Key Facts

Sarcoidosis is a multisystem disorder of unknown aetiology characterised by the formation of non-caseating granulomas in affected organs, most commonly the lungs, lymph nodes, skin, and eyes.

Epidemiology

• UK incidence: ~5-10 per 100,000 per year
• Afro-Caribbean populations: 3-4× higher incidence, more severe disease
• Peak onset: 25-40 years; second peak in women at 50-65
• Female slight predominance overall
• Scandinavian and Afro-Caribbean populations most affected

Aetiology

• Unknown; likely interplay of genetic susceptibility and environmental trigger
• Genetic: HLA-DRB1 associations; familial clustering
• Environmental: possible infectious trigger (mycobacteria, Propionibacterium acnes debated)
• Immune dysregulation: exaggerated Th1 immune response

Pathophysiology

• Activated CD4+ T helper cells (Th1) accumulate at sites of disease
• Release of cytokines (IL-2, IFN-γ, TNF-α) → macrophage activation → granuloma formation
• Non-caseating granulomas composed of epithelioid cells, multinucleated giant cells, and surrounding lymphocytes
• Granulomas may resolve, persist, or progress to fibrosis
• Hypercalcaemia: macrophages in granulomas express 1-alpha hydroxylase → unregulated conversion of 25-OH vitamin D to 1,25-OH vitamin D → increased calcium absorption

Pulmonary (>90%)

• Bilateral hilar lymphadenopathy (often incidental on CXR)
• Dry cough, breathlessness
• May be asymptomatic

Constitutional

• Fatigue (most common symptom), malaise, fever, weight loss

Skin (~25-35%)

• Erythema nodosum: tender red nodules on shins (Löfgren syndrome)
• Lupus pernio: violaceous plaques on nose, cheeks, ears (chronic, associated with pulmonary fibrosis)
• Papules, plaques, scar infiltration

Eyes (~25-50%)

• Anterior uveitis (most common ocular manifestation): pain, redness, photophobia
• Posterior uveitis, lacrimal gland enlargement, keratoconjunctivitis sicca

Other

• Liver: hepatomegaly, granulomatous hepatitis, raised ALP
• Spleen: splenomegaly
• Joints: polyarthralgia/arthritis (ankles most common)
• Neurological (~5%): cranial nerve palsies (VII most common), meningitis, hypothalamic/pituitary involvement, peripheral neuropathy
• Cardiac (~5%): conduction abnormalities, cardiomyopathy, sudden death
• Renal: hypercalcaemia, nephrocalcinosis, interstitial nephritis
• Parotid enlargement: Heerfordt syndrome (parotitis + uveitis + VII nerve palsy + fever)

Red Flags

• Cardiac sarcoidosis (arrhythmias, heart block, sudden death)
• Neurosarcoidosis (cranial nerve palsies, seizures)
• Progressive pulmonary fibrosis (stage IV)
• Severe hypercalcaemia
• Lupus pernio (marker of chronic disease)

Bedside

• CXR: staging (I-IV)
• ECG: conduction abnormalities (cardiac sarcoidosis)
• Pulse oximetry: baseline

Bloods

• Serum ACE: elevated in ~60-70% (non-specific; also elevated in TB, lymphoma, diabetes)
• Calcium: hypercalcaemia (~10-15%); check 24h urinary calcium
• FBC: lymphopenia, sometimes anaemia
• U&Es: renal function (hypercalcaemia, renal sarcoidosis)
• LFTs: raised ALP (hepatic granulomas)
• ESR/CRP: elevated in active disease
• Immunoglobulins: raised IgG
• Vitamin D: 1,25-OH vitamin D elevated (not 25-OH)

Imaging

• CXR staging:
  • Stage 0: normal
  • Stage I: bilateral hilar lymphadenopathy (BHL) alone
  • Stage II: BHL + pulmonary infiltrates
  • Stage III: pulmonary infiltrates without BHL
  • Stage IV: pulmonary fibrosis
• HRCT: lymphadenopathy, perilymphatic nodules (along fissures, bronchovascular bundles), ground-glass opacity, fibrosis
• PET-CT: assess disease activity, guide biopsy, cardiac sarcoidosis
• Cardiac MRI: if cardiac involvement suspected (late gadolinium enhancement)

Special Tests

• Tissue biopsy: non-caseating granulomas; endobronchial biopsy (EBUS), transbronchial biopsy, lymph node biopsy, skin biopsy
• BAL: lymphocytosis with raised CD4:CD8 ratio (>3.5 highly suggestive)
• Pulmonary function tests: restrictive or obstructive or mixed; reduced TLCO
• Ophthalmology slit-lamp examination: all patients at diagnosis (uveitis)
• Kveim test: historical — no longer used
• 24h Holter/cardiac MRI: if cardiac symptoms or ECG abnormalities

Non-pharmacological

• Many patients (especially Löfgren syndrome, stage I) require observation only
• Monitor FVC, TLCO, CXR every 3-6 months
• Sun protection and adequate hydration (hypercalcaemia risk)
• Avoid excess vitamin D/calcium supplementation

Pharmacological

Indications for treatment: symptomatic pulmonary disease (progressive dyspnoea, declining FVC), hypercalcaemia, neurological involvement, cardiac involvement, sight-threatening uveitis, disfiguring skin disease, hepatic involvement

First-line:

• Prednisolone 0.5mg/kg/day (typically 20-40mg/day) for 4-6 weeks, then taper over 6-12 months
• Maintenance: 5-10mg/day for 6-24 months total
• Bone protection: calcium + vitamin D (if normocalcaemic) + bisphosphonate if prolonged steroid use

Steroid-sparing agents (if steroid-dependent/intolerant):

• Methotrexate 10-25mg weekly (most commonly used; NICE off-label)
• Azathioprine 1-2mg/kg/day
• Mycophenolate mofetil 1-1.5g BD
• Hydroxychloroquine 200mg BD: particularly for skin and joint disease, hypercalcaemia

Refractory disease:

• Anti-TNF-α therapy: infliximab 3-5mg/kg (specialist use; evidence from case series)
• Consider clinical trial enrolment

Specific situations:

• Cardiac sarcoidosis: high-dose corticosteroids; consider ICD for VT/VF risk; methotrexate/infliximab
• Neurosarcoidosis: high-dose corticosteroids; consider infliximab for refractory

Surgical/Interventional

• Lung transplantation for end-stage pulmonary fibrosis
• ICD implantation for cardiac sarcoidosis with high arrhythmia risk

Referral Criteria

• All suspected sarcoidosis: respiratory referral for tissue diagnosis and staging
• Ophthalmology: all patients at diagnosis
• Cardiology: if cardiac involvement suspected
• Neurology: if neurological involvement
• Specialist sarcoidosis centre for complex/refractory disease

• ~60-70% resolve spontaneously (especially Löfgren syndrome — ~90% resolve within 2 years)
• ~10-30% develop chronic progressive disease
• ~5% die from sarcoidosis (pulmonary fibrosis, cardiac sarcoidosis, neurosarcoidosis)
• CXR stage I: ~60-80% spontaneous resolution
• CXR stage II: ~50-60% resolution
• CXR stage III: ~30% resolution
• CXR stage IV: irreversible fibrosis, poor prognosis
• Afro-Caribbean patients: more severe disease, worse prognosis
• Cardiac sarcoidosis: risk of sudden death; significant cause of mortality
• Lupus pernio: marker of chronic fibrotic disease with poor prognosis

CXR Staging and Prognosis

Löfgren Syndrome

Heerfordt Syndrome (Uveoparotid Fever)