Sarcoidosis
Description
- Multisystem granulomatous disease of unknown cause
- Defining lesion: non-caseating (non-necrotising) epithelioid cell granuloma
- *A diagnosis of exclusion - compatible clinical picture + granulomas + no alternative cause*
Organ involvement
| Organ | Frequency | Presentation |
|---|---|---|
| Lung | 89-99% | Cough, dyspnoea, wheeze, stridor |
| Skin | 16-32% | Lupus pernio, nodules, plaques, infiltration of old scars and tattoos |
| Eye | 5-23% | Painful red eye, uveitis |
| Liver | 12-20% | Deranged LFTs (cholestatic), abdominal pain |
| Lymph nodes | 13-15% | Peripheral lymphadenopathy |
| Spleen | 5-10% | Splenomegaly, abdominal pain, cytopenias |
| Nervous system | 3-9% | Facial palsy, headache, gait disturbance, hearing loss, paraesthesia |
| Heart | 2-5% clinically (~25% at autopsy) | Conduction block, VT, heart failure, syncope, sudden death |
Named syndromes
- Lofgren syndrome - erythema nodosum + bilateral hilar lymphadenopathy + fever + arthralgia (typically ankles)
- *Acute, self-limiting, >80-90% spontaneous resolution - a good-prognosis presentation that needs no biopsy*
- Heerfordt syndrome (uveoparotid fever) - uveitis + parotid enlargement + fever + facial nerve palsy
- Blau syndrome - genetic (NOD2) granulomatous disease of childhood; not sarcoidosis
Epidemiology
- Prevalence ~10-40/100,000; bimodal peaks at 25-35 and 45-65 (second peak more prominent in women)
- F slightly > M
- Much higher incidence and severity in people of African ancestry (~3x, more chronic and multi-organ); Scandinavian populations have high incidence but more Lofgren and better outcomes
- Familial clustering - ~5x risk in first-degree relatives
Aetiopathogenesis
- Exaggerated Th1/Th17 response to an unidentified antigen in a genetically susceptible host
- Antigen -> APC presents on HLA class II -> CD4 Th1 cells -> IFN-gamma, IL-2, TNF-alpha -> macrophage aggregation -> epithelioid and giant cells -> non-caseating granuloma
- TNF-alpha maintains the granuloma - the rationale for infliximab, and the reason TNF inhibitors used for other diseases can cause a sarcoid-like reaction
- Fibrosis in a minority - Th2/TGF-beta shift
Genetics and triggers
- *HLA-DRB103:01 -> Lofgren syndrome and spontaneous resolution*; DRB115:01 -> chronic disease
- BTNL2, ANXA11
- Candidate triggers: *mycobacterial (mKatG) and Cutibacterium acnes antigens, inorganic dust, World Trade Center dust*, silica, insecticides
- *Not infectious and not transmissible*
Hypercalcaemia mechanism
- Activated macrophages within granulomas express 1-alpha-hydroxylase
- -> unregulated conversion of 25-OH to 1,25-(OH)2 vitamin D (calcitriol) - not under PTH control
- -> inc intestinal calcium absorption -> hypercalciuria (more common) then hypercalcaemia
- PTH suppressed, calcitriol high, 25-OH vitamin D often low or normal
- *Vitamin D supplementation can precipitate hypercalcaemia - a classic trap*
Diagnosis
Chest radiographic (Scadding) stages - prognosis, not severity
| Stage | Finding | Spontaneous resolution |
|---|---|---|
| 0 | Normal | - |
| I | Bilateral hilar lymphadenopathy alone | ~60-90% |
| II | BHL + parenchymal infiltrates | ~40-70% |
| III | Parenchymal infiltrates alone | ~10-20% |
| IV | Fibrosis, volume loss, honeycombing | 0% |
Imaging
- HRCT - the leading modality
- Upper- and mid-zone predominant, perilymphatic micronodules along bronchovascular bundles and fissures
- "Bronchovascular beading", subpleural nodules
- Advanced: upper-lobe fibrosis, traction bronchiectasis, hilar retraction, conglomerate masses
- Contrast IPF: lower-zone, subpleural, honeycombing
- FDG-PET - high value for occult disease, particularly cardiac and for identifying an active biopsy target
- Cardiac MRI with late gadolinium enhancement - basal septal and mid-wall patterns
- Bronchoscopy: endobronchial "cobblestoning"
Laboratory
- Hypercalcaemia (~10%) and hypercalciuria (~30-50%) with suppressed PTH and raised calcitriol
- Raised serum ACE (~60%) - reflects granuloma burden. Poor sensitivity and specificity - not diagnostic, and only marginally useful for monitoring**
- False positives: TB, histoplasmosis, hyperthyroidism, diabetes, silicosis, leprosy, lymphoma
- ACE inhibitors suppress the level
- Polyclonal hypergammaglobulinaemia (raised IgG), raised soluble IL-2 receptor
- Lymphopenia, anergy to tuberculin, raised ALP (hepatic), raised creatinine
- Raised 24-h urinary calcium - the earliest calcium abnormality
Tissue diagnosis
- Biopsy the most accessible involved site: skin, peripheral node, lip/minor salivary gland, conjunctival nodule
- EBUS-TBNA of mediastinal nodes is the pulmonary procedure of choice (yield >80%, higher than transbronchial biopsy)
- BAL: lymphocytosis with CD4:CD8 ratio >3.5 (specific ~95%, sensitive only ~50%)
- Always send tissue for mycobacterial and fungal stain and culture - TB is the mimic that must be excluded
- *Biopsy is NOT required in classic Lofgren syndrome or asymptomatic stage I disease*
Mandatory screening at diagnosis
- ECG in everyone; echocardiogram + cardiac MRI or PET if any cardiac symptom or ECG abnormality
- Ophthalmology review in everyone (uveitis is frequently asymptomatic)
- Serum calcium, 24-h urinary calcium, creatinine, LFTs
- PFTs including DLCO and CXR; 6-minute walk
- FBE, TSH
Differential for non-caseating granulomas
- TB and non-tuberculous mycobacteria, fungal infection
- Berylliosis (clinically identical - occupational history + beryllium lymphocyte proliferation test)
- Hypersensitivity pneumonitis, lymphoma, GPA, Crohn disease, PBC
- Drug reaction - TNF inhibitors, checkpoint inhibitors, interferon
- Sarcoid-like reaction in nodes draining a malignancy
- Common variable immunodeficiency (GLILD)
Management
Axis: treat only when organ function or quality of life is threatened. Many patients need no treatment at all.
A. When NOT to treat
- Asymptomatic stage I or II pulmonary disease with normal lung function
- Lofgren syndrome - NSAIDs and observation only
- Isolated hypercalciuria without hypercalcaemia
- Observation with 3-6 monthly PFTs and CXR
B. Indications to treat
- Absolute: cardiac, neurological, ocular (sight-threatening), hypercalcaemia, renal involvement
- Progressive or symptomatic pulmonary disease, declining FVC or DLCO
- Disfiguring skin disease (lupus pernio), severe constitutional symptoms
C. Therapy tiers
- 1. Oral prednis(ol)one - typically 20-40 mg/day, taper over 6-12 months minimum
- Higher doses (1 mg/kg) for cardiac, neurological and ocular disease
- Relapse on withdrawal is common - many need low-dose maintenance
- 2. Steroid-sparing agent - add if relapse, steroid dependence, or intolerance
- Methotrexate is the preferred second-line agent
- Azathioprine, mycophenolate, leflunomide
- Hydroxychloroquine - particularly useful for skin disease and hypercalcaemia
- 3. TNF inhibitors for refractory disease
- Infliximab (best evidence) or adalimumab
- Screen for TB first - and remember TNF inhibitors themselves cause sarcoid-like reactions
- *Cyclophosphamide has no established benefit in pulmonary sarcoidosis* - reserved for severe refractory neurosarcoidosis
- Rituximab, JAK inhibitors: emerging in refractory disease
D. Organ-specific
- Cardiac: high-dose steroid + steroid-sparing agent; ICD for VT, LVEF <35%, or extensive scar on MRI (conduction disease alone may need a pacemaker; consider an ICD rather than a pacemaker given the arrhythmic risk); heart failure therapy
- Neurosarcoidosis: high-dose steroid; early infliximab increasingly used first-line for severe disease
- Hypercalcaemia: steroid (rapidly effective), hydration, avoid vitamin D and calcium supplements, avoid sun exposure, low-calcium diet; bisphosphonate if persistent
- Ocular: topical + systemic steroid, methotrexate, adalimumab
- Advanced fibrotic lung disease: oxygen, pulmonary rehabilitation, transplant assessment; antifibrotic if a progressive pulmonary fibrosis phenotype; treat pulmonary hypertension and aspergilloma
- Fatigue - common, often persists after inflammation is controlled; does not respond to escalating immunosuppression. Exercise, small-fibre neuropathy assessment
E. On treatment
- Bone protection with prolonged glucocorticoid (but check calcium first - vitamin D can precipitate hypercalcaemia)
- PJP prophylaxis if prednisolone >=20 mg for >4 weeks with a second agent
- Monitor PFTs, calcium, renal and liver function 3-6 monthly
Associations
- Lupus pernio - violaceous indurated plaques on nose, cheeks and ears; marks chronic disease with pulmonary and upper airway involvement, and predicts poor response to steroid alone
- Erythema nodosum - the opposite: acute, good prognosis
- Infection - HR ~2.1 (higher on immunosuppression)
- Heart failure - HR ~1.7-2.7
- Stroke - HR ~3.3
- VTE - HR ~2-4
- Autoimmune disease: Sjogren syndrome HR ~11.6, ankylosing spondylitis HR ~3.8, SLE HR ~3.0, autoimmune thyroiditis HR ~1.3
- Malignancy: haematological RR ~1.92, skin RR ~2.0, upper GI RR ~1.73, liver RR ~1.79, kidney RR ~1.55, colorectal RR ~1.33
- Nephrolithiasis and nephrocalcinosis (hypercalciuria); granulomatous interstitial nephritis
- Small-fibre neuropathy and chronic fatigue
- Hypopituitarism (hypothalamic/pituitary granulomas -> diabetes insipidus)
Natural history & complications
- ~2/3 remit spontaneously, usually within 2-3 years; ~1/3 develop chronic or progressive disease
- Stage at presentation predicts resolution (stage I ~60-90%, stage IV 0%)
- Relapse after stopping steroid is common; relapse after >1 year off treatment is unusual
- Overall mortality 1-8% - from advanced pulmonary fibrosis with pulmonary hypertension, cardiac disease and neurosarcoidosis
- Cardiac and neurological involvement are the causes of death in developed settings
Good prognosis
- Lofgren syndrome, erythema nodosum, *HLA-DRB103:01**
- Stage I disease, acute onset, younger age
Poor prognosis
- Lupus pernio
- Chronic uveitis, cardiac and neurological involvement
- Stage III/IV fibrotic lung disease, low DLCO
- Pulmonary hypertension (the strongest predictor of mortality in advanced disease)
- Nephrocalcinosis and chronic hypercalcaemia
- Age >40 at onset, African ancestry, splenomegaly, extensive skin disease
Complications
- Pulmonary fibrosis, pulmonary hypertension, aspergilloma in cavities, haemoptysis
- Sudden cardiac death, complete heart block, ventricular arrhythmia
- Blindness from chronic uveitis, glaucoma, cataract
- Nephrocalcinosis, renal stones, CKD
- Hypopituitarism; cranial neuropathies
- Glucocorticoid toxicity - frequently exceeds the burden of the disease
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