Sarcoidosis

Sarcoidosis is a multisystem inflammatory disorder characterized by noncaseating granuloma formation, most commonly in the lungs and hilar lymph nodes. Many patients are asymptomatic, especially in the early stages of disease. Symptomatic patients typically present with constitutional symptoms, cough, and dyspnea. The cause of sarcoidosis is unknown but is thought to be related to an environmental exposure in a genetically predisposed individual. Chest x-ray is the preferred initial test for individuals with suspected sarcoidosis since bilateral hilar lymphadenopathy and/or pulmonary involvement is present in ∼ 90% of affected patients. Sarcoidosis is a diagnosis of exclusion that typically requires characteristic clinical features and/or findings on chest imaging, noncaseating granulomas on biopsy, and exclusion of more common causes of granulomatous disease or lymphadenopathy. While most patients with pulmonary sarcoidosis do not require immunosuppressive therapy, patients with symptomatic or progressive disease are typically treated with glucocorticoids. Spontaneous remission without complications is common in patients with early-stage pulmonary disease, but the risk of irreversible lung fibrosis increases with disease recurrence and progression.

• Average age of onset: 30–55 years ^[1][2]
• Sex: : ♀ > ♂ (2:1)
• Prevalence
  • Highest in African American and Scandinavian populations
  • 2–4 times higher in Black individuals than in non-Hispanic white individuals ^[3][4]

Epidemiological data refers to the US, unless otherwise specified.

The cause of sarcoidosis is unknown, but genetic predisposition (e.g., HLA-linked), exposure to substances associated with granuloma formation (e.g., beryllium and its salts), and infectious agents (e.g., mycobacteria) are believed to play a role. ^[5]

Sarcoidosis is a systemic disorder characterized by widespread, immune-mediated formation of noncaseating granulomas.

• General
  • Inhalation of foreign antigen → monocyte differentiation → activation of interstitial dendritic cells and alveolar macrophages
  • Interstitial dendritic cells migrate towards mediastinal lymph nodes and alveolar macrophages differentiate, serving as antigen-presenting cells to circulating T helper (Th) cells → differentiation and clonal expansion of T cells
  • T cell recruitment and ↑ B-cell activity → local immune hyperactivity and inflammation → formation of noncaseating granulomas in the lungs and the lymphatic system
• Granuloma formation: Mature granulomas are composed of epithelioid cells and macrophages surrounded by lymphocytes and fibroblasts.
  • Macrophages activate Th1 cells.
  • Th1 cells stimulate the formation of epithelioid cells and multinucleated giant cells by releasing IFN-γ.
  • Epithelioid cells produce angiotensin-converting enzyme (ACE) and release cytokines that recruit more immune cells.
  • See “Granulomatous inflammation” for more details.
• Fibrosis: Epithelioid cells secrete cytokines to recruit fibroblasts, leading to fibrosis → damage of organs and tissue
• Calcium dysregulation: : activated pulmonary alveolar macrophages → ↑ 1-alpha hydroxylase expression and activity → ↑ 1,25-dihydroxyvitamin D (calcitriol) → hypervitaminosis D → hyperphosphatemia, hypercalcemia, and, possibly, renal failure ^[6]

Overview

• Sarcoidosis is a disease with highly variable manifestations, ranging from asymptomatic to progressive, relapsing disease.
  • Typically sudden onset with spontaneous remission in approximately two-thirds of patients ^[3]
  • Approx. one-third of patients develop progressive chronic disease.
• Most common presenting signs and symptoms
  • Often asymptomatic (in early stages)
  • General: fever, malaise, lack of appetite, weight loss, lymphadenopathy
  • Pulmonary: dyspnea, cough, chest pain
  • Extrapulmonary: arthritis, erythema nodosum, anterior uveitis

Pulmonary sarcoidosis

• Lungs are the most commonly affected organ (90% of affected individuals).
• Often asymptomatic in the early stages
• Interstitial fibrosis
  • Cough, exertional dyspnea, chest pain
  • Mild rales on pulmonary auscultation

Extrapulmonary sarcoidosis ^[7]

• Occurs in approx. 30% of affected individuals
• Extrapulmonary findings usually involve the skin, eyes, heart, and/or the renal and central nervous systems.

Cutaneous sarcoidosis ^[8]

• Occurs in approx. 30% of affected individuals ^[7]
• Erythema nodosum: most common nonspecific cutaneous manifestation
• Lupus pernio
  • A pathognomonic manifestation of sarcoidosis characterized by extensive, violaceous skin plaques (i.e., epithelioid granulomas of the dermis) on the nose, cheeks, chin, and/or ears
  • Butterfly rash as seen in systemic lupus erythematosus
• Papular sarcoidosis
  • A common specific sarcoid cutaneous lesion showing noncaseating granulomas on biopsy
  • Multiple scattered or confluent lesions, located on the face (lips, nostrils, eyelids, forehead, and neck hairline)
• Plaque-like lesions
  • Specific sarcoid cutaneous lesions
  • Sharply demarcated, scaling, erythematous lesions
• Scar sarcoidosis: papular lesions in preexisting scars (e.g., venipuncture sites) and/or elevation of scars or tattoos

Lymph node findings

• Most commonly affected extrapulmonary site
• Occurs in 70–90% of affected individuals
• Mediastinal lymph nodes: bilateral, hilar, and/or paratracheal mediastinal adenopathies (approx. 90% of affected individuals)
• Intraabdominal lymphadenopathy ^[7]

Ocular sarcoidosis

• Occurs in 10–25% of affected individuals ^[7]
• Can affect any part of the eye and associated structures
• Common manifestations include uveitis, conjunctival nodules, keratoconjunctivitis sicca
• Sarcoid uveitis
  • Most common ocular manifestation
  • Manifests with pain, redness, and photophobia

Musculoskeletal findings

• Occurs in approx. 10% of affected individuals ^[7]
• Arthralgias and arthritis
  • Polyarthritis with involvement of the small joints of the hands (resembles rheumatoid arthritis)
  • Acute oligoarthritis with bilateral involvement of the ankle joints
• Sarcoid myopathy
  • Initially asymptomatic with insidious course
  • Clinical patterns
    • Chronic sarcoid myopathy: progressive, bilateral proximal muscle weakness
    • Acute sarcoid myositis: diffuse, bilateral, proximal muscle pain and swelling
    • Nodular sarcoid myopathy: one or more tender nodules; typically affects the lower limbs
• Bone lesions
  • Hands and feet are most commonly affected.
  • Can appear as lytic, sclerotic, or punched-out lesions on x-ray
  • Bone biopsy to rule out malignancy and infections

Neurosarcoidosis

• Occurs in approx. 5% of affected individuals ^[7]
• Cranial nerve palsy (unilateral or bilateral facial nerve palsy is the most common)
• Diabetes insipidus
• Hypopituitarism
• Meningitis (e.g., acute aseptic meningitis, chronic meningitis)
• Peripheral neuropathy (e.g., mononeuropathy, mononeuritis multiplex, polyneuropathies)
• Myopathy (e.g., proximal myopathy, muscle atrophy)

Other findings ^[7]

• Cardiac sarcoidosis: dilated or restrictive cardiomyopathy, myocarditis, pericardial effusion, arrhythmias (e.g., AV block), sudden cardiac death
• Kidneys: acute interstitial nephritis, nephrocalcinosis, nephrolithiasis
• Hepatic sarcoidosis
  • Asymptomatic (approx. 80% of affected individuals)
  • Common manifestations: hepatic granulomas, hepatomegaly (∼ 30% of affected individuals)
• Spleen: splenomegaly in ∼ 30% of affected individuals
• Exocrine glands: enlarged salivary and lacrimal glands

Features of sarcoidosis are GRUELING: Granulomas, aRthritis, Uveitis, Erythema nodosum, Lymphadenopathy, Interstitial fibrosis, Negative TB test, and Gammaglobulinemia.

Lofgren syndrome ^[9]

• An acute clinical manifestation with fever and the following triad of symptoms:
  • Migratory polyarthritis: symmetrical arthritis that primarily affects the ankles
  • Erythema nodosum: primarily affects the extensor surface of the lower legs
  • Bilateral hilar lymphadenopathy
• Prognosis is good (spontaneous remission occurs in 70–80% of affected individuals). ^[9]

Heerfordt syndrome

• A rare form of sarcoidosis characterized by fever and the following triad of symptoms:
  • Parotitis
  • Uveitis
  • Facial palsy

General principles ^[7][10][11]

• Sarcoidosis is a diagnosis of exclusion supported by:
  • Characteristic clinical features and/or findings on chest imaging
  • Noncaseating granulomas on biopsy
  • Exclusion of more common causes of granulomatous disease or lymphadenopathy
• Obtain initial studies to:
  • Rule out differential diagnoses (e.g., other granulomatous diseases).
  • Assess pulmonary and extrapulmonary disease (including ophthalmological evaluation).
• Consider additional studies (e.g., biopsy) under specialist guidance based on suspected organ involvement.

Pulmonary involvement and/or hilar lymphadenopathy are present in ∼ 90% of patients. Obtain chest imaging in all patients. ^[7]

The eye and the skin are the most common sites of extrathoracic disease. ^[7]

Initial studies ^[9][11]

• Laboratory studies
  • CBC and differential: leukocytopenia
  • Inflammatory markers: ↑ ESR, CRP
  • CMP
    • Hypercalcemia (due to elevated 1,25-dihydroxy-vitamin D)
    • ↑ BUN, creatinine: may indicate tubulointerstitial disease
    • ↑ ALP and/or GGT (> 3 × ULN): may indicate hepatic involvement ^[7]
  • Urinalysis: hypercalciuria
  • 1,25-OH and 25-OH vitamin D levels in patients with hypercalcemia
  • ↑ IgG
  • TB screening: interferon-γ release assay
• 12-lead ECG: concerning findings include heart block, frequent PVCs, tachyarrhythmias

Increased ACE levels may be seen. However, they are not specific for sarcoidosis and should not be used in isolation for diagnosis or monitoring. ^[9]

Cardiac sarcoidosis can lead to sudden cardiac death. Perform an ECG in all patients with suspected sarcoidosis regardless of symptoms. ^[10]

Imaging

• Chest x-ray ^[12]
  • Preferred initial test for all patients with suspected sarcoidosis
  • Classic findings: bilateral hilar lymphadenopathy with or without pulmonary infiltrates (i.e., reticular and/or ground glass opacities)
  • Pulmonary sarcoidosis is staged according to radiographic findings.

Stage I pulmonary sarcoidosis is often an incidental finding detected on chest imaging. ^[10]

• High-resolution CT (HRCT) ^[10][12]
  • Obtain an HRCT in all patients with confirmed or suspected pulmonary sarcoidosis.
  • Findings
    • Extensive hilar and mediastinal lymphadenopathy
    • Bronchocentric and perilymphatic micronodules (i.e., bronchovascular beading)
    • Peribronchial thickening
    • Fibrosis

Patients with pulmonary sarcoidosis may have minimal to no symptoms despite significant radiographic abnormalities.

Pulmonary function testing (PFTs) ^[12]

Obtain PFTs to assess disease severity in patients with pulmonary sarcoidosis.

• Spirometry
  • Typically shows a restrictive pattern
  • Obstructive and mixed patterns may also be seen. (See “Obstructive vs. restrictive lung disease.”)
• Diffusing capacity of the lung for carbon monoxide (DLCO) is decreased.

PFTs show an early reduction of DLCO and lung compliance.

Additional studies ^[11]

Consider the following studies under specialist guidance based on suspected organ involvement:

• Bronchoalveolar lavage (BAL):↑ CD4:CD8 ratio ^[9]
• TTE for pulmonary hypertension screening if ↓ DLCO or if enlarged pulmonary artery is present on HRCT
• Cardiac MRI and/or cardiac FDG-PET if there are concerning findings on 12-lead ECG or suspected cardiac sarcoidosis
• Cross-sectional imaging (abdomen) to assess for splenic involvement if CBC demonstrates cytopenias

Biopsy ^[10][11]

• Gold standard for the diagnosis
• Tissue should be obtained from the most easily accessible lesions (e.g., cutaneous lesions, superficial lymph nodes).
• Request fungal and mycobacterial staining and culture to rule out differential diagnoses. ^[7]
• Histopathology findings
  • Noncaseating granulomas with giant cells
  • Asteroid bodies
  • Schaumann bodies

Histopathological confirmation is not required in patients with pathognomonic presentations, i.e., Lofgren syndrome, Heerfordt syndrome, and lupus pernio. ^[10]

Differential diagnosis of granulomatous disease

The differential diagnoses listed here are not exhaustive.

General principles ^[7][10]

• Consult a pulmonologist and/or other specialists as required.
• Most patients with pulmonary sarcoidosis do not require immunosuppressive therapy.
• Glucocorticoids with/without DMARDs are indicated for patients with any of the following:
  • Symptomatic progressive disease
  • Persistent pulmonary infiltration
  • Progressive decline of lung function
• Organ transplantation (e.g., lung, heart, liver) may be indicated in patients with severe, refractory disease.

Immunosuppressive therapy ^[10][12]

• First-line: glucocorticoids, e.g., prednisone ^[11][12]
• If no response or adverse effects to glucocorticoids: DMARDs may be added.
  • Methotrexate (preferred choice) or azathioprine (alone or with glucocorticoids)
  • Chloroquine or hydroxychloroquine ^[11]
  • Biologics (e.g., TNF-alpha inhibitors) ^[11]

Supportive therapy ^[11]

• Prevent complications of glucocorticoid therapy and adverse effects of immunosuppressants.
• Provide individualized supportive care (e.g., NSAIDs for pain relief, noninvasive ventilation, supplemental oxygen).

• Individuals with sarcoidosis have an increased risk of malignancy (especially lung cancer and malignant lymphomas).
• Pulmonary complications
  • Bronchiectasis
  • Pulmonary hypertension (PH) due to pulmonary fibrosis
  • Aspergilloma
• Chronic renal failure (see “Clinical features” above)

We list the most important complications. The selection is not exhaustive.

• Increased calcium indicates renal involvement with the risk of chronic renal failure.
• Remission rate according to staging ^[16]
  • Stage I: approx. 70%
  • Stage II: approx. 50%
  • Stage III: approx. 20%
  • Stage IV: Life expectancy is limited because of severely impaired lung function.