Sarcoidosis

Sarcoidosis is a multisystem disorder characterized by noncaseating granulomatous inflammation and typically manifests with constitutional symptoms (e.g., fever, malaise), cough, dyspnea, anterior uveitis, erythema nodosum, and arthralgia. Sarcoidosis primarily affects the lungs, but systemic manifestations (e.g., erythema nodosum, uveitis, arthritis) are also possible. Chest x-ray is the preferred initial test in patients with suspected sarcoidosis; parenchymal disease with bilateral hilar lymphadenopathy is a characteristic sign, although results are often normal or inconclusive. A high-resolution CT is indicated in patients with an abnormal or inconclusive x-ray and in those with unexplained cough or dyspnea. Endobronchial and/or transbronchial biopsy is the gold standard; the most common histopathological finding being noncaseating granulomas with giant cells. Further laboratory tests (e.g., angiotensin-converting enzyme levels, serum calcium, and urinalysis) showing elevated angiotensin-converting enzyme (ACE) levels, hypercalcemia, and hypercalciuria may support the diagnosis. Glucocorticoid therapy is indicated with disease progression and/or to prevent organ damage (e.g., to the eyes, lungs, and heart). Spontaneous remission without complications is common during the early stages, 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, anterior uveitis, erythema nodosum

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]

• Heart: 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

• 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 in ∼ 90% of affected individuals)

Heerfordt syndrome

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

Chest x-ray is the most appropriate initial test for suspected sarcoidosis and would likely reveal parenchymal disease with hilar lymphadenopathy. A high-resolution CT is indicated in patients with an abnormal or inconclusive x-ray and in those with unexplained cough or dyspnea. Endobronchial and/or transbronchial biopsy is the gold standard, with the most common histopathological finding being noncaseating granulomas with giant cells. Further laboratory tests (e.g., angiotensin-converting enzyme levels, serum calcium, and urinalysis) showing elevated angiotensin-converting enzyme (ACE) levels, hypercalcemia, and hypercalciuria may support the diagnosis.

Chest x-ray

• Preferred initial test
• Sarcoidosis is often an incidental finding detected on chest x-ray
• Findings: bilateral hilar lymphadenopathy with or without reticular opacities
• Radiographic findings are categorized into stages according to the affected lung structures.

Patients with pulmonary sarcoidosis may have moderate symptoms despite radiographic evidence of advanced disease.

High-resolution CT (HRCT) ^[11]

• Next diagnostic test if chest x-ray is abnormal or inconclusive and in patients with unexplained cough or dyspnea
• HRCT can detect parenchymal and mediastinal abnormalities such as:
  • Extensive hilar and mediastinal lymphadenopathy
  • Parenchymal masses and nodules predominantly in the upper lobes
  • Irregular thickening of the bronchial wall and bronchovascular bundles
  • Fibrosis with traction bronchiectasis

Laboratory tests

• CBC and differential: leukocytopenia
• Inflammatory markers: ↑ ESR, CRP
• LFTs: ↑ alkaline phosphatase ^[12]
• BUN and creatinine
• Serum electrolytes and calcium: hypercalcemia (due to elevated levels of 1,25-dihydroxy-vitamin D)
• Urinalysis: hypercalciuria
• Serum markers
  • ↑ ACE levels: may be used to monitor disease activity and therapy
  • ↑ Soluble interleukin-2 receptor (S-IL-2R) and neopterin levels ^[13]
• Additional tests
  • ↓ CD4⁺ T cells
  • ↑ IgG

Bronchoscopy ^[14][15]

• Biopsy: the gold standard for diagnosis
  • Site of biopsy: lung tissue, lymph nodes, cutaneous lesions, enlarged exocrine glands
  • Histological findings
    • Noncaseating granulomas with giant cells
    • Asteroid bodies
    • Schaumann bodies
  • Fungal and mycobacterial staining and culture to rule out differential diagnosis
• Bronchoalveolar lavage (BAL): increased CD4:CD8 ratio

Pulmonary function tests

Pulmonary function tests (PFTs) show an early reduction of diffusion capacity and lung compliance.

• Spirometry
  • Restrictive pattern (see “Restrictive lung disease”)
  • Obstructive and mixed patterns may also be seen (see “Obstructive lung disease”).
• Diffusing capacity of the lung for carbon monoxide (DLCO)
  • Decreased diffusion capacity
  • Sensitive parameter for disease activity

Other tests

• Indications
  • Exclusion of differential diagnoses, particularly granulomatous diseases
  • Suspicion of extrapulmonary manifestations
• Procedures
  • TB skin test (PPD) or interferon-γ release assay (exclusion of pulmonary tuberculosis)
  • ECG and echocardiography (to exclude, e.g., AV block, arrhythmias, cardiomyopathy)
  • Eye examination (e.g., slit lamp detection to exclude uveitis)

Differential diagnosis of granulomatous disease

The differential diagnoses listed here are not exhaustive.

Treatment is indicated for patients with symptomatic progressive disease, persistent pulmonary infiltration, and/or progressive decline of lung function. ^[9]

• Isolated pulmonary sarcoidosis
  • In most cases, no treatment is required.
  • The disease is usually asymptomatic, nonprogressive, and has a high rate of spontaneous remission.
• Symptomatic or extrapulmonary sarcoidosis
  • First line: glucocorticoids
  • Second line
    • Alternative immunosuppressive therapy (e.g., methotrexate, azathioprine), possibly in combination with glucocorticoids
    • Antimalarial drugs (e.g., chloroquine, hydroxychloroquine)
  • Third line: biological agents (e.g., TNF-alpha inhibitors) for refractory disease
  • Lung transplantation may be indicated in severe pulmonary disease that does not respond to other treatments.
  • NSAIDs are always indicated for symptom relief.

• 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 ^[19]
  • Type I: approx. 70%
  • Type II: approx. 50%
  • Type III: approx. 20%
  • Type IV: Life expectancy is limited because of severely impaired lung function.