Sarcoidosis — Causes, Granulomas, Löfgren Syndrome & Steroid Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Sarcoidosis is a systemic granulomatous disease of unknown aetiology characterised by the formation of non-caseating (non-cheesy) granulomas — organised collections of immune cells (predominantly CD4+ T helper cells, macrophages, and epithelioid cells) — that can affect virtually any organ. The lungs and mediastinal lymph nodes are involved in over 90% of cases, but sarcoidosis can affect the skin (25%), eyes (25%), liver (25%), heart (5–10%), nervous system (5–10%), and many other organs. It most commonly affects adults aged 25–45 years and is significantly more prevalent in Black Americans (prevalence 35–80 per 100,000, threefold higher than White Americans) and in Scandinavian populations (particularly Sweden and Denmark). The clinical course is highly variable — 60–70% of patients have spontaneous remission within 2–3 years; 20–30% have persistent or progressive disease; approximately 5% develop severe organ damage or die from the disease.

The precise aetiology of sarcoidosis remains unknown — it is thought to result from an exaggerated granulomatous immune response to environmental, occupational, or infectious antigens in genetically susceptible individuals. Proposed triggers: microbial antigens (Mycobacterium tuberculosis and Propionibacterium acnes proteins — molecular mimicry or persistent antigen stimulation); organic dusts and aerosols (wood dust, mould, metal dusts); occupational exposures (firefighters — first responders to the World Trade Center attacks had significantly elevated sarcoidosis rates; farming; stone cutting). Genetic susceptibility: HLA-DRB1 and HLA-DQB1 alleles are strongly associated with sarcoidosis and specific disease phenotypes — HLA-DRB1*03 is associated with Löfgren syndrome (acute, self-limiting sarcoidosis with good prognosis). Immune dysregulation: impaired regulatory T cell function allows unchecked CD4+ T helper cell activation and macrophage accumulation; TNF-alpha plays a central role in granuloma formation and maintenance — explaining why anti-TNF therapy (infliximab) is effective in refractory sarcoidosis. Familial clustering: first-degree relatives have a 3.6–4.7-fold increased risk — supports a genetic component.

Pulmonary sarcoidosis (90%): dry cough, exertional breathlessness, and chest tightness — often insidious; incidentally discovered on chest X-ray in 30–60% of cases (bilateral hilar lymphadenopathy — BHL — the classic radiological sign). Löfgren syndrome (acute sarcoidosis): the classic acute presentation — triad of bilateral hilar lymphadenopathy, erythema nodosum (raised, tender, red nodules on the shins), and polyarthritis/periarthritis (predominantly ankle joints); accompanied by fever, malaise, and uveitis; strongly associated with HLA-DRB1*03 — carries an excellent prognosis with spontaneous resolution in 85–90% within 2 years. Cutaneous manifestations: erythema nodosum (non-specific); lupus pernio (indurated, violaceous plaques on the nose, cheeks, and ears — highly specific for chronic sarcoidosis); scar sarcoidosis (granulomas infiltrating old scars or tattoos). Ocular sarcoidosis: anterior uveitis (red eye, pain, photophobia, blurred vision — may be asymptomatic); posterior uveitis; chorioretinitis; optic neuritis. Cardiac sarcoidosis (5–10% clinically, 25% in autopsy series): heart block (first, second, or third degree — Holter monitoring); ventricular arrhythmias (can cause sudden cardiac death); cardiomyopathy; pericardial effusion. Neurosarcoidosis (5%): facial nerve palsy (commonest); diabetes insipidus (hypothalamic granulomas); meningitis; peripheral neuropathy. Hypercalcaemia: granulomas express 1-alpha-hydroxylase enzyme — excessive conversion of 25-OH vitamin D to 1,25-(OH)2 vitamin D (calcitriol) — causes elevated serum calcium in 10–15%; symptoms include polydipsia, polyuria, constipation, renal stones.

Diagnosis of sarcoidosis requires a compatible clinical and radiological picture, histological demonstration of non-caseating granulomas on biopsy, and exclusion of other causes (TB, fungal infections, malignancy, foreign body granulomas). Chest X-ray: bilateral hilar lymphadenopathy (BHL) is the most common finding; Scadding staging: Stage 0 (normal); I (BHL alone); II (BHL + pulmonary infiltrates); III (infiltrates without BHL); IV (pulmonary fibrosis). HRCT chest: more sensitive than CXR — shows perilymphatic nodules (along bronchovascular bundles, fissures, and pleura), peri-bronchial thickening, mediastinal lymphadenopathy. Serum angiotensin-converting enzyme (ACE): elevated in approximately 60% of active pulmonary sarcoidosis — useful for monitoring disease activity but non-specific (normal ACE does not exclude sarcoidosis). Serum calcium: hypercalcaemia in 10–15%; elevated 24-hour urinary calcium. 24-hour urinary calcium: more sensitive than serum calcium for detecting calciuria. Serum lysozyme: elevated in active disease. Pulmonary function tests: restriction (reduced TLC, FVC, DLCO) in parenchymal disease; obstruction (reduced FEV1/FVC) in endobronchial involvement. ECG and Holter monitoring: mandatory in all newly diagnosed sarcoidosis to detect cardiac involvement. Cardiac MRI with gadolinium: gold standard for cardiac sarcoidosis — late gadolinium enhancement in a non-coronary distribution. Ophthalmological slit-lamp examination: for all newly diagnosed sarcoidosis — detects subclinical uveitis. Biopsy: transbronchial lung biopsy (TBLB) during flexible bronchoscopy — non-caseating granulomas in bronchial mucosa, peribronchial tissue, or lung parenchyma (yield 70–90% in pulmonary sarcoidosis); EBUS-TBNA (endobronchial ultrasound-guided transbronchial needle aspiration) of mediastinal lymph nodes (yield >80%). Skin or lymph node biopsy: if skin lesions or palpable nodes present — easier to access than lung. Serum and urine tests to exclude other causes: Mantoux/IGRA test (TB); calcium, phosphate, PTH (hyperparathyroidism); serum protein electrophoresis (lymphoma).

Indications for treatment: not all sarcoidosis requires treatment — many patients have self-limiting disease. Treatment is indicated for: progressive symptomatic pulmonary disease (worsening breathlessness, declining FVC by >10%); hypercalcaemia or nephrocalcinosis; cardiac sarcoidosis (heart block, arrhythmias, cardiomyopathy); neurosarcoidosis; ocular sarcoidosis not responding to topical treatment; significant skin involvement (lupus pernio); hepatic or splenic involvement causing organ dysfunction. Acute Löfgren syndrome: NSAIDs (ibuprofen, indomethacin) — usually sufficient for arthritis and fever; spontaneous resolution in 85–90%. Corticosteroids (first-line treatment for significant organ involvement): prednisolone 20–40 mg/day for pulmonary sarcoidosis; taper over 6–12 months targeting 7.5–10 mg/day maintenance dose; 50–70% improvement in symptoms and radiological findings. Steroid-sparing agents (to reduce long-term steroid exposure): methotrexate 10–15 mg weekly — most widely used; azathioprine 1.5–2 mg/kg/day; hydroxychloroquine 200–400 mg/day (particularly effective for cutaneous sarcoidosis, fatigue, and hypercalcaemia — lower cost, good tolerability). Anti-TNF therapy (refractory sarcoidosis): infliximab 3–5 mg/kg IV (8-weekly) — effective in chronic, progressive, treatment-resistant sarcoidosis (CRYSTAL trial); used under specialist supervision. Cardiac sarcoidosis: corticosteroids (reduce inflammation and prevent progression); implantable cardioverter-defibrillator (ICD) for ventricular arrhythmias or severe LV dysfunction (EF below 35%); cardiac pacing for complete heart block; cardiac transplantation in end-stage refractory disease. Hypercalcaemia: prednisolone (reduces calcitriol production); hydroxychloroquine; ketoconazole (reduces calcitriol synthesis); avoid excess vitamin D and sunlight; ensure adequate hydration. Inhaled corticosteroids (ICS): modest benefit for cough and endobronchial disease but do not alter the natural history of pulmonary sarcoidosis.

While 60–70% of sarcoidosis patients experience spontaneous remission, a significant minority develop progressive, organ-threatening complications. Pulmonary complications: progressive pulmonary fibrosis (Scadding stage IV) leads to irreversible restrictive lung disease, chronic hypoxia, pulmonary hypertension, and respiratory failure in approximately 5% of patients; bronchiectasis and mycetoma (Aspergillus colonisation of fibrotic cavities) can cause life-threatening haemoptysis. Cardiac sarcoidosis: the most dangerous complication — granulomatous infiltration of the myocardium causes complete heart block (requiring permanent pacemaker), ventricular arrhythmias, sudden cardiac death, and dilated cardiomyopathy; cardiac sarcoidosis accounts for up to 85% of sudden sarcoidosis-related deaths in Japan and is a significant cause in Western countries. Ocular complications: chronic anterior or posterior uveitis causes cataracts, glaucoma, macular oedema, and irreversible visual loss if untreated; routine ophthalmological monitoring is mandatory for all sarcoidosis patients. Neurosarcoidosis: cranial nerve palsies (particularly VII — causing facial palsy), meningitis, hydrocephalus, hypothalamic-pituitary dysfunction, and spinal cord granulomas causing paraplegia; affects 5–10% of sarcoidosis patients and is often difficult to treat. Renal complications: nephrocalcinosis from hypercalcaemia, nephrolithiasis (renal stones), and granulomatous interstitial nephritis causing chronic kidney disease. Lupus pernio: disfiguring purple-red indurated facial granulomatous skin plaques — indicate chronic systemic disease. Bone and joint complications: cystic bone lesions (phalanges) and chronic arthritis. Corticosteroid treatment complications: osteoporosis, diabetes, hypertension, Cushingoid features, avascular necrosis, cataracts, and increased infection risk are significant long-term consequences.

No preventive strategies exist for sarcoidosis as the trigger is unknown. However, early diagnosis and monitoring prevent end-organ damage. All patients with confirmed sarcoidosis should be enrolled in regular specialist follow-up for monitoring of disease activity and organ function. Monitoring schedule (typically every 3–6 months during active disease): chest X-ray and/or HRCT (annually or more frequently if disease is active); pulmonary function tests; serum ACE, calcium, LFTs, renal function; ECG and Holter monitoring (annual or more frequently if cardiac disease suspected). Patients with cardiac sarcoidosis should be seen by a cardiologist and have regular cardiac MRI surveillance. Patients with ocular involvement should have regular ophthalmological review (anterior uveitis can be asymptomatic and sight-threatening if untreated). Sun exposure and vitamin D supplementation: patients with sarcoidosis should be cautious about excessive sunlight — UV light increases calcitriol production from skin and may worsen hypercalcaemia; vitamin D supplementation should be avoided unless serum calcium and 25-OH vitamin D levels are carefully monitored.

Seek medical assessment if you develop: persistent dry cough and breathlessness without an obvious cause; bilateral hilar lymphadenopathy incidentally found on chest X-ray or CT; tender, red lumps on the shins (erythema nodosum) with joint pain; red or painful eyes; or facial nerve weakness — all of these may indicate sarcoidosis. Established sarcoidosis patients should seek urgent review for: palpitations, dizziness, or blackouts (cardiac sarcoidosis with arrhythmia); sudden deterioration in breathlessness; any new neurological symptoms (seizures, facial weakness, headache, confusion — neurosarcoidosis); visual disturbance (uveitis); and any features of hypercalcaemia (excessive thirst, frequent urination, nausea, confusion). Contact your specialist team urgently if experiencing breathlessness severe enough to limit daily activity, or any symptoms suggesting cardiac involvement — cardiac sarcoidosis can cause sudden cardiac death and requires prompt specialist cardiology assessment.