Sarcoidosis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Pulmonary sarcoidosis ranges from asymptomatic hilar lymphadenopathy to nodular parenchymal disease, airway involvement, progressive fibrosis and pulmonary hypertension. Extrapulmonary manifestations include uveitis, skin lesions, lymphadenopathy, hepatic disease, hypercalcaemia, renal stones, neurosarcoidosis and cardiac disease. The diagnosis requires a compatible syndrome, supportive histology when needed and reasoned exclusion of alternative granulomatous disorders; granulomas themselves are not specific.

Diagnostic intensity should be proportionate. A patient with classic Löfgren syndrome—bilateral hilar lymphadenopathy, erythema nodosum and ankle periarthritis—often has a favourable course and may not need invasive confirmation. By contrast, atypical nodes, constitutional loss, occupational beryllium or silica exposure, immunosuppression or an unusual organ pattern demands broader evaluation for lymphoma, tuberculosis, fungal infection and exposure-related disease before corticosteroids.

The BTS clinical statement emphasises shared decision-making because the evidence base is limited and treatment can create substantial harm. Observation is active care when disease is stable and organs are safe. Corticosteroids remain usual first-line systemic therapy for clinically important pulmonary disease, with methotrexate often used as a steroid-sparing agent. Cardiac, neurological, ocular or pulmonary-hypertension presentations need the corresponding expert MDT and local commissioned pathway.

Key points

Sarcoidosis is a multisystem granulomatous disorder of uncertain cause; pulmonary involvement is common but symptoms and organ risk vary widely.
Bilateral hilar and mediastinal lymphadenopathy, perilymphatic nodules and upper-zone fibrosis are characteristic imaging patterns, not independently diagnostic findings.
Many patients with typical, non-threatening disease improve spontaneously and do not need systemic treatment.
Treatment has two broad indications: prevention of death or irreversible organ disability, and relief of symptoms that materially impair quality of life.
A tissue diagnosis should show non-caseating granulomas from the safest useful site, while infection, exposure-related granulomatous disease and malignancy are excluded.
A highly typical presentation such as Löfgren syndrome may be managed without biopsy after specialist review when alternative disease is unlikely.
Serum ACE lacks adequate sensitivity and specificity for diagnosis or routine treatment decisions; it must never replace clinical synthesis.
Ask every patient about palpitations, presyncope, syncope, chest pain, visual symptoms and neurological change because these may reveal high-risk organ involvement.
Check calcium and renal function, and avoid uncritical vitamin D or calcium supplementation because sarcoid granulomas can increase active vitamin D production.
Pulmonary monitoring relies on symptoms, chest imaging and serial physiology; radiographic stage alone does not determine functional severity or need for therapy.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Immune susceptibility

Genetic variation in antigen presentation and immune regulation predisposes certain people to a granulomatous response, with marked differences across ancestry and families.

Environmental triggers

Inhaled microbial, occupational or inorganic antigens are suspected initiators, but no single exposure explains most cases.

Dysregulated cell-mediated immunity

An exaggerated T-cell and macrophage response persists after an unknown antigenic stimulus rather than representing ordinary infection.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Antigen presentation
Macrophages present an incompletely defined antigen to susceptible T lymphocytes within affected organs, contributing to the resulting loss of respiratory reserve.
2
Granuloma assembly
Activated T cells and macrophages cluster into compact non-caseating granulomas to contain the perceived stimulus, which links the underlying lesion to the observed respiratory dysfunction.
3
Organ infiltration
Granulomas accumulate in lung, lymph nodes, skin, eyes, heart, nervous system or other tissues and alter local function.
4
Resolution or fibrosis
Inflammation may resolve spontaneously, persist, or activate fibroblasts and cause permanent architectural distortion, especially in lung.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Thoracic nodal disease

Incidental symmetrical bilateral hilar and right paratracheal lymphadenopathy with or without cough, breathlessness or chest discomfort is a common presentation, particularly when the person is otherwise well.

Löfgren syndrome

Acute erythema nodosum, bilateral ankle periarthritis and bilateral hilar lymphadenopathy form a highly characteristic phenotype that usually carries a favourable prognosis.

Parenchymal and fibrotic disease

Perilymphatic nodules follow bronchovascular bundles and fissures; upper-zone volume loss, traction bronchiectasis and conglomerate fibrosis may produce respiratory impairment and pulmonary hypertension.

Cardiac warning featuresRed flag

Unexplained syncope or presyncope, persistent palpitations, conduction block, ventricular arrhythmia or new heart failure may indicate cardiac sarcoidosis and requires urgent specialist evaluation.

Eye or neurological involvementRed flag

Painful red eye, photophobia, reduced vision, facial weakness, neuropathy, seizures, pituitary symptoms or meningeal features demand rapid organ-specific assessment because delay risks irreversible disability.

Calcium and renal complicationsRed flag

Thirst, polyuria, constipation, confusion, nephrolithiasis or renal dysfunction may reflect disordered calcium metabolism and should prompt urgent biochemical assessment when severe.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Chest radiograph and thin-section CTFirst step
Why
Define thoracic distribution and select a safe diagnostic site.
Interpretation and limitations
Symmetrical hilar and mediastinal nodes and perilymphatic nodules support sarcoidosis. Asymmetric bulky nodes, cavitation, effusion or a focal mass should widen the differential; CT is particularly useful when the radiograph is atypical.
02
Spirometry and gas transfer
Why
Measure respiratory impairment and establish a follow-up baseline.
Interpretation and limitations
Restriction, obstruction or mixed physiology can occur. A falling FVC or TLCO is more clinically useful than radiographic stage alone and may also raise pulmonary hypertension or another complication.
03
Full blood count, renal and liver profiles, calcium
Why
Screen for organ involvement and treatment-relevant abnormalities.
Interpretation and limitations
Hypercalcaemia, renal dysfunction, cytopenias or cholestatic liver results require context. Measure vitamin D metabolites only through a specialist plan; routine supplementation can be hazardous.
04
Baseline ECG and cardiac assessment
Why
Detect otherwise silent conduction or rhythm disease.
Interpretation and limitations
An abnormal ECG or cardiac symptoms prompt echocardiography and expert consideration of ambulatory monitoring, cardiac MRI or FDG-PET. A normal resting ECG does not fully exclude cardiac sarcoidosis.
05
Tissue sampling
Why
Confirm granulomatous inflammation when diagnostic certainty is required.
Interpretation and limitations
Choose the least invasive high-yield target, such as skin lesion, peripheral node or EBUS-guided thoracic node. Send samples for appropriate microbiology and pathology; non-caseating granulomas still require exclusion of alternative causes.
06
Eye and organ-directed assessment
Why
Identify involvement that may be silent or time-critical.
Interpretation and limitations
Visual symptoms need prompt ophthalmology, while neurological, cardiac, renal or endocrine findings trigger the relevant specialist pathway. Routine tests should follow clinical features and local sarcoidosis practice.
07
Serum ACE
Why
Occasionally provide supportive context after diagnosis.
Interpretation and limitations
Levels vary with genotype, medicines and other diseases and can be normal in active sarcoidosis. It cannot confirm sarcoidosis, decide treatment or reliably measure response by itself.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Tuberculosis

Epidemiology, constitutional symptoms, necrosis and mycobacterial culture distinguish infection that could worsen catastrophically with immunosuppression, while chronology and directed testing distinguish the competing explanation.

Lymphoma

Bulky or asymmetric nodes, systemic symptoms and clonal tissue findings support malignancy; granulomas can occur near tumours and do not automatically exclude them.

Chronic beryllium disease

Aerospace, electronics or metal-work exposure can produce an indistinguishable granulomatous lung pattern and requires occupational testing.

Hypersensitivity pneumonitis

Antigen-linked bronchiolocentric inflammation, air trapping and poorly formed granulomas favour HP over perilymphatic sarcoidosis, while chronology and directed testing distinguish the competing explanation.

Fungal infection

Geographical exposure and fungal microbiology or histology are essential because several endemic mycoses closely mimic sarcoidosis.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01DiagnosisProve only what needs provingFirst stepImaging and clinical findings suggest pulmonary sarcoidosis.

1Assess severity and ask deliberately about cardiac, eye and neurological red flags, exposures, travel, immune status, constitutional symptoms and medicines.
2Review chest imaging with thoracic radiology, obtain physiology and baseline blood tests, then decide whether the presentation is sufficiently typical for observation without biopsy.
3When tissue is needed, sample the safest accessible site or use EBUS for thoracic nodes, requesting microbiological exclusion of infection as well as histology.
4AlternativeRecord diagnostic confidence and alternative diagnoses; reconsider lymphoma, tuberculosis, fungal infection, berylliosis and silicosis when the course or imaging is atypical.

02High-risk organsEscalate cardiac, eye and neurological diseaseEscalationSyncope, arrhythmia, visual disturbance, focal neurology or other organ-threatening features occur.

1Arrange urgent organ-specific assessment and monitor physiological risk, including cardiac rhythm or vision as indicated; do not wait for routine respiratory follow-up.
2Use an expert MDT to select cardiac MRI, FDG-PET, ambulatory ECG, ophthalmic imaging, neuroimaging or lumbar-puncture testing according to the presentation.
3Agree immunosuppression and device, electrophysiology or other protective treatment with the relevant specialists because corticosteroid response alone does not control sudden-death risk.
4Provide explicit emergency safety-netting for recurrent syncope, sustained palpitations, chest pain, visual loss, seizure or rapidly worsening weakness.

03Pulmonary treatmentTreat impairment rather than the radiographPulmonary disease threatens function or causes unacceptable symptoms.

1Compare symptoms, exercise capacity, FVC, TLCO and imaging trajectory, and exclude infection, cardiac disease and pulmonary hypertension before attributing decline to active granulomatous inflammation.
2Discuss observation versus corticosteroid treatment using the person's priorities, comorbidities and likelihood of spontaneous improvement; document a measurable treatment goal.
3If prolonged steroid exposure or inadequate response becomes problematic, involve the sarcoidosis specialist team for methotrexate or another steroid-sparing strategy with protocolled monitoring.
4Review response and toxicity at planned intervals, taper to the lowest effective exposure when possible, and refer fibrotic or pulmonary-hypertension complications to expert services.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

First-line systemic anti-inflammatory treatment when pulmonary impairment, organ risk or intolerable symptom burden justifies therapy.

Prednisolone

For clinically significant pulmonary disease, BTS describes an initial specialist regimen commonly around 20–40 mg orally daily for several weeks, followed by response-guided tapering toward 5–10 mg daily; individual schedules and duration vary.

Exclude important infection first and define an outcome before starting. Monitor glucose, blood pressure, mood, weight, eye and bone effects; relapse during taper is common and does not automatically justify indefinite high dosing.

Steroid-sparing immunomodulation for selected persistent pulmonary or extrapulmonary sarcoidosis.

Methotrexate

A sarcoidosis specialist prescribes a once-weekly oral or subcutaneous dose, usually titrated from a low starting regimen according to local protocol, with folic acid given on separate days.

Weekly—not daily—administration is safety critical. Check blood count, liver and renal function, infection and pregnancy status; avoid in pregnancy and investigate new respiratory symptoms for infection, sarcoid progression or methotrexate pneumonitis.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Pulmonary fibrosis

Chronic granulomatous inflammation can distort upper-zone airways and vessels, causing restriction, bronchiectasis and respiratory failure, and increasing the burden of otherwise local respiratory disease.

Cardiac sarcoidosis

Granulomas and scar in myocardium or conduction tissue cause heart block, ventricular arrhythmia, heart failure and sudden death.

Neurosarcoidosis

Cranial neuropathy, meningeal, hypothalamic or spinal involvement can cause persistent neurological and endocrine disability, and increasing the burden of otherwise local respiratory disease.

Ocular damage

Uveitis and other eye involvement may cause pain, visual loss, glaucoma or cataract if not recognised promptly.

Calcium and renal disease

Activated macrophages increase vitamin-D activation, causing hypercalcaemia, stones, nephrocalcinosis and renal impairment in susceptible patients, creating an additional need for recognition and targeted treatment.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

At every review ask about breathlessness, cough, exercise tolerance, fatigue, palpitations, presyncope, syncope, visual and neurological symptoms.
Trend spirometry and TLCO at a frequency matched to activity, using imaging when functional or clinical change needs anatomical explanation.
Repeat calcium, renal and liver tests according to organ involvement and treatment; investigate symptomatic or substantial abnormalities promptly.
For corticosteroids, monitor metabolic, cardiovascular, bone, ocular and infection toxicity and document the planned taper and prevention measures.
For methotrexate or other steroid-sparing treatment, follow specialist full-blood-count, liver and renal monitoring without assuming another clinic has performed it.
Reassess pulmonary hypertension and cardiac disease when symptoms become disproportionate to chest imaging or lung volumes.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Observation is a decision

Stable, low-risk disease often needs no systemic therapy, but planned physiology, organ screening and safety-netting make observation active management rather than neglect.

Granulomas are not proprietary

Tuberculosis, fungal infection, beryllium, medicines, immune disorders and malignancy-associated reactions can produce granulomas; compatible context and exclusion remain essential.

Chest stage is not function

Traditional radiographic staging describes appearances, not disease activity or a direct treatment ladder. Symptoms and physiology may be discordant with the film.

Cardiac disease can be quiet

A patient with modest pulmonary symptoms may still have consequential conduction or myocardial disease, which is why targeted symptom enquiry and baseline ECG matter.

Vitamin advice needs care

Granulomatous conversion of vitamin D can promote hypercalcaemia. Do not prescribe calcium or vitamin D reflexively without reviewing calcium metabolism and specialist guidance.

11Common pitfallsFrequent interpretation and management errors.

01
Treating a raised ACE level as diagnostic proof or using it alone to escalate corticosteroids.
02
Biopsying a classic low-risk presentation automatically when the result would not alter management.
03
Missing tuberculosis, lymphoma or occupational beryllium and silica exposure in an atypical granulomatous presentation.
04
Starting systemic treatment because a chest radiograph looks dramatic despite stable function and acceptable symptoms.
05
Failing to ask about syncope, palpitations, visual loss and neurological symptoms at routine pulmonary follow-up.
06
Giving routine vitamin D replacement without checking calcium-related risk and the local sarcoidosis plan.