Sarcoidosis
Exam Tips
- Diagnosis in exams is clinico-radiological plus histology: non-caseating granulomas after excluding TB/fungal infection and malignancy.
- Classic OSCE clue set: bilateral hilar lymphadenopathy + erythema nodosum + acute ankle arthritis (Lofgren syndrome) suggests good prognosis.
- Do not over-rely on serum ACE: supportive only, poor standalone diagnostic accuracy.
- If breathlessness seems out of proportion to spirometry, think pulmonary hypertension or cardiac sarcoidosis and escalate to echo/cardiac work-up.
- Remember hypercalcaemia mechanism (granuloma-driven calcitriol production) and advise reduced vitamin D/calcium exposure when elevated calcium is present.
- In viva questions, mention urgent specialist treatment for eye, cardiac, or neurological involvement to prevent irreversible organ damage.
Definition
Sarcoidosis is a multisystem inflammatory disease of uncertain cause, defined histologically by non-caseating granulomas in affected tissue after alternative causes (especially infection and malignancy) are excluded. It most often involves the lungs and intrathoracic lymph nodes, but can also affect skin, eyes, heart, liver, kidneys, and nervous system, giving a highly variable clinical presentation.
Pathophysiology
The core mechanism is dysregulated cell-mediated immunity: antigen-presenting cells activate CD4+ T cells (predominantly Th1/Th17 pathways), with cytokines such as TNF-alpha, IFN-gamma, IL-2 and IL-12 driving macrophage recruitment and granuloma formation. Granulomas are non-necrotising and can either resolve or progress to fibrosis (especially pulmonary upper-lobe fibrosis), causing restrictive lung disease and pulmonary hypertension. Macrophage 1-alpha-hydroxylase activity in granulomas increases extra-renal calcitriol production, which can cause hypercalcaemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis.
Risk Factors
- Age peak around 30-55 years
- Female sex (often older at diagnosis)
- Family/genetic susceptibility (including HLA-associated risk; higher risk in monozygotic twin pairs)
- African or African-Caribbean ancestry (worse prognostic profile also reported)
- Geographical clustering (for example Scandinavia)
- Possible environmental exposures: mould, silica/inorganic dusts, soil, wood-smoke exposure, insecticides, tree pollen
- Occupational associations: healthcare workers, firefighters, aircraft carrier personnel
- Potential infectious triggers (association rather than proven causation), including mycobacterial and some viral organisms
Clinical Features
Symptoms
- Dyspnoea, persistent dry cough, occasional wheeze, pleuritic/non-cardiac chest discomfort
- Constitutional symptoms: fatigue, fever, night sweats, anorexia, weight loss, diffuse myalgia
- Ocular symptoms: painful red eye, photophobia, blurred vision, watery eyes (often anterior uveitis)
- Cutaneous symptoms: tender shin nodules (erythema nodosum), facial/nasal plaques or nodules (lupus pernio), scar/tattoo infiltration, pigment change
- Upper airway symptoms: hoarseness, nasal blockage, recurrent sinus symptoms
- Cardiac symptoms: palpitations, syncope, exertional chest pain, heart failure symptoms
- Neurological symptoms: facial weakness (VII palsy), headache, seizures, encephalopathy
- Musculoskeletal symptoms: acute ankle/lower-limb arthralgia or arthritis
- Renal colic symptoms from nephrolithiasis in calcium dysregulation
Signs
- May be normal on chest examination in early disease
- Peripheral non-tender lymphadenopathy (commonly cervical/submandibular)
- Hepatomegaly (often non-tender)
- Erythema nodosum on shins; lupus pernio on nose/cheeks/ears/digits
- Uveitis signs on eye examination
- End-inspiratory crackles in fibrotic pulmonary disease
- Features of pulmonary hypertension/cor pulmonale in advanced disease
Investigations
Management
Lifestyle Modifications
- Many patients can be monitored without immediate drug treatment if mild disease and stable organ function
- Stop smoking and optimise exercise tolerance/pulmonary rehabilitation where breathless
- Avoid excess sunlight and vitamin D/calcium supplements in hypercalcaemia/hypercalciuria
- Vaccination review before immunosuppression (influenza, pneumococcal; avoid live vaccines once significantly immunosuppressed)
- Psychological support and fatigue management; screen for depression/anxiety
Pharmacological Treatment
Oral corticosteroid (first-line when treatment is indicated)
- Prednisolone 20-40 mg once daily for 4-6 weeks, then taper to lowest effective dose (often 5-10 mg daily maintenance)
Use for significant pulmonary symptoms, worsening lung function, or important extrapulmonary disease (cardiac, neuro, ocular risk to vision). Exclude active infection (especially TB) before prolonged steroids. Monitor BP, glucose/HbA1c, weight, mood, bone protection (consider calcium/vitamin D carefully if not hypercalcaemic, and bisphosphonate by fracture risk), cataract/glaucoma risk, and adrenal suppression.
Steroid-sparing immunosuppressants (specialist-led, usually second-line)
- Methotrexate 10-15 mg once weekly, titrated (commonly up to 20-25 mg once weekly) + folic acid 5 mg once weekly on a different day
- Azathioprine 1-2 mg/kg/day in divided doses
- Mycophenolate mofetil 500 mg twice daily, increased to 1 g twice daily as tolerated
Check baseline FBC, LFT, renal function; screen hepatitis B/C, HIV and TB risk before major immunosuppression. Methotrexate is teratogenic and contraindicated in pregnancy; avoid in significant liver disease/alcohol excess. Azathioprine requires TPMT (or NUDT15 where available) assessment before full dosing. Counsel on infection risk and myelosuppression; monitor bloods regularly.
Biologic therapy for refractory severe disease (specialist tertiary use)
- Infliximab 5 mg/kg IV at weeks 0, 2, 6 then every 8 weeks
- Adalimumab 40 mg subcutaneously every 2 weeks (regimen may vary by centre/indication)
Use after failure/intolerance of corticosteroid plus conventional steroid-sparing agents. Contraindicated in untreated latent/active TB and severe uncontrolled infection; caution in demyelinating disease and moderate-severe heart failure. Pre-treatment screening: TB, hepatitis B/C, HIV, varicella immunity.
Organ-specific adjuncts
- Hydroxychloroquine 200 mg once or twice daily (especially cutaneous sarcoidosis or hypercalcaemia)
- Topical corticosteroids (cutaneous lesions) and ophthalmic steroids/cycloplegics for anterior uveitis under specialist care
Hydroxychloroquine requires baseline and periodic retinal monitoring due to retinopathy risk. Ocular disease should be co-managed urgently with ophthalmology to prevent vision loss.
Surgical / Interventional
- Implantable cardioverter-defibrillator (ICD) or pacemaker for significant cardiac conduction disease/ventricular arrhythmia
- Lung transplantation assessment for end-stage fibrotic pulmonary sarcoidosis
- Selected advanced heart failure therapies (including transplantation) in severe cardiac sarcoidosis
Complications
- Chronic fatigue and reduced quality of life
- Depression and anxiety
- Progressive pulmonary fibrosis with chronic respiratory failure
- Pulmonary hypertension and cor pulmonale
- Bronchiectasis, cavitation, and Aspergillus colonisation
- Pneumothorax
- Cardiac arrhythmias, conduction block, sudden cardiac death
- Hypercalcaemia/hypercalciuria with nephrolithiasis or nephrocalcinosis
- Visual impairment from uveitis/optic involvement
- Adverse effects of long-term corticosteroids and immunosuppressants
Prognosis
Overall prognosis is often good: around two-thirds remit within 2-5 years, frequently without long-term treatment. Remission is more likely with stage I-II thoracic disease and presentations such as erythema nodosum; chronic disease develops in roughly 10-30%, and about a quarter develop residual fibrosis. Worse outcomes are linked to older age at presentation, African/African-Caribbean origin, lupus pernio, posterior uveitis, cardiac or CNS disease, severe calcium disturbance, and radiographic stage III-IV disease; mortality is mainly related to advanced lung disease/pulmonary hypertension and cardiac involvement.
Sources & References
🏥BMJ Best Practice(2)
💊BNF Drug References(8)
- Calcium acetate[cautions]
- Calcium carbonate[cautions]
- Calcium chloride[cautions]
- Calcium gluconate[cautions]
- Calcium lactate[cautions]
- Calcium phosphate[cautions]
- Calcium polystyrene sulfonate[contraindications]
- Colecalciferol[cautions]
✅NICE Guidelines(1)
- Sarcoidosis[overview]
📖Textbook References(6)
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1659, 1660)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 608, 609)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 608, 609)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 752, 753)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 753)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 752, 753)[context]