SARCOIDOSIS

• DEFINITIONS

• Granuloma - a granuloma is an immune complex formed to confine pathogens, restrict inflammation, and protect surrounding tissue. Granulomas are made up of macrophages, lymphocytes, and epithelioid cells that surround a pathogen. Macrophages that are confined within a granuloma may fuse to form multinucleated giant cells. Over time, fibrosis and collagen deposition may encase the granuloma. Granulomas may form in response to a pathogen (e.g. tuberculosis) that the body is unable to eliminate. These granulomas are sometimes called "caseating" because the center contains necrotic debris. Granulomas may also form in the absence of an obvious pathogen (e.g. sarcoidosis), and these are sometimes referred to as "noncaseating" because the center does not contain necrotic debris. [2,3]
• Heerfordt's syndrome - rare syndrome caused by sarcoidosis that is marked by uveitis, parotid gland swelling, fever, and facial nerve palsy [5]
• Löfgren's syndrome - acute presentation of sarcoidosis marked by arthritis (typically of the ankles), erythema nodosum, and bilateral hilar adenopathy. Löfgren's syndrome is considered diagnostic for sarcoidosis. [3]
• Lupus pernio - violaceous plaques of the cheek and nose caused by sarcoidal granulomas; can be disfiguring; unrelated to lupus erythematosus [3,4]

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• INCIDENCE

• Annual incidence
• United States:
• 35 per 100,000 for blacks
• 11 per 100,000 for whites
• Global:
• 1 - 36 per 100,000
• Highest incidence in Northern Europeans and African-Americans and lowest in Japanese (1-2 per 100,000)

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• RISK FACTORS

• Known risk factors
• African-American race
• Female sex
• Northern European descent
• Age - peak incidence 25 - 45 years; a second peak occurs in women > 50 years


• Possible risk factors
• Mold
• Insecticides
• Metal-processing industries
• Genetics - HLA-DRB1
• Occupational - firefighting, metalworking, naval [1,2,3]

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• SYMPTOMS

• Fatigue - 20 - 70% of patients
• Incidental abnormal chest X-ray (asymptomatic) - 30 - 60% of patients
• Löfgren's syndrome - 9 - 34% of patients
• Skin disease - 20 - 35% of patients; erythema nodosum, subcutaneous granulomas, lupus pernio
• Eye disease (uveitis) - 10 - 60% of patients; marked by tearing, photophobia, pain, injection
• Lung symptoms - 9 - 19% of patients; marked by cough, shortness of breath, chest pain [2,3,4]

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• PATHOLOGY

• Sarcoidosis is marked by noncaseating granuloma formation most often in the lungs. The eyes and skin are also commonly involved. Other organ systems including the liver, spleen, heart, kidneys, and brain may be involved, but this is much less common.
• Granuloma formation in sarcoidosis is thought to occur from an exaggerated immune response to partially degraded molecules of killed mycobacteria and propionibacteria
• Sarcoidal granulomas have a highly variable clinical course. Some resolve spontaneously (half of patients within 2 years) while others incite chronic inflammatory responses that can lead to pulmonary fibrosis and other sequelae. [2,3]

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• DIAGNOSTIC TESTING

• Labs
• Angiotensin-converting enzyme (ACE) levels
• Sarcoidal granulomas produce ACE, and ACE levels are elevated in 60% of patients with sarcoidosis. Despite this, ACE levels have poor sensitivity and specificity in diagnosing sarcoidosis. ACE levels are also poor predictors of disease activity
• Because of these limitations, ACE levels have no clear role in diagnosing or monitoring disease activity in sarcoidosis [2,3]
• Serum calcium (Ca⁺⁺)
• Sarcoidal macrophages possess an enzyme (25-hydroxyvitamin D–1α-hydroxylase) that converts 25-hydroxyvitamin D to the more active form, 1,25 dihydroxyvitamin D (see vitamin D metabolism for more). The increase in vitamin D activity from macrophages can lead to elevated calcium levels in both the blood (hypercalcemia) and the urine (hypercalciuria)
• Hypercalcemia occurs in 10 - 20% of patients with sarcoidosis, and hypercalciuria is present in 50% of patients [4]

• Chest X-ray
• Bilateral hilar lymphadenopathy is the most common finding in sarcoidosis (25 - 65% of patients)
• In more extensive disease, pulmonary infiltrates (40% of patients) and/or pulmonary fibrosis (5% of patients) may be seen [2]

• Electrocardiogram (ECG)
• Cardiac involvement is present in about 5% of patients with sarcoidosis
• Abnormalities that may be seen on an EKG are nonspecific and may include PR prolongation, AV node block, bundle branch block, and atrial and ventricular premature beats [4,5]

• Pulmonary function tests (PFTs)
• About 65% of patients with sarcoidosis have airflow limitation at presentation
• Spirometry usually shows a restrictive pattern with decreased FVC and FEV₁
• Obstructive patterns are also present in 50% of patients with a reduced FEV₁/FVC ratio [3]
• See spirometry for more

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• DIAGNOSTIC CRITERIA

• Overview
• No formal diagnostic criteria for sarcoidosis have been published
• The diagnosis of sarcoidosis is based on clinical findings, histological findings from biopsies, and the exclusion of other granuloma-forming diseases, particularly infections
• Diagnosis very likely - biopsy not necessary
• Löfgren's syndrome - acute presentation of sarcoidosis marked by arthritis (typically of the ankles), erythema nodosum, and bilateral hilar adenopathy. Löfgren's syndrome is considered diagnostic for sarcoidosis. [2,3]
• Heerfordt's syndrome - rare syndrome caused by sarcoidosis that is marked by uveitis, parotid gland swelling, fever, and facial nerve palsy [5]
• Biopsy
• Biopsy of affected tissue is generally necessary to establish the presence of noncaseating granulomas when diagnosing sarcoidosis
• In some cases, nodules may be easily accessible - skin lesions, affected lymph nodes, conjunctival nodules
• In most cases, only pulmonary nodules are obvious and bronchoscopy with lung biopsy will be necessary [2]
• Other causes of granulomas should be ruled out

• Differential (other causes of granulomatous disease)
• Tuberculosis and other infections
• Occupational exposures - beryllium, aluminum, zirconium
• Drug-induced - Interferon alpha and beta, anti-tumor necrosis factor inhibitors, intravesical BCG therapy, natalizumab, alemtuzumab
• Immune syndromes - common variable immunodeficiency, chronic granulomatous disease
• Blau's syndrome
• Cancers - lymphomas, solid tumors
• Wegener’s granulomatosis
• Crohn’s disease
• Primary biliary cirrhosis [2]

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• MANAGEMENT

Management of sarcoidosis
Overview The management of patients with sarcoidosis is complicated by the fact that there are no clear guidelines to help determine who to treat, when to treat, or how to monitor disease activity In half of patients, the disease will resolve spontaneously within 2 years. After 10 years, up to two-thirds of patients will have complete remission. About one-third of patients have chronic disease that leads to significant organ impairment. [2,3]
Pulmonary disease Incidence - ≥ 90% of patients Symptoms - cough, shortness of breath, chest discomfort, abnormal PFTs, wheezing Whom to treat There is no clear guideline or consensus on when, or if, pulmonary sarcoidosis should be treated General points on treatment: Treatment should typically be reserved for patients who are symptomatic Symptomatic disease should be confirmed with pulmonary function tests Radiographic findings do not correlate well with disease chronicity or changes in pulmonary function There is no clear evidence that treatment affects long-term outcomes in sarcoidosis (e.g. fibrosis) [2,3,6] Treatment First-line: Prednisone 20 - 40 mg/day for 6 - 12 weeks, then taper to 5 - 10 mg/day; typical treatment duration is 12 months, although course may be shortened in quick-responders [2,5,6] Second-line: Methotrexate 5 - 15 mg/week; give with folic acid 1 mg/day; requires lab monitoring [7] Monitoring Active disease: chest X-ray and PFTs every 3 - 6 months Stable disease: monitor annually Remission: follow for 3 years after remission [3,5] Chronic sequelae Pulmonary fibrosis Pulmonary hypertension [3]
Eye disease (uveitis) Incidence - 10 - 60% of patients Symptoms - redness, injection, tearing, photophobia, pain; up to a one-third may be asymptomatic Treatment Anterior uveitis (65%) - treat with topical corticosteroids Posterior uveitis (30%) - treat with systemic corticosteroids Refractory cases: methotrexate, infliximab, adalimumab, and rituximab may be beneficial [2] Monitoring Active disease: as needed No eye disease: at least yearly eye exam Chronic sequelae Glaucoma Vision loss [3]
Skin disease Incidence - 20 - 35% of patients Symptoms - erythema nodosum, papular and plaque lesions, lupus pernio; lesions may be precipitated by skin trauma Treatment Typical lesions - topical or systemic corticosteroids; intralesional steroid injections Lupus pernio - systemic corticosteroids, infliximab, thalidomide [2,6] A case report found tofacitinib (Xeljanz®) to be highly effective in a patient with treatment-resistant disease [PMID 30586518] Studies A randomized controlled trial (N=39) published in 2014 found that thalidomide was no better than placebo in treating cutaneous sarcoidosis [PMID 24945194]
Cardiac disease Incidence - 5% of patients have symptomatic disease Symptoms - palpitations, syncope, EKG changes (e.g. AV node and bundle branch block), sudden death Treatment: prednisone 30 - 40 mg/day; pacemaker/implantable defibrillator when indicated Monitoring: periodic EKG (every 6 - 12 months); holter, PET scan, MRI, ECHO, when indicated [2,4,6]
Neurologic disease Incidence - 5% of patients Symptoms - cranial nerve dysfunction (particularly the facial nerve), peripheral neuropathy Treatment: - prednisone, may require higher doses (40 - 80 mg/day), infliximab [3,4,6] Studies A case series published in 2017 reviewed the efficacy of infliximab in treating CNS sarcoidosis [PMID 29030454]
Bone disease Incidence - up to 5% of patients Symptoms - typically affects the hands and feet; is usually asymptomatic Treatment: prednisone, denosumab [8]
Hypercalcemia / hypercalciuria Hypercalcemia - occurs in 10 - 20% of patients Caused by macrophages that convert vitamin D to more active form Treat with hydroxychloroquine or corticosteroids Typically treat when serum calcium is ≥ 11 mg/dl [4,6] Hypercalciuria - occurs in up to 50% of patients; may lead to kidney stones; treat with corticosteroids or hydroxychloroquine [4]
Liver / kidney disease Liver granulomas: occur in 50 - 80% of patients; liver enzymes are elevated in one-third of patients; severe liver disease is rare [4] Kidney granulomas: occur in 7 - 23% of patients; significant kidney disease is rare [4]

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• RELAPSE RATES

• After spontaneous remission - about 8% of patients
• After treatment with corticosteroids - 37 - 74% of patients; typically occurs within 2 - 6 months after stopping; relapses are rare after 3 years without symptoms [2]

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• BIBLIOGRAPHY

• 1 - PMID 12824213 JAMA review
• 2 - PMID 24090799 Lancet review
• 3 - PMID 18032765 NEJM review
• 4 - PMID 23597964 Extrapulmonary review
• 5 - PMID 10430755 ATS diagnostic criteria
• 6 - PMID 23596348 Sarc tx recs
• 7 - PMID 23880702 MTX recs
• 8 - PMID 28379797 A Bare-Bones Approach, NEJM (2017)