BOTTOM LINE

Sarcoidosis is a systemic inflammatory disorder characterized by noncaseating granulomas classically involving lungs causing a spectrum of disease from asymptomatic hilar adenopathy to progressive interstitial lung disease. Virtually any other organ can be affected; manifestations include uveitis, skin rash, inflammatory arthritis, myopathy, hepatic granulomas, lymphadenopathy, and peripheral/central nervous involvement. Cardiac sarcoid has high mortality; all patients should be screened with history, ECG, and echo at minimum. Unlike many rheumatological diseases, not all manifestations require treatment, and sarcoid can often resolve. Treatment, if indicated, includes steroids with/without steroid sparing agents like methotrexate, azathioprine, and TNF inhibitors.
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EPIDEMIOLOGY

Epidemiology varies depending on geographic and ethnic characteristics of population under study

• Population
  • Prevalence: 14/1,000,000 (Canada)
  • Incidence: 0.68/1,000,000 annually (Canada)
  • Ethnicity: all ethnicities affected
    • Highest among Scandinavian countries and patients of African origin
    • African: higher prevalence, younger onset, more severe disease compared to Caucasians or Asians
    • Japanese: higher prevalence of cardiac sarcoid
• Age, Sex
  • Sex: slight female predominance, 1.3-2.0:1, F:M.
  • Women more likely skin/eye sarcoid; Men more likely cardiac or severe respiratory sarcoid
  • Age: average age at onset 40-55 years
    • Men: younger peak age at diagnosis, 30-50 years
    • Women: older peak age at diagnosis, 50-60 years
• Risk factors
  • Genetic
    • Familial: Risk increases 2-4X if family member has sarcoid, risk increases with more family members
    • Twin studies: concordance rates 0.148 in monozygotic twins, 0.012 in dizygotic twins
    • Heritability of sarcoid ~39-70%
    • Various HLA Class II and non-HLA genes implicated in sarcoid risk
      HLA-DR3: association with Lofgren syndrome
  • Environmental
    • More frequent in spring and at higher latitudes
    • Obesity
    • Inhaled exposure (mold, insecticides, silica dust, firefighters, agricultural work)
    • Low socioeconomic status: more severe disease at diagnosis
    • Protective against sarcoid: smoking (nicotine) may be protective, later menopause, higher estrogen

CLINICAL MANIFESTATIONS

~95% of patients have pulmonary involvement, up to 30% can have extra-pulmonary sarcoid

—Pulmonary

• Upper Respiratory Tract (3%)
  • Larynx: supra>subglottic sarcoid, vocal cord rarely involved. Dysphagia, dyspnea, cough, hoarse
  • Sinonasal: sinus pain/pressure, nasal obstruction, epistaxis, nasal crusting, anosmia
• Lower Respiratory Tract (95%)
  • Onset varies from acute/symptomatic to incidental/asymptomatic and chronic/progressive
  • If symptomatic: Cough, dyspnea, wheezing, (pleuritic) chest pain, with systemic symptoms
  • Exam may show crackles; clubbing happens rarely if significant ILD
  • Pulmonary hypertension can occur in end-stage ILD from progressive sarcoid
  • Uncommon: lymphocytic pleural effusions, cavitating/necrotizing granuloma
• Imaging: X-rays: Abnormal in 90%
  • The stages below do not reflect disease activity, disease order, or functional deficits.
    The “radiographic stages” may be more accurately conceived of as “radiographic types”.

Stage	Findings	Spontaneous remission rate
Stage 0	Normal	—
Stage 1	Bihilar adenopathy	55-90%
Stage 2	Bihilar adenopathy, pulmonary infiltrates	40-70%
Stage 3	Pulmonary infiltrates, no bihilar adenopathy	10-20%
Stage 4	Pulmonary fibrosis	0-5%

• Imaging: CT
  • Lymph nodes
    • Mediastinal/hilar adenopathy
  • Inflammatory changes
    • Mid-upper zone ground glass, micro/nodular opacities along bronchovascular bundles.
    • Pleural/subpleural nodules; can become confluent and mass-like “galaxy sign” usually adjacent to airways, vessels, and subpleural locations
  • Fibrotic changes
    • Architectural distortion, fibrosis, hilar retraction, traction bronchiectasis, honeycombing, fibrocystic disease
• Imaging examples from Radiopedia.org
• Pulmonary function testing
  • Typically restrictive pattern and reduced DLCO
  • Abnormal PFT: Stage I (20%), stage II-IV (40-60%)
• Bronchoalveolar lavage
  • Lymphocytosis ≥25% may suggest granulomatous process on brochoalveolar lavage (BAL)
  • Not routine for diagnosis; may be done to exclude differentials (infection, malignancy)
  • May be done during endo/transbronchial biopsy, if biopsy needed

—Cutaneous

• Prevalence: (15-25%) 
• Non-specific
  • Erythema nodosum (20%), Calcinosis cutis, neutrophilic dermatoses
• Specific
  • Papular (face, eyelids, nasolabial folds), nodular, nodular-subcutaneous, maculopapular, plaque, psoriasiform, lupus pernio (plaque sarcoid, usually on central face, that scars and can infiltrate into cartilage and bone; increased risk of extra-cutaneous sarcoid), hypopigmented sarcoid, atrophic/ulcerative sarcoid
• Other
  • Scar sarcoid, Tattoo sarcoid (granuloma at site of scar or tattoo)

—Ocular

 All patients should have baseline screening ocular exam by optometry/opthalmology

• Prevalence: 10-50%
• Intra-ocular
  • Most common ocular sarcoid manifestation; generally bilateral (80-90%)
  • Anterior (41-75%) > posterior (28%) > pan (9-30%) > intermediate (6-10%) uveitis
  • Anterior uveitis: red, painful, photophobic red eye
  • Intermediate, posterior uveitis: can be painless with floaters
• Peri-ocular
  • Lacrimal glands, conjunctiva, extraocular muscles, and optic sheath
  • May present as periorbital pseudotumor, palpable mass

—Lymphatic

• Prevalence: 10-40%
• Cervical, supraclavicular, hilar, paratracheal, intra-abdominal lymph nodes.
• Consider malignancy (lymphoma) in differential

—Gastro-intestinal

• Liver: 5-15%
  • Twice more common in patients of African descent
  • Hepatic granuloma found in 50-65% on biopsy, but only 5-15% are symptomatic
  • If symptomatic: abdominal pain, pruritis; rarely fever, weight loss, cholestasis, jaundice, portal hypertension, and cirrhosis
• Other organ
  • Spleen: asymptomatic usually, can have left upper quadrant pain
  • Pancreas: rare, can be an asymptomatic pancreatic head mass
• Upper GI tract
  • Oral: nodules, edema, or ulcers on the mucosa, gingiva, lips, mouth floor, glands, tongue or palate
  • Esophageal: rare; dysphagia, dysmotility, weight loss. Endoscopic ulcers, plaques, or strictures
  • Stomach: post-prandial pain, nausea/vomiting, weight loss. Endoscopically normal or visible ulcers.
• Lower GI tract
  • Small bowel: rare; diarrhea, malabsorption, pain, hemorrhage
  • Large bowel: rare; nodules, polyps, ulcers, stenosis/obstruction, punctate bleeds
  • Can mimic Crohn’s disease
• Peritoneum
  • Ascites rare, transudative from heart failure/ portal hypertension; rare exudative ascites in cases where granuloma are on peritoneum or serosal surface liver  

—Musculoskeletal

• Inflammatory arthritis 0.5-25%
  • Acute inflammatory arthritis, usually with Lofgren’s syndrome, 5-10%
    • Lower-limb oligoarticular most common; mono/polyarticular less common
    • Ankles >  knees > wrists; rare small joint, tendinitis, enthesitis
    • Majority resolve within 6 weeks; 90% within first year
  • Chronic inflammatory arthritis in 1-2% of patients with arthritis
    • Usually older aged patients
    • Associated with lung and skin disease
    • Ankle, knees, hands, wrist, MCPs, rarely SI joints
• Myopathy: uncommon
  • More common in women; acute in younger patients (<40y), chronic in older
    • Chronic: insidious symmetrical proximal muscle weakness, ↑CK
    • Acute: painful proximal > distal muscle swelling, ↑CK; can happen with Lofgren’s
    • Nodular: single or multiple discrete tender muscle nodules; normal CK
    • Respiratory muscles can be affected
    • Rarely sole or initial sarcoid manifestation. Consider steroid myopathy as differential diagnosis.
• Bone: uncommon
  • Cystic, reticular, or destructive lesions in appendicular or axial skeleton
  • Usually asymptomatic but can be painful
  • Appendicular: commonly affects finger bones which can cause asymmetric dactylitis; also affects toes, humerus, or femur
  • Axial: lytic-appearing lesions in lower dorsal/upper lumbar spine; can effect any part of axial skeleton (ex: skull, sternum, pelvis reported)
  • Rarely the sole presentation of sarcoid

—Neurological

• Prevalence: 5%
• Central
  • Cranial nerves
    50-75% of neurosarcoid; most common CN VII, II, and VIII can cause facial palsy, visual, auditory and vestibular dysfunction.
  • Meninges
    10-20% of neurosarcoid; aseptic meningitis.
    CSF: lymphocytic pleocytosis, ↑protein, 20-40% have low glucose
  • Seizures
    5-10% of neurosarcoid; generalized tonic-clinic most common
  • Brain
    50% of neurosarcoid have parenchymal lesions, often at base of brain.
    Hypothalamic/pituitary lesions may manifest as various endocrinopathies (ex: hyperprolactinaemia, low testosterone/FSH/LH, diabetes insipidus)
  • Spine
    10% of neurosarcoid; may present as paraesthesias, weakness, ataxia, radiculopathy, autonomic dysreflexia, cauda equina, bladder dysfunction
  • Psychiatric
    20% of neurosarcoid; cognitive, mood, or behavioral changes
• Peripheral
  • 15% of neurosarcoid
  • Large fiber: mononeuropathy, polyradiculopathy, Guillan-Barre, polyneuropathy
  • Small-fiber: restless leg, paraesthesias, autonomic dysfunction, neuropathic pain
• Investigations
  • Imaging
    • MRI Brain
      • Leptomeningeal enhancement most common (basal predilection); ddx carcinomatosis, lymphoma, leukemia, TB or fungal meningitis
      • Enhancing lesions in parenchyma, midline structures, hypothalamus, pituitary, cranial nerves, dura; hydrocephalus
      • MR brain can be normal (ex: if cranial neuropathy only)
    • MRI Spine
      • Leptomeningeal/Intramedullary enhancement, cord edema/atrophy, Nerve root thickening—especially of the cauda equina
    • CSF studies
      • Normal in 1/3 of patients
      • Nonspecific lymphocytic pleocytosis, ↑protein, ↓glucose , ↑opening pressure; oligoclonal bands, ↑ACE concentration.
      • CSF ACE insensitive (24-55%) but specific (94-95%) for diagnosis
  • Other
    • Seizure activity may show on EEG
    • Cranial neuropathy and spinal cord lesions may be detected by visual, auditory, and somatosensory evoked potentials
    • Large fiber peripheral neuropathy may show on EMG

—Cardiac

All patients should be screened for cardiac sarcoid, given high mortality

• Prevalence 2-7%, occult myocardial involvement is likely much higher
• Ethnicity: cardiac sarcoid prevalence >25% in the Japanese cohorts, 5% in the American and European cohorts
• Screen with symptoms:  palpitations, pre/syncope, dyspnea, orthopnea
• Consider baseline testing in all: ECG; consider adding Holter monitor, Echo

• Dysrhythmias
  • AV block most common cardiac sarcoid manifestation (44%)
  • Tachy-arrythmias, supraventricular and ventricular
  • Sudden cardiac death: 25-65% of deaths attributed to sarcoidosis
• Cardiomyopathy, heart failure
  • Arrhythmogenic cardiomyopathy: heart block, arrhythmia
  • Dilated cardiomyopathy: Heart failure with reduced EF
  • Restrictive cardiomyopathy: heart failure with preserved EF
• Coronary
  • Rare coronary vasculitis and coronary dissection
• Testing
  • Baseline
    • ECG, Holter: ventricular premature beats, non/ sustained VT, AV block, atrial arrhythmias.
    • Echo: Focal increased wall thickness, focal akinesis/dyskinesis of wall, wall thinning or aneurysm. LVEF can be low (dilated cardiomyopathy) or normal (restrictive cardiomyopathy)
  • Advanced imaging
    • Cardiac MR:
      • Get if extracardiac sarcoid + cardiac symptoms or abnormal baseline cardiac testing
      • Late Gadolinium Enhancement (LGE): represents cardiac fibrosis; appears as multifocal, sub/mid epicardial LGE (i.e.: unlike an MI), or direct LGE extension from left to right ventricle.
      • Can also assess ventricular dysfunction, edema, and myocardial perfusion defects 
    • FDG-PET:
      • Get if indication for cardiac MR, however cardiac MR is unavailable or results are equivocal
      • Reveals focal myocardial uptake of radiotracer, indicating active sarcoid cardiomyopathy
  • Biopsy
    • Consider cardiac biopsy only if no other biopsy target available and confirmation is required
    • Noncaseating granulomas is a specific but insensitive finding

—Renal

• Nephrocalcinosis, Nephrolithiasis
  Granulomas increase 1,25-Vit D production and GI Ca²⁺ absorption, resulting in:
  • Hypercalciuria 40%
  • Hypercalcemia 2-20%
  • Calcium oxalate nephrolithiasis
  • Nephrocalcinosis: can get CKD and nephrogenic diabetes insipidus
• Interstitial Nephritis
  • Presents with ↑Creatinine. Urinalysis is normal or shows pyuria, proteinuria
  • Biopsy: interstitial infiltration (usually Monocytes), noncaseating granuloma, tubular injury, interstitial fibrosis. Can be nonspecific.
• Glomerulonephritis
  • Rare. Reported crescentic, membranous, membranoproliferative, focal segmental GN
  • Consider alternate diagnosis if GN present

—Glandular

• Exocrine
  • Painless swelling of salivary and parotid glands; Sicca syndrome
  • Gallium and PET scan: may show parotid gland uptake in patients
• Endocrine
  • Hypothalamic/pituitary lesions:
    • Abnormal ACTH, TSH, FSH, LH, IGF-1, prolactin
    • Presents as central diabetes insipidus, hypothalamic hypopituitarism, amenorrhea-galactorrhea, hypogonadotropic hypogonadism, and secondary hypothyroidism. 
  • Goiter, usually euthyroid but can be hypothyroid

—Specific Syndromes

• Lofgren’s Syndrome
  Migratory polyarthralgias, fever, erythema nodosum, bihilar adenopathy
  Often onset in spring months of the year
• Heerfordt’s Syndrome
  Parotid or salivary glands enlargement, facial nerve paralysis and anterior uveitis
  Rare sarcoid syndrome

INVESTIGATIONS

• CBC
  • Leukopenia, lymphopenia, anemia, thrombocytopenia, and/or pancytopenia may suggest sarcoidosis manifesting in bone marrow or spleen
• Creatinine, urinalysis
  • Baseline creatinine and urinalysis for renal sarcoid
• ALT, ALP
  • Baseline creatinine and urinalysis for renal sarcoid
• CK
  • Consider baseline if suspected muscle involvement
• Calcium, Vitamin D
  • Baseline for ?hypercalcemia; corrected for albumin
  • 25- and 1,25- OH vitamin D level; could be elevated in sarcoid
• ESR, CRP
  • May be elevated; non-specific
• Cardiac
  • Asymptomatic: (history/exam and) ECG for all; can consider echocardiogram (TTE) and 24h+ Holter monitor
  • Symptomatic: above investigations plus Cardiac MRI ± Cardiac PET (depending on availability)
• Pulmonary
  • X-ray chest, CT chest, Pulmonary function tests in all patients (particularly if symptomatic)
  • If suspected pulmonary hypertension: TTE, if suspicious, follow-up with right-heart catheterization
• Serum ACE level
  • Serum Angiotensin converting enzyme (ACE); not ordered routinely
  • Elevated serum ACE reflects general burden of granuloma
  • Sensitivity 41% – 100%, Specificity 83% – 99% for sarcoidosis
  • Variation in literature due to different assays, cutoffs, cohorts, sarcoid definition, ACE-inhibitor drugs, genetics
  • Serum ACE >2x upper limit normal or >50 U/L may be specific for sarcoidosis
• Soluble IL-2 receptor (sIL-2R)
  • Increased in many sarcoid patients
• Imaging
  • Additional imaging depending on clinical manifestations (see above)
  • Nuclear imaging (ex: 18F-FDG-PET) may help identify occult lesions for potential biopsy
• Bronchoscopy
  • Endoscopically: may show “cobble stone” appearance of endobronchial granulomas
  • Histologically: transbronchial biopsy may confirm granulomatous inflammation
  • Lavage: supportive findings include lymphocytosis with increased CD4+ T cell/CD8+ T cell ratio (>3.5) or a decreased CD4+CD103+ T cell/CD4+ T cell ratio (<0.2). Also helpful to exclude infection
• Other
  • Ocular
  • Infection
    • Consider TB skin test or interferon-gamma release assay
    • Consider HIV testing (can present with adenopathy and granuloma)
    • Consider quantitative immunoglobulins for ?CVID (can present with adenopathy and granuloma)
  • Auto-antibodies
• Biopsy
  • High clinical suspicion
    • Sarcoid syndrome (ex: Heerfordt’s, Lofgren’s, lupus pernio, multiple compatible symptoms )
    • No biopsy
  • Intermediate suspicion
    • Ex: asymptomatic bihilar adenopathy, possible compatible syndrome
    • Consider biopsy versus clinical monitoring ± empiric treatment
  • Biopsy
    • Target
      • If thoracic lymph node, endobronchial ultrasound guided suggested
      • Other target (ex: skin, sural nerve, submandibular glands) depends on presentation
    • Histology
      • Non-necrotizing/caseating granuloma made up of epithelial cells, monocytes, lymphocytes, macrophages, fibroblast; multinucleated giant cells are common

DIAGNOSIS

Suspect sarcoid in patients, usually 20-60 years old, presenting with a compatible clinical presentation which may include bihilar adenopathy and/or interstitial lung disease with systemic features which can include Lofgren’s syndrome, submandibular swelling, lupus pernio, uveitis, optic neuritis, cranial neuropathy erythema nodosum or hypercalcemia. All suspected patients should be screened for cardiac involvement with history and ECG; further cardiac testing with TTE, Holter, Cardiac MR/PET can be considered if symptomatic and high suspicion. In patients with intermediate suspicion for sarcoid, a tissue biopsy showing non-necrotizing granuloma is helpful. Differential diagnoses should be considered (below), and this clinical diagnosis requires ongoing re-evaluation and consideration. A diagnosis of sarcoidosis is made in the first physician visit in only 15% of cases.

DIFFERENTIAL DIAGNOSIS

Cancer	Lymphoma, nearby tumours can manifest non-necrotizing granuloma on biopsy
Infection	Mycobacteria (TB), fungal infections (aspergillosis) cause granulomatous inflammation
Exposure	Pneumoconioses (silicosis, berylliosis, talc, zirconium), hypersensitivity pneumonitis
Rheumatologic	GPA vasculitis, IgG4-RD
Immunologic	Common-variable immunodeficiency (CVID)
Drug	Drug-induced granulomas (ex: immune checkpoint inhibition, chemotherapy, TNF inhibitors, HAART therapy)

TREATMENT

Sarcoidosis may resolve spontaneously, but this is difficult to predict. Inflammatory markers do not necessarily suggest poor prognosis.

Risk-stratify patients based on indications below (severity, progression, reversibility), quality of life, treatment-related risks

Most treatment guidelines/recommendations are based on low-quality evidence and expert opinion

— Treatment initiation

• Asympomatic
  • Consider watchful waiting, or treat if danger of organ dysfunction (below)
• Indications to treat include
  • Consider treating if symptoms are affecting quality of life and are attributable to reversible inflammation from sarcoidosis, such as the indications below, based on shared decision with patient and other specialists

Respiratory	Severe or progressive deterioration in FVC and/or DLCO, moderate-severe radiographic fibrosis, pre-capillary pulmonary hypertension
Cardiological	Age >50, Dysrhythmias, high-degree heart block, cardiomyopathy, CHF LVEF <40% NYHA III-IV
Opthalmologic	Persistent uveitis
Neurological	Symptomatic central and peripheral manifestations, meningitis, diabetes insipidus
Endocrinology	Hypercalcemia, recurrent nephrolithiasis
Dermatologic	Cosmetically or otherwise significant cutaneous sarcoid, lupus pernio
Gastrointestinal	Pronounced liver abnormalities, splenomegaly, thrombocytopenia

— Therapeutic Choices

• “First line”
  • Prednisone, initial dose 0.5-0.75mg/kg/day or 20mg/d for 4 weeks, tapered to 5mg/d or less by 6-12 months
• “Second line”
  • Add to prednisone first or second line if difficult to treat or unfavourable steroid comorbidities (ex: diabetes)
    • Methotrexate 15-25mg/week
    • Azathioprine 1-2mg/kg/day
    • Leflunomide 10-20mg/d
    • Mycophenolate mofetil 500-1500mg BID
    • Hydroxychloroquine 5mg/kg/day
• “Third line”
  • Infliximab 3-5mg/kg IV week 0, 2, and q4-6 weeks
  • Adalimumab 40mg SC q1-2 weeks
• Severe, refractory
  • Rituximab 500-1000mg IV q6 months
  • Cyclophosphamide (can use dosing regimen used for ANCA vasculitis)

Always reconsider diagnosis if ongoing, severe, refractory sarcoidosis

— Organ-Specific Treatment

• Respiratory
  • Low Risk
    • Observe, treat with glucocorticoids if progression (see indications above)
  • Intermediate or high risk
    • Prednisone 20mg/d x 4 weeks, taper <5mg/d in 6-12 months
    • Add methotrexate (MTX) if difficult to control disease or intolerance to prednisone
    • Switch, if MTX intolerant, to: azathioprine, leflunomide, mycophenolate mofetil
    • Add TNF inhibitor (ex: infliximab or adalimumab) if progression despite methotrexate
    • Switch to rituximab or JAK inhibitor if progression despite TNF inhibition
  • Progressive fibrotic ILD
    • Role of anti-fibrotics, such as nintendinib and pirfenidone, unknown
• Cutaneous
  If cosmetically important, significant surface area, or lupus pernio:
  • Topical or oral glucocorticoids
  • Add Methotrexate, hydroxychloroquine, TNF inhibitor if refractory disease
  • Apremilast, tofacitinib also described
• Cardiological
  If clinically relevant cardiac sarcoid, including dysrhythmias, high-degree heart block, cardiomyopathy, CHF
  • Prednisone 0.50-0.75mg/kg/day tapered to 5mg or less by 12+ months
    ± Methotrexate; azathioprine, leflunomide or mycophenolate mofetil
  • Add TNF inhibitor or cyclophosphamide for refractory or relapsing disease
  • Pacemaker, implanted cardioverter defibrillator: as indicated by cardiology consultation
• Neurological
  • Symptomatic
    • Prednisone 0.5-1.0 mg/kg/day x 4-6 weeks, tapering 0.1-0.25mg/kg/day for total 1 year
      ± Methotrexate; azathioprine, leflunomide or mycophenolate mofetil
    • Severe or refractory neurosarcoidosis: infliximab or IV cyclophosphamide
  • Small-fiber neuropathy
    • Mild non/disabling nuisance symptoms: watchful waiting
    • Severe/disabling symptoms: no strong evidence for immunotherapy
• Inflammatory Arthritis
  • Treatment approach similar to rheumatoid or psoriatic arthritis
  • NSAIDs, can consider intra-articular steroids or prednisone 20mg/d with quick taper
  • Persistent disease: consider adding methotrexate, leflunomide, hydroxychloroquine, azathioprine, or TNF inhibitor

PROGNOSIS

• Global sarcoidosis mortality: 9-14 cases/1,000 person-years
• 5-year survival 93-95%
• Natural history:
  • Self-limited, chronic but stable, or chronic-progressive disease course
  • Spontaneous resolution in50% within 2-5 years; remission much less likely after 5 years.
• Morbidity:
  • Higher risk of infection, congestive heart failure, stroke, VTE, cancer risk (including skin cancer, hematologic, colorectal)
  • Higher risk of other autoimmune disease (thyroiditis, Sjogren’s, ankylosing spondylitis, systemic lupus erythematosus)
• Risk factors for mortality
  • African women 2.4X increased mortality risk
  • Severe disease at diagnosis (ex: Stage IV pulmonary sarcoid)
  • Cardiac sarcoidosis
  • Neurosarcoid
  • Male sex

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