Sarcoidosis – MD Nexus

Epidemiology

Prevalence: varies from 0.04/100 K in Spain to 64/100 K in Sweden
Sex: slight F>M
Race: American blacks have 10-17x incidence that of whites
Age of onset: most commonly between 20-40 y/o (can occur in children and elderly: elderly are usually chronic cases)
Tobacco: higher incidence of Sarcoid in non-smokers (compared to smokers)
Genetics: slightly increased (possibly due to low penetrance) incidence in twins (monozygotic > dizygotic) and other family members (including spouses)
- Increased incidence in blacks with HLA-Bw 15
- Alleles which increase risk of disease: HLA DR 11, 12, 14, 15, and 17
- Alleles which are protective: HLA DR1, DR4, and possibly HLA DQ 0202
- Resolution of disease is linked to HLA-B8 (this antigen also occurs more commonly in patients with sarcoid arthritis and E. nodosum)

Physiology

Immunologic Disease of Unknown Etiology
T-cell alveolitis: initial process (BAL shows increased CD4 cells and increased amount of alveolar macrophages)
Decreased peripheral blood CD4: CD8 ratio
Granuloma formation (found in most organs): alveolar macrophages are incorporated into granulomas (alveolar macs take up Gallium when scanned)
- Even early in disease, granulomas can be found in lungs and liver [Hunninghake; Sarc Vasc Diff Lung Dis, 1999]
PCR has detected Mycobacteria Tuberculosis in tissue from 7/16 patients in one series
Upper Airway Involvement: laryngeal/ posterior pharyngeal/ vocal cord infiltration by granulomas
Lower Airway Involvement: granulomatous involvement of trachea/ bronchi (or stenosis due to scarring associated with disease)
- Extrinsic compression of bronchus by adenopathy is rare in Sarcoidosis

Pathology

Non-caseating granulomas (typically along lymphatic routes)
Whorls of elongated fibroblasts/ epithelioid cells with mononuclear cells
Extensive necrosis is rare
Giant cells (may be either Langhan or foreign-body type) with multinucleated crystalline or cellular inclusions (inclusions: Asteroid bodies, Schaumann bodies, or Hamasaki-Wesenberg bodies)
Similar granulomas may also be seen in Berylliosis/ certain malignancies/ immune deficiencies/ Foreign Body Granulomatosis
Nodular/Necrotizing Sarcoid: confluent granulomas/necrotic granulomatous vasculitis of pulmonary arteries, veins

Diagnosis

Arterial Blood Gas (ABG)/Oximetry

Exercise-Related Desaturation: due mainly to diffusion defect
- Exercise pO2 correlates with right ventricular ejection fraction

Serum Chemistry

Hypercalcemia (see Hypercalcemia)

Tuberculin Skin Testing (TST) (see Tuberculin Skin Testing)

Usually Partial or Complete Anergy: PPD is negative in >66% of patients
- Sometimes positive PPD seen initially or with remission
- Previously positive PPD may revert to negative during active disease, returning to positive with cure of sarcoidosis
- Strongly positive PPD is rare in sarcoidosis

Kveim Test

Positive: although not currently used

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests)

No correlation of PFT’s with CXR Findings, Disease Activity, and Disease Reversibility
- Radiographic Stage 1: PFT’s are abnormal in 20% of cases
- Radiographic Stage 2-3: PFT’s are abnormal in 40-70% of cases
Spirometry: obstruction is observed in 30% of cases
Lung Volumes
- TLC: correlates with RV-EF
- VC: decreased
DLCO: decreased early (due to interstitial and pulmonary vascular disease)

Bronchoscopy (see Bronchoscopy)

General Comments

Appearance of Airways: granular “cobble-stoning” of airways

Bronchoalveolar Lavage (BAL) (American Thoracic Society Guidelines for Bronchoalveolar Lavage Cellular Analysis in Interstitial Lung Disease, 2012) (Am J Respir Crit Care Med, 2012) [MEDLINE]

BAL Lymphocytosis (>15% Lymphocytes)
- High CD4/CD8 Ratio >3.5: CD41/CD81 >4 is highly specific for sarcoidosis in the absence of an increased proportion of other inflammatory cell types
  - Especially High in Patients with Lofgren Syndrome
  - Previous Studies Suggest that BAL Lymphocytosis >28% Predicts Clinical Deterioration: however, this is controversial
- Neutrophilic Predominance: may correlate with presence of end-stage pulmonary fibrosis

Endobronchial Biopsy (EBB)

Indications
- Presence of Gross Airway Findings

Transbronchial Biopsy (TBB)

Positive in 50-60% of Cases with Normal CXR
*Positive in 85-90% with Abnormal CXR

Chest X-Ray (CXR)/Chest Computed Tomography (CT) Pattern (see Chest X-Ray and Chest Computed Tomography)

Usually, adenopathy precedes parenchymal disease (rare for adenopathy/parenchymal disease to recur after spontaneous clearing)
CXR Patterns
- Hilar Lymphadenopathy
- Interstitial Lung Disease
- Bullous-Cystic Disease
- Lung Nodules: may cavitate
Radiographic Staging: however, disease does not progress temporarily through these “stages”
- Stage 0 (5-10% of cases): normal
  - In these cases, HRCT may demonstrate parenchymal abnormalities and adenopathy
- Stage 1: bilateral hilar adenopathy
- Stage 2a: bilateral hilar adenopathy + diffuse lung disease
- Stage 2b: diffuse lung disease without hilar adenopathy
- Stage 3: fibrosis + distortion of lung parenchyma

High-Resolution Chest Computed Tomography (HRCT) (see High-Resolution Chest Computed Tomography)

Findings
- Nodules Along Bronchovascular Bundles: particularly in upper lung fields (“beading”)
- Pleural or Subpleural Nodules
- Septal Lines
- Confluent Opacities with Air Bronchograms
- Cystic or Bronchiectatic Lucencies
- Honeycombing
- Bullae

Bone Scan (ses Bone Scan)

Findings
- xxxx

Gallium Scan (see Gallium Scan)

“Panda Pattern”: uptake in hilar and mediastinal nodes, lacrimal glands, and salivary glands
Non-specific
May guide biopsy site
Does not reliably predict prognosis or responsiveness to therapy
May aid in monitoring of disease

Cardiac MRI (see Cardiac Magnetic Resonance Imaging)

Useful to Evaluate Cardiac Sarcoidosis

Brain MRI (see Brain Magnetic Resonance Imaging)

Useful to Evaluate Neurosarcoidosis

Serology/Inflammatory Markers

ANA/RF/Anti-Lymphocyte Ab: may be positive
Circulating Immune Complexes: may be seen (increased levels may occur with symptoms)
Polyclonal Hyperglobulinemia/Macroglobulinemia: may be present
Lysozyme/Thermolysin-Like Metallopeptidase: elevated

Serum Angiotensin Converting Enzyme (ACE) Level (see Serum Angiotensin Converting Enzyme)

Elevated >2 Standard Deviations in 41-80% of Sarcoidosis Cases
- However, ACE level may also be elevated in HIV, hepatitis, miliary TB, Gaucher’s, Histoplasmosis
- May be decreased with corticosteroid or ACE inhibitor use
May Be Useful to Monitor Disease Activity

Biopsy

Liver/Lymph Node Biopsy: high Incidence of false-positives
Skin/Conjunctival Biopsy: low sensitivity, but high specificity
Nasal Mucosal/Muscle/Spleen/Lacrimal Gland/Salivary Gland Biopsy: may be useful in some cases

Clinical Manifestations

General Comments

Immune Reconstitution Inflammatory Syndrome (IRIS) (see Immune Reconstitution Inflammatory Syndrome)

Cardiovascular Manifestations

General Comments

General Comments: cardiac involvement may occur in the absence of other organ involvement

Conduction Defects (see Heart Blocks)

Epidemiology
Clinical
- Syncope (see Syncope)

Arrhythmias

Epidemiology
Clinical
- Premature Ventricular Contractions (PVC’s)/Ventricular Tachycardia (VT) (see Ventricular Tachycardia)
- Syncope (see Syncope)

Restrictive Cardiomyopathy

Epidemiology:

Pericardial Effusion/Tamponade (see Pericardial Effusion and Tamponade)

Epidemiology: uncommon

Constrictive Pericarditis (see Constrictive Pericarditis)

Epidemiology: uncommon

Pulmonary Hypertension with Cor Pulmonale (see Pulmonary Hypertension)

Epidemiology:

Superior Vena Cava (SVC) Syndrome (see Superior Vena Cava Syndrome)

Epidemiology: uncommon
Physiology: due to mediastinal lymphadenopathy

Substernal Chest Pain (see Chest Pain)

Epidemiology: common

Constitutional Manifestations

Fever (see Fever)

Dermatologic Manifestations

Erythema Nodosum (see Erythema Nodosum): painful, nodular panniculitis, and vasculitis
Subcutaneous Nodules: on extremities
Nodular or Flat Plaques/Papules
Lupus Pernio: bluish-purplish elevations
Loffgren’s Syndrome
- Arthralgias
- Bihilar Lymphadenopathy
- Erythema Nodosum

Endocrine Manifestations

Hypercalcemia (see Hypercalcemia)

Epidemiology:
Physiology: due to increased calcium absorption, enhanced sensitivity to vitamin D, or increased vitamine D metabolite production by granulomas
Diagnosis
- Serum Parathyroid Hormone (PTH) (see Serum Parathyroid Hormone): PTH may be decreased (due to hypercalcemia)
Treatment
- Corticosteroids (see Corticosteroids): hypercalcemia is usually extremely sensitive to low-moderate doses of prednisone (15-25 mg PO qday)
  - Lack of Response to Prednisone Should Raise the Suspicion for Other Potential Cause of Hypercalcemia (Other than Sarcoidosis)
- Hydroxychloroquine (Plaquenil) (see Hydroxychloroquine): efficacious
- Anti-Tumor Necrosis-α Therapy (see Anti-Tumor Necrosis-α Therapy): case reports of efficacy

Hypercalciuria (see Hypercalciuria)

Physiology: xxx

Parotid Gland Enlargement

Epidemiology

Other

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)
Diabetes Insipidus (DI) (see Diabetes Insipidus)
Primary Polydipsia
Glandular Involvement of Pituitary/Thyroid/Parathyroid/Adrenal Glands/Testes/Epididymis/Uterus: rare
- No direct effect on fertility
Pregnancy (see Pregnancy): disease probably improves during pregnancy, with disease exacerbation post-partum

Gastrointestinal Manifestations

Anorexia (see Anorexia)
Appendiceal Involvement
- Clinical: pain may mimic appendicitis
Dysphagia (see Dysphagia)
- Physiology
  - Esophageal Compression by Mediastinal Lymphadenopathy
  - Infiltration of Esophageal Wall
Esophageal Achalasia (see Esophageal Achalasia)
- Physiology: due to involvement of Auerbach’s plexus
Gall Bladder Involvement
- Clinical: RUQ pain may mimic cholecystitis
Malabsorption
- PhysiologyL due to jejunal atrophy/non-necrotizing granuloma of stomach, small intestine, colon
Pancreatic Involvement
- Clinical: pain may mimic pancreatitis
Weight Loss (see Weight Loss)

Hematologic Manifestations

Cervical/Supraclavicular/Epitrochlear Lymphadenopathy (see Lymphadenopathy)
- Clinical: usually small, discrete, mobile nodes
Hypersplenism (see Splenomegaly)
- Clinical: marked splenomegaly occurs more often with chronic disease
  - May produce pancytopenia
Thrombocytopenia (see Thrombocytopenia)
- Clinical: may occur without splenomegaly

Hepatic Manifestations

General Comments: usually asymptomatic
Hepatic Parenchymal Lesions (see Hepatic Mass)
- Clinical
  - Right Upper Quadrant (RUQ) Pain
  - Jaundice
  - Hepatomegaly (see Hepatomegaly)
Portal Fibrosis
Cirrhosis (see End-Stage Liver Disease)
- Epidemiology: rare
Hepatitis
- Epidemiology: rare
Portal Hypertension (see Portal Hypertension)
- Physiology: due to damaged hepatic veins

Neurologic Manifestations (Neurosarcoidosis)

General Comments

Incidence: neurologic manifestations occur in 5% of sarcoidosis cases

Cranial Nerve Palsies

General Comments: cranial nerve palsies are the most common neurologic presentation of sarcoidosis
Cranial Nerve 7 (Facial Nerve) Palsy: most commonly affected cranial nerve
- Heerfordt’s Syndrome (Uveoparotid Fever): CN-7 Palsy + Parotid Involvement + Uveitis
Hearing Loss/Vestibular Dysfunction: due to neuropathy or vasculitis of cranial nerve

Meningitis (see Meningitis)

Diagnosis
- Lumbar Puncture (see Lumbar Puncture): CSF may be normal (or may demonstrate increased protein, pleocytosis, hypoglycorrhachia, elevated CSF pressure)

Peripheral Neuropathy (see Peripheral Neuropathy)

Clinical
- Parasthesias (see Parasthesias)

Space-Occupying Brain Lesions

Clinical
- Brainstem Dysfunction: due to brainstem lesions
  - Acute Hypoventilation (see Acute Hypoventilation)
  - Chronic Hypoventilation (see Chronic Hypoventilation)
- Cerebellar Dysfunction
- Headache (see Headache)
- Obtundation-Coma/Encephalopathy (see Obtundation-Coma)
- Seizures (see Seizures)

Spinal Cord Dysfunction

Physiology
- May Present with Intramedullary or Extramedullary Lesions
- May Involve Spinal Cord or Cauda Equina
Diagnosis
- Spine MRI (see Spine Magnetic Resonance Imaging): signal abnormalities are non-specific
- Lumbar Puncture (LP) (see Lumbar Puncture): pleocytosis, elevated protein
  - CSF Angiotensin Converting Enzyme: neither sensitive nor specific for neurosarcoidosis
Clinical
- Acute or Subacute Segmental Myelopathy

Other

Fatigue (see Fatigue)

Ophthalmologic Manifestations

Uveitis (see Uveitis): most common ophthalmologic manifestation of sarcoidosis
- Anterior Uveitis: inflammation in the portion of the uveal tract extending forward from the iris and ciliary body -> asymptomatic or red painful eye with photophobia
  - Exam: “mutton fat” in anterior chamber and/or posterior cornea
- Intermediate Uveitis: inflammation in the vitreous, pars plana, or peripheral retina -> floaters or other visual disturbances
- Posterior Uveitis: involves central portions of the retina (with venulitis that causes exudation of protein out of the retinal veins) -> retinal scarring and permanent vision loss
  - Fluorescence Angiogram: leaking retinal veins, leads to appearance of candle wax drippings
Optic Neuritis (rare): usually presents with sudden loss of vision or color vision
- Exam: papillitis, papilledema, neovascularization with optic atrophy
Vitreous Opacities/Choroiditis/Conjunctival Granulomas: photophobia, eye pain, visual loss
Lacrimal Gland Enlargement (25% of cases): may produce sicca-like syndrome
- Diagnosis
  - Biopsy of Lacrimal Gland: may be useful
Exophthalmos: due to orbital disease

Otolaryngologic Manifestations

Nasal Polyps (see Nasal Polyps)

Clinical: nasal congestion

Laryngeal/Posterior Pharyngeal/Vocal Cord Granulomas

Clinical
- Hoarseness (see Hoarseness)
- Upper Airway Obstruction (see Obstructive Lung Disease): laryngeal granulomas seen mostly with lupus pernio, but occur with other dermatologic manifestations

Pulmonary Manifestations

General Comments

Predominant Anatomic Sites of Pulmonary Involvement
- Bronchovascular Bundles: lesions along airways are common (and lesions involving the pulmonary vasculature may explain the occasional development of pulmonary hypertension)
- Perilymphatic Areas: subpleural lesions are common
Distribution: upper lobe-predominant

Alveolar Sarcoidosis (see Pneumonia)

Diagnosis
- CXR/Chest CT
  - Fluffy alveolar densities
  - “Reverse pulmonary edema” peripheral infiltrates, resembling chronic eosinophilic pneumonia or COP, have been reported
  - “Fairy Ring”/”Atoll Sign”/”Reverse Halo Sign”: normal or ground-glass region of parenchyma surrounded by dense ring of alveolar consolidation

Bullous-Cystic Sarcoid (see Cystic-Cavitary Lung Lesions)

Clinical
- Cavities may become colonized with Aspergillus
- Severe bullous disease may cause the “Vanishing Lung Syndrome”
Treatment/Prognosis: cavities may resolve with or without therapy

Hilar/Mediastinal Lymphadenopathy (see Mediastinal Mass)

Epidemiology: occurs in 75-90% of cases
Diagnosis
- CXR/Chest CT
  - Usually bilateral and symmetric
  - Involves hilar, paratracheal, subcarinal, and other mediastinal lymph nodes
  - Hilar Nodes: “eggshell” calcification may occur
  - Subcarinal/Other Mediastinal Nodes: non-specific calcification may occur with long-standing disease
  - Posterior Mediastinal Mass: may occur
Clinical: substernal chest pain
Treatment/Prognosis: may regress, remain stable for years, or grow slowly

Nodular/Necrotizing Sarcoidosis (see Lung Nodule or Mass and Cystic-Cavitary Lung Lesions)

Epidemiology: first described in 1973 by Liebow
- Rare: only 3 of 150 cases in one series
- Sex: female predominance
Physiology: granulomatous vasculitis -> necrosis may develop within the granulomatous lesion
Clinical: may be asymptomatic
- Chest Pain
- Cough
- Dyspnea
- Fatigure/Malaise
- Fever
- Hemoptysis
- Ocular or Central Nervous System Involvement
- Weight Loss
Diagnosis
- Chest CT: confluent or diffuse >1 cm solitary or multiple lung nodules (possibly associated with lymphadenopathy)
  - Nodules may cavitate (calcification is usually absent): cavitation (and granulomatous vasculitis or pulmonary arteries and veins/necrosis of nodules) clinically distinguishes nodular/necrotizing sarcoidosis from typical sarcoidosis
  - No lobar predilection
  - Predominantly located subpleural and along bronchovascular bundles (similar to other Sarcoid lesions)
Treatment/Prognosis
- Usually benign clinical course with or without corticosteroids
- Some cases have severe pulmonary or extrapulmonary involvement
- Few cases develop pulmonary hypertension due to pulmonary vasculitis

Pleural Involvement

Epidemiology: uncommon
Clinical
- Chylothorax (see Pleural Effusion-Chylothorax): only 2 reported cases
- Pleural Effusion (see Pleural Effusion-Exudate): occur in <3% of cases
  - Small and May be Bilateral
  - Lymphocyte-Predominant: may be >80%
  - Exudate (usually): by total protein criteria alone (since pleural LDH is usually normal)
- Pleural Thickening
- Pneumothorax (see Pneumothorax)
  - Most cases are associated with fibrocystic disease
  - May be recurrent

Pulmonary Hypertension (see Pulmonary Hypertension)

Epidemiology: occurs in 1-28% of sarcoidosis cases
- Most Commonly Occurs in Advanced Sarcoidosis: but may occur in some patients with preserved parenchymal architecture
Physiology
- Likely Due to Destruction of the Capillary Bed by Fibrosis and/or Resultant Chronic Hypoxemia: however, the severity of pulmonary hypertension does not correlate well with the degree of parenchymal lung disease and blood gas abnormalities
- Other Potential Mechanisms: extrinsic compression of large pulmonary arteries by mediastinal and hilar adenopathy, and direct granulomatous infiltration of the pulmonary vasculature (especially the pulmonary veins, which sometimes mimic pulmonary veno-occlusive disease)
- More Rarely: portopulmonary hypertension secondary to hepatic sarcoidosis can occur
Diagnosis
- Brain Natriuretic Peptide (BNP) (see Brain Natriuretic Peptide): elevated BNP in chronic lung disease indicates a poor prognosis
Clinical
- Exertional Dyspnea (see Dyspnea)
- Right-Sided Congestive Heart Failure (see Congestive Heart Failure): occur in only 21% of cases
Prognosis
- Presence of Pulmonary Hypertension in Sarcoidosis Correlates with Higher Supplemental Oxygen Requirements, Decreased Functional Capacity (by 6MWT Distance), and Higher Caregiver Dependency
- Presence of Pulmonary Hypertension in Sarcoidosis Increases the Mortality Rate >10x: 5-year survival is only 59% in these patients
- Pulmonary Hypertension in Sarcoidosis without Left Ventricular Dysfunction is Associated with Increased Mortality, as Compared to Absence of Pulmonary Hypertension (Hazard Ratio: 10.39) and Pulmonary Hypertension with Left Ventricular Dysfunction (Hazard Ratio: 3.14) (Chest, 2010) [MEDLINE]

Pulmonary Veno-Occlusive Disease (VOD) (see Pulmonary Veno-Occlusive Disease)

Epidemiology: few case reports

Reticulonodular Interstitial Lung Disease (see Interstitial Lung Disease)

Epidemiology: most common CXR pattern in sarcoidosis
Diagnosis
- HRCT (superior to normal CT in assessing fine parenchymal abnormalities and separating alveolitis from fibrosis): lymphadenopathy/focal nodular (usually miliary <3 mm micronodules/ may be up to 3-5 mm nodules) or ground-glass opacities (peribronchovascular distribution/predilection for upper, middle, posterior lung zones)
  - Patchy nodules or segmental ground glass opacities without distortion are characteristic of early alveolitis (with minimal pulmonary dysfunction)
  - HRCT scores do not correlate with the Gallium and BAL scores of disease activity

Rounded Atelectasis (see Rounded Atelectasis)

Epidemiology: case reports

Tracheobronchial Airway Obstruction (see Obstructive Lung Disease)

Physiology: granulomatosus tracheobronchial involvement
- May Progress to Stenotic Tracheobronchial Scarring
Diagnosis
- CXR/Chest CT (see Chest X-Ray and Chest Computed Tomography): right middle lobe involvement is uncommon
- Pulmonary Function Tests (PFT’s) (see xxxx): obstruction
- Bronchoscopy: characteristic diffuse granular bronchial mucosa (“cobble-stoning”), obstructing lesions, stenoses
Clinical: may present as either large or small airway obstruction
- Bronchiectasis (see Bronchiectasis)
- Dyspnea (see Dyspnea)
- Paroxysmal Cough (see Cough)
- Post-Obstructive Pneumonia (see Pneumonia)
- Wheezing (see Obstructive Lung Disease)

Renal Manifestations

Chronic Kidney Disease (CKD) (see Chronic Kidney Disease): due to renal granulomas, calculi (due to hypercalcemia/hypercalcuria)

Rheumatologic Manifestations

Polyarthritis/Monoarthritis (see Arthritis): usually associated with Loffgren’s syndrome
- Predominant Anatomic Sites of Involvement
  - Ankles
  - Wrists
Myopathy (see Myopathy): muscle granulomas are usually symptomatic (may occasionally produce acute myopathy with marked CK elevation)
Lytic or Sclerotic Bone Lesions: usually associated with skin or visceral disease
- Predominant Anatomic Sites of Involvement
  - Tubular hand bones: 3% of cases
  - Thoracic spine
  - Ribs
  - Sternum
- Gallium Scan: increased uptake in “Panda” pattern
- Bone Scan
Asymmetric Pseudoclubbing: due to bone cysts with dactylitis

Treatment

Corticosteroids (see Corticosteroids)

Indications
- Brain Disease
- Cardiac Disease
- Hypercalcemia: hypercalcemia is extremely sensitive to low-moderate prednisone doses (15-25 mg PO qday)
- Ophthalmologic Disease
- Persistent Hypercalcemia: see below
- Pulmonary Disease (Progressive)
- Renal Disease
Administration
- Prednisone (see Prednisone): 20-40 mg PO qday x6-12 wks, then taper over months to lowest effective dose, continue for months-years
Adverse Effects: lead to discontinuation in 5-10% of cases

Antimalarial Agents

Pharmacology

Antimalarial Drugs with Immunomodulatory Properties
Inhibition of 25-Hydroxylation of Vitamin D: the effect decreases hypercalcemia in sarcoidosis

Agents

Chloroquine (Aralen) (see Chloroquine): no longer used, as has been replaced by hydroxychloroquine
Hydroxychloroquine (Plaquenil) (see Hydroxychloroquine)
- Safer and Almost as Effective as Chloroquine: for this reason, hydroxychloroquine has replaced chloroquine in in use today
- Indications: may be used as corticosteroid-sparing agent
  - Central Nervous System Disease (Neurosarcoidosis)
  - Cutaneous Disease
  - Hypercalcemia (see Hypercalcemia)
- Administration: 200 mg qday-BID PO qday x 3-6 mo
- Adverse Effects
  - Hypoglycemia (see Hypoglycemia): may be useful in cases with coexistent diabetes mellitus
  - Myopathy (see Myopathy): reversible
  - Peripheral Neuropathy (see Peripheral Neuropathy)
- Monitoring
  - Retinal Exam (q3 mo): to detect retinopathy (although retinopathy has not been reported)

Methotrexate (see Methotrexate)

Methotrexate is the Most Commonly Used Non-Corticosteroid Immunosuppressive Agent for Sarcoidosis
Indications: methotrexate has a corticosteroid-sparing effect
- Central Nervous System Disease (Neurosarcoidosis)
- Cutaneous Disease
- Musculoskeletal Disease
- Ophthalmologic Disease
- Pulmonary Disease: improves lung function
Pharmacology: antimetabolite with both immunosuppressive and antiinflammatory properties
Administration: 10-15 mg PO q week x 3-6 mo or to disease activity
Adverse Effects
- Hepatic Fibrosis (see Hepatic Fibrosis): rare in cases treated with low-dose treated methotrexate
Clinical Efficacy: clinical response rate of pulmonary sarcoidosis is approximately 40-60%
- Meta-Analysis of Immunosuppressives in the Treatment of Sarcoidosis (Respir Med, 2008) [MEDLINE]
  - Due to Insufficient Published Data, Clinical Benefit Could Not Be Ascertained
- Two Year Retrospective Study Comparing Methotrexate vs Azathioprine as Second-Line Therapies for Sarcoidosis (Chest, 2013) [MEDLINE]
  - Both Methotrexate and Azathioprine Had Significant Steroid-Sparing Potency, Similar Positive Effects on Lung Function, and Comparable Adverse Effects
  - However, the Azathioprine Group Had a Higher Rate of Infection
- Trial of Methotrexate as a Single Agent in the Treatment of Sarcoidosis (Pneumonol Alergol Pol, 2014)[MEDLINE]
  - Methotrexate is Effective as a Single Agent in the Treatment of Sarcoidosis
Recommendations (World Association of Sarcoidosis and Other Granulomatous Disorders Recommendations for the Use of Methotrexate in Sarcoidosis) (Curr Opin Pulm Med, 2013) [MEDLINE]
- Indications for Methotrexate in Sarcoidosis
  - Second-line Treatment Option in Corticosteroid-Refractory Cases, in the Presence of Corticosteroid-Associated Adverse Effects, or as Corticosteroid-Sparing Agent
  - First-line Treatment Option as a Methotrexate/Corticosteroid Combination Therapy or Monotherapy in Exceptional Situations*
- Before Starting Methotrexate, Contraindications Should Be Considered
  - Acute/Chronic Infection
  - Myelosuppression
  - Significant Hepatic Disease (Other than Sarcoidosis)
  - Significant Renal Disease
- Preadministration Work-up Prior to Starting Methotrexate
  - Liver Function Tests (LFT’s): Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase, Bilirubin
  - Complete Blood Count (CBC) (see Complete Blood Count)
  - Creatinine
  - Serology for HIV: when indicated
  - Serology for Hepatitis B/C
  - Interferon–γ Release Assay (IGRA) Testing for Mycobacterium Tuberculosis Infection
- Recommended Initial Dosage of Oral Methotrexate: 5–15 mg qweek
- Folic Acid Supplementation is Recommended with Methotrexate Therapy: at least folic acid 5 mg qweek or 1 mg qday
- When Starting Methotrexate or Increasing the Dose, ALT (With or Without AST, Creatinine, and CBC) Should Be Monitored q3–6 wks Until a Stable Dose is Reached, and q1–3 mo Thereafter: after stabilization the monitoring interval can be extended to q6 mo
- With Methotrexate-Induced Gastrointestinal Adverse Effects (Including Mucositis), Splitting the Oral Dose Should Be Considered, Provided the Total Methotrexate Dose is Ingested Within a 12 hr Period
  - Parenteral Administration or an Alternative Immunosuppressive Drug Should Be Considered in Case of persistent Intolerance
- Caution is Warranted if There is a Confirmed Increase in ALT or AST
  - If There are No Other Causes, Methotrexate Dose Should Be Reduced Dose or Drug Withdrawn, Liver Biopsy Should Be Performed to Evaluate for Methotrexate Toxicity, or Additional Folic Acid Supplementation Should Be Administered
  - Consider an Alternative Immunosuppressive Drug After Normalization
- Methotrexate is Appropriate for Long-Term Use
- Methotrexate Should Not Be Used by Men or Women for At Least 3 mo Before Planned Pregnancy and Should Not Be Used During Pregnancy or Breast Feeding (Absolute Contraindication)

Azathioprine (Imuran) (see Azathioprine)

Indications: usually used in patients who have failed methotrexate (due to adverse effects) or demonstrate lack of benefit with methotrexate
Pharmacology: affects RNA/DNA synthesis, resulting in inhibition of lymphocyte proliferation
Administration: 150 mg PO qday x 3-6 mo
Adverse Effects
- Immunosuppression
Clinical Efficacy
- Retrospective Study Comparing Methotrexate vs Azathioprine as Second-Line Therapies for Sarcoidosis (Chest, 2013) [MEDLINE]
  - Both Methotrexate and Azathioprine Had Significant Steroid-Sparing Potency, Similar Positive Effects on Lung Function, and Comparable Adverse Effects
  - However, the Azathioprine Group Had a Higher Rate of Infection

Leflunomide (Arava) (see Leflunomide)

Indications
- xxx
Pharmacology: antimetabolite similar to methotrexate, but with decreased gastrointestinal toxicity
Administration: 20 mg per day
- Avoid Alcohol During Leflunomide Administration
Adverse Effects
- Abdominal Pain (see Abdominal Pain)
- Diarrhea (see Diarrhea)
- Nausea (see Nausea and Vomiting)
- Hepatotoxicity (see Drug-Induced Hepatotoxicity): acute hepatic events generally occur during the 6 mo of treatment (age and sex do not appear to influence the risk of hepatotoxicity)
  - Transaminase Elevation Occurs in >5% of Cases
  - Acute Liver Failure is Rare
- Peripheral Neuropathy (see Peripheral Neuropathy)
- Rash

Anti-Tumor Necrosis-α (Anti-TNFα) Therapy (see Anti-Tumor Necrosis-α Therapy)

Indications
- Disease Unresponsive to Corticosteroids and At Least One of the Second-Line Immunosuppressive Agents (Methotrexate, Azathioprine, Leflunomide)
- Hypercalcemia: case reports of efficacy
- Ophthalmologic Disease
Agents
- Adalimumab (Humira) (see Adalimumab)
- Etanercept (Enbrel) (see Etanercept)
- Golimumab (Simponi, Simponi Aria) (see Golimumab)
- Infliximab (Remicade) (see Infliximab)
Pharmacology: anti-TNFα (TNFα is believed to accelerate the inflammatory process in sacoidosis)
Adverse Effects
- xxxx
Clinical Efficacy
- Trial of Infliximab in Extrapulmonary Sarcoidosis (Eur Respir J, 2008)[MEDLINE]
  - Modest Improvement was Demonstrated in the Infliximab Group: however, the improvement was not maintained during the 24 mo follow-up period
- Trial of Adalimumab in Infliximab-Intolerant Patients with Sarcoidosis (Respir Med, 2016) [MEDLINE]
  - Adalimumab is an Effective Alternative for Sarcoidosis Patients Who are Intolerant to Infliximab
- Trial of Anti-TNFα Therapy in Refractory Uveitis (Semin Arthritis Rheum, 2015) [MEDLINE]
  - Anti-TNFα Therapy (Infliximab, Adalimumab) is Effective in Sarcoid Uveitis, Refractory to Other Immmunosuppressives

Specific Treatment of Sarcoidosis-Associated Pulmonary Hypertension (see Pulmonary Hypertension)

Endothelin Receptor Antagonists (see Endothelin Receptor Antagonists)

Clinical Efficacy
- Small Trial of Bosentan in Sarcoidosis-Associated Pulmonary Hypertension (Chest, 2014) [MEDLINE]
  - Bosentan Significantly Improved Pulmonary Hemodynamics in Patients with Sarcoidosis-Associated Pulmonary Hypertension
  - Bosentan Did Not Improve 6MWT Distance in Patients with Sarcoidosis-Associated Pulmonary Hypertension

Sildenafil (Viagra, Revatio) (see Sildenafil)

Clinical Efficacy
- Trial of Sildenafil in Sarcoidosis-Associated Pulmonary Hypertension (Clin Respir J, 2009) [MEDLINE]
  - Approximately 25% of Patients with End-Stage Sarcoidosis an Associated Pulmonary Hypertension were Vasoreactive to iNO
  - However, the Degree of iNO Vasoresponsiveness was a Poor Predictor of the Response of the Pulmonary Hypertension to Treatment with Sildenafil

Other Potential Treatments

Cyclophosphamide (Cytoxan) (see Cyclophosphamide)

Indications: rarely-used corticosteroid-sparing agent
- xxxx
Pharmacology: alkylating agent
Administration: 50 mg PO qday x 3 wks
Adverse Effects
- Myelosuppression

Mycophenolate Mofetil (Cellcept) (see Mycophenolate Mofetil)

Indications
- Unclear
Pharmacology: inhibitor of lymphocyte proliferation and activity

Pentoxifylline (Trental) (see Pentoxifylline)

Indications
- Unclear
Pharmacology
- Xanthine Which Possesses Hemorheologic Activity: improves blood flow
- Inhibition of Synthesis of Tumor Necrosis Factor-α by Alveolar Macrophages from Sarcoidosis Patients: potentially inhibiting granuloma formation

Quinacrine (xxx) (see Quinacrine)

Indications
- Chronic Cutaneous Disease
Adverse Effects
- Ocular Toxicity
- Psychosis

Agents Which are Generally Avoided (Due to Unclear or Lack of Efficacy)

Allopurinol (see Allopurinol)

Clinical Efficacy: no clinical benefit in pulmonary sarcoidosis

Chlorambucil (see Chlorambucil)

Administration: 5 mg PO qday x 3 mo
Adverse Effects
- Amenorrhea (see xxxx)
- Azospermia
- Gastrointestinal Symptoms
- Hepatitis (see xxxx)
- Immunosuppression
- Pulmonary Fibrosis (see xxxx)
- Seizures (see xxxx)
Clinical Efficacy: no clinical benefit

Colchicine (see Colchicine)

Clinical Efficacy: no clinical benefit

Cyclosporine A (see Cyclosporine A)

Clinical Efficacy: no clinical benefit in pulmonary sarcoidosis

Nonsteroidal Anti-Inflammatory Drugs (NSAID’s) (see Nonsteroidal Anti-Inflammatory Drug)

Agents
- Ibuprofen (Motrin) (see Ibuprofen)
- Indomethacin (Indocin) (see Indomethacin)
- Salicylates (see Salicylates)
Indications: may help decrease the acute inflammatory or constitutional symptoms in sarcoidosis (arthritis, fever), but are not recommended for the treatment of pulmonary sarcoidosis

Tetracyclines (see Tetracyclines)

Indications
- Cutaneous Disease: tetracyclines have been used with variable efficacy
- Pulmonary Disease: no clinical benefit
Agents
- Doxycycline (see Doxycycline)
- Minocycline (see Minocycline)
Clinical Efficacy: no clinical benefit in pulmonary sarcoidosis

Oxyphenbutazone (see Oxyphenbutazone)

Indications: improvement most evident in patients treated within 2 yrs of disease onset
Administration: 400 mg PO qday x 3-6 months
Adverse Effects
- Peptic Ulcer Disease (PUD (see Peptic Ulcer Disease)

Thalidomide (see Thalidomide)

Indications: may be useful for corticosteroid-unresponsive disease
- Cutaneous Disease: small trials demonstrate clinical benefit
- Pulmonary Disease: no clinical benefit
Administration: 200 mg PO qday x 2 wks, then 100 mg PO qday x 11 wks

Tranilest (see Tranilest)

Pharmacology: anti-allergic agent, may have some anti-fibrotic effects

Vitamin D Supplementation (see Vitamin D)

Rationale: sarcoidosis patients have low 25-hydroxyvitamin D3 levels, but have normal 1,25-hydroxyvitamin D3 levels -> therefore, they are not deemed vitamin D-deficient
- Vitamin D Replacement in Sarcoidosis is Currently Controversial

Radiation Therapy (see Radiation Therapy)

Formerly used to treat hilar and mediastinal adenopathy
Whole brain irradiation has been used to control meningeal and neurosarcoid (one case with thalamic, posterior third ventricle granuloma showed improvement)
Megavoltage XRT has been used to treat laryngeal Sarcoid refractory to steroids

Transplantation

Lung Transplant (see Lung Transplant)

Complications
- Recurrence of Sarcoidosis in the Transplanted Lung
  - Recurrence of Sarcoidosis Occurs in Approximately 50% of Transplanted Lungs, But Does Not Appear to Affect Outcome (Sarcoidosis Vasc Diffuse Lung Dis, 2005) [MEDLINE]
- Donor Organ Sarcoidosis Transfer to Organ Recipient: case reports

Heart Transplant (see Heart Transplant)

xxx

Liver Transplant (see Liver Transplant)

xxx

Monitors of Sarcoidosis Disease Activity

ACE level: decreasing level correlates with remission and response to steroids
Gallium scan: may be useful in some settings
Lung DTPA: increased clearance correlates with deterioration of lung function
BAL CD4/CD8 ratio: persistent elevation for >12 months predicts a greater probability of non-remission or deterioration

Prognosis

Course: 30-50% remit (within 3 years)/30% progress/20-30% remain stable (over 5-10 years)

References

Pulmonary Hypertension

Pulmonary haemodynamics at rest and during exercise in patients with sarcoidosis. Respiration 1984;46:26–32
Pulmonary hypertension in advanced sarcoidosis: epidemiology and clinical characteristics. Eur Respir J 2005;25:783–8
Clinical predictors of pulmonary hypertension in sarcoidosis. Eur Respir J 2008;32:296–302
Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis. Thorax 2006;61:68–74
Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis. Chest 2006;129:1246-52
The pathology of pulmonary sarcoidosis: update. Semin Diagn Pathol. 2007 Aug;24(3):150-61 [MEDLINE]
Sarcoidosis-associated pulmonary hypertension: acute vasoresponsiveness to inhaled nitric oxide and the relation to long-term effect of sildenafil. Clin Respir J. 2009 Oct;3(4):207-13. doi: 10.1111/j.1752-699X.2008.00120.x [MEDLINE]
Survival in sarcoidosis-associated pulmonary hypertension: the importance of hemodynamic evaluation. Chest. 2010 Nov;138(5):1078-85. doi: 10.1378/chest.09-2002. Epub 2010 Mar 26 [MEDLINE]
Management of end-stage sarcoidosis: pulmonary hypertension and lung transplantation. Eur Respir J. 2012 Jun;39(6):1520-33. doi: 10.1183/09031936.00175511. Epub 2012 Jan 12 [MEDLINE]
The Clinical Features of Sarcoidosis: A Comprehensive Review. Clin Rev Allergy Immunol. 2014 Oct 2 (Epub ahead of print) [MEDLINE]
Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest. 2014 Apr;145(4):810-7. doi: 10.1378/chest.13-1766 [MEDLINE]

Diagnosis

An Official American Thoracic Society Clinical Practice Guideline: The Clinical Utility of Bronchoalveolar Lavage Cellular Analysis in Interstitial Lung Disease. Am J Respir Crit Care Med. 2012 May 1;185(9):1004-14. doi: 10.1164/rccm.201202-0320ST [MEDLINE]

Treatment

General

Recurrent sarcoid granulomas in a transplanted lung derive from recipient immune cells. Eur Respir J. 2005 Sep;26(3):549-52 [MEDLINE]
Lung transplantation for end-stage pulmonary sarcoidosis: outcome in a series of seven consecutive patients. Sarcoidosis Vasc Diffuse Lung Dis. 2005 Oct;22(3):222-8 [MEDLINE]
Lung transplantation in sarcoidosis. Semin Respir Crit Care Med. 2007 Feb;28(1):134-40 [MEDLINE]
Management of end-stage sarcoidosis: pulmonary hypertension and lung transplantation. Eur Respir J. 2012 Jun;39(6):1520-33. doi: 10.1183/09031936.00175511. Epub 2012 Jan 12 [MEDLINE]

Anti-Tumor Necrosis Factor-α Therapy (see Anti-Tumor Necrosis Factor-α Therapy,)

Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial. Eur Respir J. 2008;31(6):1189 [MEDLINE]
Efficacy of adalimumab in sarcoidosis patients who developed intolerance to infliximab. Respir Med. 2016 Jun;115:72-7. doi: 10.1016/j.rmed.2016.04.011. Epub 2016 Apr 23 [MEDLINE]
Anti-TNF-α therapy in refractory uveitis associated with sarcoidosis: Multicenter study of 17 patients. Semin Arthritis Rheum. 2015 Dec;45(3):361-8. doi: 10.1016/j.semarthrit.2015.05.010. Epub 2015 May 21 [MEDLINE]

Methotrexate (see Methotrexate)

Treatments for pulmonary sarcoidosis. Respir Med. 2008;102(1):1 [MEDLINE]
Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144(3):805 [MEDLINE]
Multinational evidence-based World Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinion of sarcoidologists worldwide. Curr Opin Pulm Med. 2013 Sep;19(5):545-61. doi: 10.1097/MCP.0b013e3283642a7a [MEDLINE]
Methotrexate as a single agent for treating pulmonary sarcoidosis: a single centre real-life prospective study. Pneumonol Alergol Pol. 2014;82(6):518-33. doi: 10.5603/PiAP.2014.0069 [MEDLINE]

Azathioprine (Imuran) (see Azathioprine

Treatments for pulmonary sarcoidosis. Respir Med. 2008;102(1):1 [MEDLINE]
Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144(3):805 [MEDLINE]

Calcium and Vitamin D

Calcium and vitamin D in sarcoidosis: how to assess and manage. Semin Respir Crit Care Med. 2010 Aug;31(4):474-84. doi: 10.1055/s-0030-1262215. Epub 2010 Jul 27 [MEDLINE]
Randomised controlled trial of vitamin D supplementation in sarcoidosis. BMJ Open. 2013 Oct 23;3(10):e003562. doi: 10.1136/bmjopen-2013-003562 [MEDLINE]
Calcium and vitamin D metabolism in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30(2):113-20 [MEDLINE]
Calcium and vitamin D in sarcoidosis: is supplementation safe? J Bone Miner Res. 2014 Nov;29(11):2498-503. doi: 10.1002/jbmr.2262 [MEDLINE]

Lung Transplant (seeLung Transplant)

Management of end-stage sarcoidosis: pulmonary hypertension and lung transplantation. Eur Respir J. 2012 Jun;39(6):1520-33. doi: 10.1183/09031936.00175511. Epub 2012 Jan 12 [MEDLINE]