of ankles, should raise suspicion of Lofgren’s syndrome. Careful search for palpable lymphadenopathy may identify an area that is safe to biopsy.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Complete blood count (CBC) – to look for cytopenias due to splenic (hypersplenism) or bone marrow involvement.
Serum blood urea nitrogen (BUN) and creatinine – may be increased due to granulomatous interstitial nephritis or hypercalcemia, hypercalciuria and nephrocalcinosis.
Serum calcium – hypercalcemia in up to 10% of patients due to production of calcitriol in the granulomas. Hypercalciuria can be seen with normal serum calcium levels.
Liver enzymes – varying, usually mild elevation of transaminases, cholestatic enzymes and bilirubin.
Serum angiotensin-converting enzyme (ACE) levels – elevated in up to 75% of patients with active sarcoidosis. Its low sensitivity and specificity limits its use in diagnosis. However, a high level can help confirm a diagnosis, but a normal level does not rule out sarcoidosis. An ACE level can also be used to monitor treatment response.
Urinalysis and 24-hour calcium excretion.
Pulmonary function testing (PFTs)
May be normal in the majority of patients especially in the early stages.

The diffusing capacity for carbon monoxide (DLCO) is a sensitive measure of early interstitial lung disease.

A disproportionate reduction in DLCO compared to lung volumes may indicate sarcoidosis-associated pulmonary hypertension.

With disease progression, PFTs can demonstrate an obstructive, restrictive, or mixed pattern.

Very rarely there is upper airway obstruction from tracheal or laryngeal disease.
Electrocardiogram – to detect conduction problems and dysrhythmias.
Ophthalmologic exam with slit lamp and fundoscopy – to detect uveitis, and conjunctival nodules (that can be biopsied).
Purified protein derivative – to differentiate sarcoidosis from tuberculosis (may not be adequate in sarcoidosis, because anergy is a common problem). Interferon-γ release assay seems to be more reliable.
Echocardiography – to assess left ventricular function and pulmonary pressures if clinically indicated.
Bronchoscopy with bronchoalveolar lavage (BAL) and/or transbronchial biopsy – frequently necessary to establish the diagnosis. BAL with lymphocytosis and CD4/CD8 ratio greater than 3.5 are very suggestive of sarcoidosis.
Pathology – to confirm the presence of noncaseating granulomas, and to exclude infections (tuberculosis and histoplasmosis) and lymphomas.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Chest X-ray

Posteroanterior and lateral in all patients. Classically used for staging that has therapeutic and prognostic implication:

Stage I – bilateral hilar adenopathy
Stage II – bilateral hilar adenopathy and pulmonary infiltrates
Stage III – pulmonary infiltrates without adenopathy
Stage IV – pulmonary fibrosis

High resolution computed tomography (HRCT) of the chest

HRCT findings suggestive of sarcoidosis are hilar lymphadenopathy and parenchymal nodules that follow the perilymphatic distribution along the vascular bundles and in subpleural locations.

CT scan of the chest can be helpful in viewing the parenchyma to assess the extent of the disease and to rule out other etiologies.

Gallium-67 scan

Not routine, will detect affected organs, can reveal typical pattern – “panda-lambda” sign – parotid and lacrimal gland uptake resembling a panda bear head, and perahilar, infrahilar, and right paratracheal adenopathy appearing like the Greek letter lambda. It is not very specific.

Magnetic resonance imaging

With gadolinium infusion – if myocardial involvement or CNS disease are suspected.

Integrated fludeoxyglucose-positron emission tomography (FDG-PET) with computed tomography scan

May not be widely available.

Other Tests

Serum (ACE) level

Lacks sensitivity and specificity and cannot be used for making the diagnosis. In patients diagnosed with sarcoidosis, who also have elevated serum ACE, the levels can be used to monitor disease activity.

III. Default Management.

Not all patients require treatment. Corticosteroids remain the mainstay of therapy but the benefits must be weighed against the potential harms. In general, indication for systemic corticosteroids is if an organ is threatened.

A. Immediate management.

Treatment of acute respiratory failure:

Systemic steroids – i) If cannot tolerate PO – IV methylprednisolone 40 mg IV every 6 hours until PO intake possible, ii) if able to take PO – prednisolone 40 mg PO daily until resolution of the acute phase. Once the respiratory status is at baseline, the dose should be reduced to the minimum or the prior maintenance dose.
Oxygen for hypoxemia and ventilatory support (invasive or noninvasive) if indicated.
Bronchodilators.
Antibiotics – if infection suspected; Stage IV disease (pulmonary fibrosis) higher risk for bacterial infections, including Pseudomonas aeruginosa. Consider reactivation tuberculosis (TB), histoplasmosis, and Pneumocystis jiroveci pneumonia (PJP) if immunosuppressed from systemic steroid therapy.

B. Physical Examination Tips to Guide Management.

Signs of respiratory distress (tachypnea, accessory muscle use, pursed lips breathing, speaking in full sentences, etc.)

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Arterial blood gases (ABGs) may be monitored to assess oxygenation and acid-base status.

ACE level may be helpful in assessing response to therapy if the level was high at diagnosis.

D. Long-term management.

1. Topical treatment:

Inhaled steroids frequently prescribed; there is limited evidence for their effectiveness as monotherapy
Topical steroids effective for cutaneous disease
Steroid ophthalmic drops effective for anterior uveitis

2. Systemic treatment:

Systemic steroids are started at doses of 20-40 mg PO daily for 1-3 months, then gradually tapered with a goal of below 10 mg daily. In some patients it is possible to eventually discontinue the steroids altogether.

Although steroids are the gold standard for treatment, steroid-sparing agents should be used to avoid the long-term complications of systemic steroids. Methotrexate is commonly used; other choices are azathioprine, cyclosporine, mycophenolate, cyclophosphamide, and leflunomide.

Hydroxychloroquine is effective in hypercalcemia and cutaneous disease. Requires annual eye exam given ocular toxicities.

Infliximab is an antibody directed against TNF. It has been shown to be effective in pulmonary and extra-pulmonary sarcoidosis especially in refractory cases. Screening for latent TB must be done prior to initiation therapy with infliximab.

Treatment of pulmonary sarcoidosis

Stage I – asymptomatic, without progressive adenopathy – no treatment
Stage I with progressive adenopathy or symptoms (cough, shortness of breath, fatigue, low-grade fever) – systemic steroids
Stage II to IV – systemic steroids

Treatment of neurosarcoidosis, hypercalcemia, renal, cardiac, ocular disease (optic neuritis and resistant uveitis) – systemic steroids.

Treatment of hepatic, splenic, cutaneous, musculoskeletal disease – sometimes systemic steroids, depending on the clinical situation.

E. Common Pitfalls and Side-Effects of Management

Major side effects from chronic systemic steroids – weight gain, worsening hypertension and hyperglycemia, osteopenia and osteoporosis, gastrointestinal (GI) bleed, immunosuppression and susceptibility to infections.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

No change in standard management. Calcium and vitamin D supplementations may need to be monitored closely as patients with sarcoidosis tend to be hypercalcemic.