Sarcoidosis

• Sarcoidosis is a systemic inflammatory disease in which clusters of immune cells called noncaseating granulomas form in organs; the lungs and intrathoracic lymph nodes are involved in about 90 percent of patients, but almost any organ can be affected.
• It most often affects young and middle-aged adults, women more than men, and people of African descent and those living in Scandinavia more than many other groups, and its cause is unknown.
• A majority of patients do well: roughly 50 to 70 percent have spontaneous remission, while 10 to 30 percent develop persistent or progressive disease that can damage organs.
• Many patients need no treatment at all; when treatment is needed, prednisone is used first, with steroid-sparing drugs such as methotrexate added for refractory or organ-threatening disease.
• Because tuberculosis, lymphoma and several other diseases look identical on imaging and under the microscope, the diagnosis is a diagnosis of exclusion that rests on compatible clinical findings, granulomas on biopsy, and reasonable exclusion of mimics.

By the end of this page you should be able to:

1. Explain what a noncaseating granuloma is and the immunology that builds it.
2. Describe the epidemiology of sarcoidosis, including the age, sex and ethnic patterns.
3. Recognise the common organ manifestations, including the skin, eye, heart, nervous system, kidney and calcium metabolism, and the chest radiograph stages.
4. Recognise Löfgren syndrome and Heerfordt syndrome.
5. Plan a sensible investigation strategy, including EBUS biopsy, bronchoalveolar lavage, ACE, PET and cardiac MRI, and explain the limitations of each test.
6. Choose when to observe and when to treat, and state the starting dose, taper and duration of prednisone and the place of methotrexate, other steroid-sparing agents and infliximab.
7. Describe the prognosis, complications and what changes when resources are limited.

The name describes the disease rather than explains it. The granulomas are the defining abnormality: tight collections of activated immune cells that can form in almost any tissue and that may either melt away or leave scar. Because no single test proves sarcoidosis, every case is a clinical judgement that combines a compatible presentation, granulomas on a sample (usually), and the exclusion of other granulomatous or sarcoid-like diseases.^[1][4]

Sarcoidosis occurs most often in young and middle-aged adults and is uncommon before the teens or after age 70. The age pattern is usually described as bimodal, with a first peak in the third and fourth decades and a second, smaller peak among older adults, particularly women.^[3][6] The average age of symptom onset was 43 years in one European study and 54 years in a Japanese study, with the female second peak near 50 years.^[3]

Women are affected at least as often as men overall, and in several cohorts more often. In Iceland, 54 percent of tissue-verified cases were women and the incidence was 4.44 per 100,000 per year in women versus 3.78 in men; women were also older at diagnosis, with a mean age of 53 years versus 48 years in men.^[6] In a United States cohort the average incidence in women was 11 per 100,000.^[3] A notable female peak occurs around 50 years of age in addition to the younger peak.^[3]

Geography and ancestry matter. Reported incidence ranges from 0.8 per 100,000 per year in Japan to between 11.5 and 24 per 100,000 per year in Sweden, with Iceland between them at 4.15 per 100,000 per year.^[6] In England the incidence rose from 6.65 to 7.73 per 100,000 person-years between 2003 and 2023.^[1] Among women in America of African descent the rate is far higher, about 107 per 100,000 in those aged 30 to 39 years, and African Americans are more likely than white people to have sarcoidosis, more advanced radiographic disease, more organs involved (about 2.48 versus 2.06) and a greater need for treatment.^[3][6] Black populations also show a much higher age-adjusted mortality.^[1] The overall prevalence in the United States is roughly 35 per 100,000 people.^[5]

Roughly half to seventy percent of patients have a spontaneous remission, while ten to thirty percent develop persistent or progressive disease with possible irreversible organ damage.^[1][3] The overall mortality is low, around 3 to 5 percent, and when death occurs it is most often from lung or heart involvement.^[3]

The cause is unknown. The leading hypothesis is that an environmental or infectious trigger, in a genetically susceptible person, sets off an exaggerated cell-mediated immune response that produces granulomas. Mycobacteria and propionibacteria are leading candidate organisms, and environmental exposures such as beryllium and silica are associated in some patients.^[3] Genetic susceptibility is important, with associations in human leucocyte antigen (HLA) genes, particularly variants of HLA-DRB1, that influence susceptibility, phenotype and prognosis.^[1] About 10 percent of patients report a family history.^[4]

Smoking is generally inversely associated with sarcoidosis, although not all studies agree, and exposure clustering in certain occupations has been described.^[6] The combination of a trigger plus genetic susceptibility explains why the same environment does not produce the same disease in everyone, and why the clinical picture varies by ethnicity and geography.^[3][6]

The disease is built by the immune system, not by a simple infection. An antigen is taken up by antigen-presenting cells such as macrophages and dendritic cells, which present it to CD4-positive T lymphocytes. These T cells polarise towards a T-helper 1 response, releasing interferon-gamma, interleukin-2 and tumour necrosis factor-alpha (TNF-alpha). The cytokines activate macrophages, which become epithelioid cells, fuse into multinucleated giant cells, and form the granuloma.^[3][4]

The granuloma in sarcoidosis is noncaseating, meaning it does not show the cheese-like necrosis typical of tuberculosis. Most lymphocytes in and around it are CD4-positive Th1 cells, with CD4 and CD8 T cells at the periphery and macrophages and giant cells in the centre. The granuloma can resolve without a trace, or it can undergo fibrosis and leave scar. Th17 cells and interleukin-17 also increase in sarcoidosis, and regulatory T-cell suppression of the response is reduced, but the exact roles of these pathways, and why some granulomas fibrose while others vanish, remain uncertain.^[3][4]

Persistent granulomatous inflammation may evolve into chronic inflammation and irreversible fibrosis, which is the mechanism behind progressive fibrotic pulmonary sarcoidosis. Activated macrophages inside granulomas also convert 25-hydroxyvitamin D to active calcitriol, which increases intestinal calcium absorption and produces the hypercalcaemia and hypercalciuria described later.^[1][3]

On microscopy sarcoidosis shows well-formed, discrete, relatively "naked" granulomas along the lymphatics: around bronchovascular bundles, in interlobular septa and on the pleural surface, with giant and epithelioid cells and no significant surrounding lymphoid cuff.^[4] The granulomas may occasionally contain cytoplasmic inclusions such as asteroid, Schaumann or Hamazaki-Wesenberg bodies, and multinucleated giant cells. Up to about 20 percent of biopsies in confirmed sarcoidosis show some small foci of necrosis, so necrosis does not automatically exclude the disease, but prominent necrosis should raise strong suspicion of infection.^[4]

Many patients are asymptomatic at diagnosis; about 30 to 50 percent are.^[1] Others present with the general symptoms of a systemic inflammatory illness: fatigue, which is the single most common symptom in some series, fever, night sweats, weight loss and arthralgia.^[6] The remaining presentation is determined by the organs involved.

The lungs and intrathoracic lymph nodes are involved in roughly 90 percent of patients and dominate the clinical picture.^[1][3] Dyspnoea and cough are the commonest respiratory symptoms, with chest pain in some.^[3] Over 80 percent of patients have an abnormal chest radiograph at presentation, yet crackles are uncommon and physical examination is often normal even with severe parenchymal disease.^[3] Pulmonary function is normal in many, but a restrictive ventilatory defect with a reduced diffusing capacity for carbon monoxide is the classical pattern when disease is advanced. Infiltrates are perilymphatic and have an upper-zone preference. Abdominal lymphadenopathy is seen in about 30 percent.^[3]

Skin involvement affects roughly one in four patients. Erythema nodosum is the most common lesion, reported in up to 25 percent, and typically accompanies acute self-limiting disease with a good prognosis.^[3] Lupus pernio, with violaceous plaques and nodules of the nose, cheeks and ears, is associated with chronic progressive disease and a poorer outcome.^[1] Other lesions include papules, plaques and subcutaneous nodules.

Eye involvement occurs in about 25 percent of patients. Uveitis, particularly anterior uveitis, is the most frequent manifestation, but sarcoidosis can also affect the conjunctiva, lacrimal gland, retina, choroid, optic nerve and extraocular muscles. Symptoms include dry eye, reduced vision, glare and redness. Untreated ocular sarcoidosis can cause permanent visual loss, which is why an ophthalmological examination is recommended even without eye symptoms.^[3] Heerfordt syndrome unites uveitis with parotid swelling and facial palsy.

Clinically apparent cardiac sarcoidosis is identified in about 5 to 10 percent of patients with systemic sarcoidosis, but autopsy and imaging studies suggest myocardial involvement in 20 to 30 percent, many of them subclinical.^[5] Presentation ranges from none to high-grade atrioventricular (AV) block, ventricular and supraventricular tachyarrhythmias, heart failure and sudden cardiac death. Complete heart block is the most frequent conduction abnormality, occurring in 23 to 30 percent (up to 44 percent when tissue is proven). Ventricular tachycardia or frequent ventricular ectopy occurs in about 30 to 32 percent. Heart failure as the first presentation is relatively uncommon, in under 20 percent. Sudden cardiac death accounts for 25 to 65 percent of sarcoidosis-related deaths. The electrocardiogram is abnormal in 30 to 50 percent of cardiac cases but a normal ECG does not exclude cardiac disease, and up to one quarter occur without known extracardiac sarcoidosis.^[5]

Neurosarcoidosis can involve any part of the central or peripheral nervous system. Cranial neuropathies are most common, in about 55 percent of neurosarcoidosis cases, particularly the facial nerve (about 24 percent) and the optic nerve (about 21 percent). Other presentations include chronic meningitis, seizures, myelopathy, peripheral neuropathy, pituitary and hypothalamic dysfunction, mood and cognitive change. Like cardiac disease, neurological sarcoidosis may be life-threatening and justifies early systemic treatment.^[1]

Hepatic and splenic granulomas are common (found in up to 80 percent at autopsy) but usually asymptomatic, picked up by abnormal liver tests or imaging. Symptomatic hepatic disease can present with hepatomegaly, cholestatic enzyme abnormalities, portal hypertension or, rarely, cirrhosis. Splenomegaly and cytopenias occur more often in multisystem disease. Abdominal lymph nodes are enlarged in about 30 percent.^[3]

The most common renal manifestations relate to calcium. Activated macrophages in granulomas produce calcitriol, which increases intestinal calcium absorption and leads to hypercalcaemia, hypercalciuria, nephrocalcinosis and renal stones. Direct renal involvement (granulomatous interstitial nephritis, glomerular disease) also occurs. Hypercalcaemia was present in roughly one in five patients in whom calcium was measured in one Icelandic cohort, although measurement was not universal.^[3][6]

Arthralgia and peripheral arthritis are frequent, sometimes as part of Löfgren syndrome. Diffuse granulomatous myositis, bone lesions and other musculoskeletal disease occur but are less common.^[3]

Two acute phenotypes are worth knowing by name.

Sarcoidosis is a diagnosis of exclusion. The most dangerous mimics are precisely those that matter most in the low-resource settings where tuberculosis is common: tuberculosis itself and lymphoma. The table compares common granulomatous and lymphatic mimics. Because occasional necrosis can occur in sarcoidosis biopsy, and because tuberculosis can also produce granulomas, histology alone is not enough; microbiology must be excluded in at-risk patients.^[4][3]

The diagnostic process is deliberately multi-modal; no single test is diagnostic. Baseline assessment typically includes blood tests (full blood count, liver and renal function, calcium studies), urinalysis, pulmonary function testing, ECG, chest imaging and an ophthalmology examination.^[1][3]

Serum angiotensin-converting enzyme (ACE) is the best-known biomarker, but it is not diagnostic: sensitivity ranges from 20 to 90.5 percent and specificity from 47 to 89.9 percent.^[4] ACE can be falsely low in patients taking ACE inhibitors, falsely high in pulmonary tuberculosis, and varies with genotype and ethnicity. Soluble interleukin-2 receptor (sIL-2R) and chitotriosidase perform somewhat better, and none of these markers establishes the diagnosis alone. They are mainly useful for monitoring.^[1][4]

Chest radiography remains the initial study and underlies the Scadding stages (below). High-resolution CT of the chest is more sensitive, showing mediastinal and hilar lymphadenopathy, a characteristic perilymphatic micronodular pattern with upper-zone predominance, ground-glass change, reticulation and, in advanced disease, fibrosis. CT alone cannot separate sarcoidosis from lymphoma reliably. Fluorodeoxyglucose PET-CT is useful when biopsy sites must be chosen, when metabolically active disease needs distinguishing from burned-out fibrosis, and for detecting extrapulmonary and cardiac involvement: a meta-analysis reports about 97 percent sensitivity and 87 percent specificity for pulmonary sarcoidosis.^[1] MRI has limited use in the lungs but is the preferred test for cardiac and neurological involvement. Cardiac MRI has a higher reported sensitivity (about 95 versus 84 percent) and specificity (about 85 versus 82 percent) than cardiac FDG-PET in cardiac sarcoidosis, and late gadolinium enhancement typical of sarcoidosis is patchy, non-ischaemic and preferentially subepicardial or mid-myocardial in the basal septum and lateral wall.^[1][5]

The preferred first biopsy site is the safest accessible involved organ. For thoracic disease this is usually hilar or mediastinal lymph nodes sampled by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), which is safer and better tolerated than mediastinoscopy and has a high yield (about 87 percent versus 98 percent for mediastinoscopy). EBUS accuracy in diagnosing sarcoidosis is roughly 80 to 90 percent, with complications (bleeding, pneumothorax) in less than 1 percent.^[3][4] Transbronchial lung biopsy yields less tissue (40 to 90 percent) and cryobiopsy can help when conventional biopsy is non-diagnostic. Surgical lung biopsy is rarely needed.^[3][4]

Bronchoalveolar lavage is supportive rather than diagnostic: lymphocytosis is present in 90 percent of patients, and a CD4 to CD8 ratio greater than 3.5 is supportive, with a specificity of 94 percent in an appropriate clinical setting. BAL also excludes infection.^[4]

Biopsy is not always necessary. Characteristic presentations such as Löfgren or Heerfordt syndrome, and patients with a very high pre-test probability on CT, may be given a working diagnosis after multidisciplinary discussion, especially if no immunosuppression is immediately needed.^[4]

In sarcoidosis patients with cardiac symptoms, conduction abnormality or abnormal ECG or echocardiogram, cardiac MRI and/or FDG-PET are the key investigations, with endomyocardial biopsy (sensitivity 20 to 30 percent, image-guided about 50 percent) reserved for difficult cases. Formal criteria from the Heart Rhythm Society, Japanese Circulation Society and World Association of Sarcoidosis are used; Japanese criteria allow a clinical diagnosis when typical cardiac findings accompany known extracardiac sarcoidosis, including isolated cardiac disease, whereas the American Heart Association and ESC approaches use a likelihood-based, multimodal strategy.^[5]

Echocardiography is the first cardiac imaging test, but it is insensitive for early disease; patchy granulomas sit in subepicardial and mid-myocardial locations that only MRI or PET reliably detect. A normal echocardiogram therefore does not rule out cardiac sarcoidosis.^[5] Neurological investigation (MRI of brain or spine, lumbar puncture, biopsy of accessible tissue) is pursued when neurological features are present.^[1]

Three criteria are needed: a compatible clinical picture, evidence of noncaseating granulomatous inflammation (usually), and exclusion of alternative causes of granulomatous disease.^[4] Because imaging can be characteristic but is not proof, the final confidence is usually a judgement rather than a yes/no answer, ideally reached in multidisciplinary discussion.^[4]

The Scadding system remains the conventional way to describe thoracic sarcoidosis, even though it is coarse and observers disagree at the margins.^[4][1]

Stage 1 carries the best chance of resolution, stage 4 essentially none; these stages are better described as radiographic types than as a natural history that every patient follows.^[4][1]

In countries where tuberculosis is common, a biopsy showing granulomas cannot be accepted as sarcoidosis until tuberculosis, non-tuberculous mycobacteria and fungal infection have been excluded by stain, culture or molecular testing.^[3][4] Necrosis on the slide makes infection more likely, and ACE (which can be false-positive in tuberculosis) must not be used to settle the question. When lymph nodes are enlarged, they cannot be distinguished reliably from lymphoma or malignancy radiologically, so histological confirmation is needed unless the presentation is classic (Löfgren or Heerfordt syndromes).^[3][4]

Management has three parts: deciding whether to treat at all, suppressing active granulomatous inflammation, and treating the complications and organs not responsive to anti-inflammatory therapy. It is best delivered by a multidisciplinary team, and treatment decisions should balance expected benefit against toxicity, in shared discussion with the patient.^[1][3]

Many patients are asymptomatic, have mild disease, or are in the natural process of remission. In such cases careful observation is appropriate, sometimes with no medication beyond analgesia: Löfgren syndrome, for example, is usually treated with NSAIDs alone, with escalation only for persistent, severe or refractory symptoms.^[1][3] Starting treatment unnecessarily exposes a patient to corticosteroid toxicity without clear benefit.

Treatment is indicated when there is a risk of death or organ failure, loss of quality of life, significant symptom burden, progressive pulmonary disease, impaired organ function or potentially life-threatening involvement such as cardiac, neurological or severe ocular disease.^[1][3] About 5 percent of patients die from sarcoidosis, most often from lung or heart involvement, so the decision is taken seriously.^[3] Corticosteroids are useful for active inflammation but not for established fibrosis.

For most pulmonary or symptomatic sarcoidosis, prednisone is started at 20 to 40 mg per day for 4 to 6 weeks, then tapered slowly to 5 to 10 mg per day over 6 to 12 months, with an aim of discontinuation if remission is achieved. Some guidelines recommend an initial 20 mg per day with a gradual taper to the lowest effective maintenance dose, usually 5 to 10 mg per day, and there is randomised evidence that 40 mg per day added no benefit over 20 mg per day for treatment failure, relapse, quality of life or lung function.^[1][2][3] For Löfgren syndrome with severe arthralgia a higher initial dose of 30 to 40 mg for 1 to 2 weeks is used.^[3] Rapidly progressive or life-threatening extrapulmonary disease (cardiac, neurological, severe optic neuritis) may need high-dose methylprednisolone; a patient whose disease persists at 10 to 15 mg per day or relapses on tapering needs a steroid-sparing agent or re-escalation.^[3]

Because prolonged prednisone is toxic, the lowest effective dose and the earliest feasible taper matter; bone protection, blood pressure and glucose monitoring, and cautious calcium and vitamin D supplementation (because of hypercalcaemia risk) should be considered.^[1][3]

Methotrexate is the preferred steroid-sparing drug, effective at reducing cumulative steroid exposure and with a delayed onset of 2 to 3 months. It is given at 10 to 25 mg per week orally (or up to 20 to 25 mg in some schemes), with folic acid, and with monitoring of full blood count, liver and renal function and awareness of drug interactions such as trimethoprim and NSAIDs.^[2][3] Recent evidence (PREDMETH) supports methotrexate as a non-inferior first-line alternative to prednisolone in selected pulmonary sarcoidosis, with a slower early response. Azathioprine, mycophenolate mofetil and leflunomide are alternatives when methotrexate is not tolerated, with azathioprine needing thiopurine methyltransferase testing and carrying a higher infection rate. Hydroxychloroquine (200 to 400 mg per day) helps cutaneous, musculoskeletal and hypercalcaemic disease but has little role in significant pulmonary disease.^[2][3]

Biologics are third line, after failure of conventional therapy. Infliximab is the preferred biologic and is often given with methotrexate. Before any anti-TNF therapy, screen for latent tuberculosis and hepatitis B and C, and be aware of infection, infusion reactions and paradoxical (sarcoid-like) granulomatous reactions. Adalimumab is an alternative. Rituximab and repository corticotropin injection have evidence limited to refractory cases.^[2][3][5]

Active cardiac disease is treated early and aggressively. Corticosteroids are started at 30 to 60 mg per day for 1 to 3 months, then tapered over 6 to 12 months to 5 to 10 mg per day, with steroid-sparing agents (methotrexate, azathioprine, mycophenolate) as in the pulmonary regimen. Infliximab or adalimumab are reserved for refractory active disease.^[5] Arrhythmia management follows cardiac guidance: beta-blockers, with caution about amiodarone and pulmonary disease, catheter ablation for drug-refractory ventricular tachycardia, and an implantable cardioverter-defibrillator for high-risk patients such as those with prior sustained ventricular tachycardia, unexplained syncope, a left ventricular ejection fraction 35 percent or below, or combined high-risk features with a mildly reduced ejection fraction. Pacemaker-dependent patients usually receive a defibrillator because of the arrhythmic risk. Beta-adrenergic blockade and standard heart-failure therapy are used for myocardial dysfunction.^[5]

Ocular sarcoidosis is managed topically when anterior and mild, but needs systemic therapy when severe, posterior, refractory or sight-threatening. Limited cutaneous disease usually responds to topical or intralesional steroids; extensive or progressive skin disease needs systemic therapy. Hepatic and peripheral lymph-node involvement usually needs no treatment unless symptomatic, progressive or associated with organ dysfunction. Neurosarcoidosis generally requires systemic therapy (corticosteroids, then methotrexate or other agents), and the same systemic stepwise approach applies.^[1][3]

Exclude alternative causes such as malignancy and primary hyperparathyroidism first. Symptomatic or moderate-to-severe hypercalcaemia is treated with systemic corticosteroids, with intravenous fluids and, if needed, bisphosphonates; recurrent or resistant cases may use hydroxychloroquine or methotrexate. Monitor serum calcium and renal function. Long-term calcium and vitamin D supplementation during corticosteroid therapy should be considered cautiously because of the hypercalcaemia risk.^[1]

Follow-up combines symptoms, chest radiograph and pulmonary function tests; a fall in forced vital capacity of 10 percent or in diffusing capacity for carbon monoxide of 15 percent from baseline is considered meaningful.^[3] Cardiac follow-up includes ECG, rhythm monitoring and echocardiography every 6 to 12 months, with a follow-up FDG-PET about 6 months after starting or changing immunosuppression to judge response and guide tapering. Annual ophthalmology review is appropriate in ocular disease, and drug-specific monitoring (blood counts, liver and kidney tests) is used for all second-line drugs.^[5] Early introduction of a steroid-sparing drug is often considered in cardiac and neurological disease because treatment is usually prolonged.^[1]

• Progressive fibrotic pulmonary sarcoidosis develops in 10 to 20 percent and may lead to respiratory failure.^[1]
• Sarcoidosis-associated pulmonary hypertension occurs in about 3 percent of all patients, but in about 30 percent of those with stage IV fibrotic disease, and it raises mortality.^[1]
• Arrhythmias and sudden cardiac death, as described above.^[5]
• Renal stones, nephrocalcinosis and renal failure from calcium metabolism.^[3]
• Osteoporosis and fractures with prolonged corticosteroids, with risk increased at prednisolone-equivalent doses of 5 mg per day or more; gastrointestinal protection and bone assessment are advised in patients on long-term therapy.^[1]
• Opportunistic infections, including Pneumocystis jirovecii pneumonia in heavily immunosuppressed patients; prophylaxis may be considered when prednisone 20 mg per day or more is used for 4 weeks or more together with additional immunosuppressive therapy.^[1]
• A minority of patients worsen with corticosteroid treatment, and steroids should be stopped if this is suspected.^[3]

The course is highly variable and hard to predict. Spontaneous remission occurs in 50 to 70 percent of patients, whereas 10 to 30 percent have chronic or progressive disease.^[1][3] In the Scadding staging system stage 1 disease resolves spontaneously in 60 to 90 percent and stage 4 (fibrosis) in none.^[1] Mortality is increased in those with advanced pulmonary fibrosis, cardiac or neurological sarcoidosis, but the overall mortality is low.^[1] Relapse after corticosteroid-induced remission has been reported in up to 74 percent of patients, versus around 8 percent after spontaneous remission, which is why relapse counselling and careful tapering matter.^[1] Cardiac sarcoidosis, once nearly fatal, now has 5-year survival of about 90 to 96 percent with modern management, although relapses are common during steroid tapering.^[5] Steroid-induced remission is good for symptoms, imaging and function in the short term, but long-term disease modification is less certain.^[1]

• In areas where tuberculosis, HIV and endemic fungi are common, a biopsy showing granulomas is not sarcoidosis until infection is excluded microbiologically; if molecular tests are unavailable, clinico-radiological judgement plus prolonged observation may be necessary.^[3][4]
• A careful exposure and occupational history, chest radiography, basic spirometry and calcium studies provide most of the diagnostic and staging information. EBUS and CT may be unavailable; mediastinoscopy or surgical biopsy should be organised when the diagnosis is unsafe.^[3][4]
• Lymph-node enlargement in the mediastinum has a broad differential and, in high-incidence regions, tuberculosis and lymphoma must be excluded before immunosuppression is started.^[4]
• Corticosteroids, NSAIDs, methotrexate and hydroxychloroquine are generally available and should be used with the same stepwise principles. Biologics, cardiac MRI, PET and transplant services may not be available, so early referral to the nearest specialist centre is important.^[3][5]
• Because anti-inflammatory therapy in tuberculosis can be disastrous, empirical steroid treatment without a reasonably secure diagnosis should be avoided.

Children. Sarcoidosis is rare in children, and presentation often differs (isolated eye, skin or nervous system disease). Management is best in a specialist centre, and genetic or infectious mimics are more likely than in adults.

Older adults. Corticosteroid toxicity, drug interactions, osteoporosis and comorbidity dominate. Older patients are more likely to receive prolonged low-dose therapy and need fracture-risk assessment and infection vigilance.

Pregnancy. Drug choice should be guided by a specialist; methotrexate and biologics are not compatible with pregnancy, and many patients with mild disease can be observed or treated with corticosteroids under specialist supervision.

• Sarcoidosis is a systemic, noncaseating granulomatous disease of unknown cause, most often involving lungs and intrathoracic nodes.
• It favours young and middle-aged adults, women (with a peak near age 50), people of African descent and Scandinavian populations, with incidence ranging from less than 1 to over 20 per 100,000 per year depending on region.
• 50 to 70 percent remit spontaneously; 10 to 30 percent develop chronic or progressive disease.
• Granulomas form from CD4 Th1 (and Th17) driven macrophage activation via TNF-alpha and interferon-gamma, and may resolve or fibrose.
• Organ manifestations span lung (over 90 percent), lymph nodes, skin (erythema nodosum up to 25 percent; lupus pernio chronic), eyes (about 25 percent, uveitis), heart (5 to 10 percent clinical; AV block the classic finding), nervous system (facial and optic neuropathy), liver and spleen, kidney (hypercalcaemia and hypercalciuria via calcitriol), bones and joints.
• Löfgren syndrome is an acute, favourable, often self-limited phenotype; Heerfordt syndrome is a rare uveoparotid fever with facial palsy.
• ACE is not a reliable diagnostic test; EBUS-TBNA is the usual biopsy route (yield about 87 percent); BAL lymphocytosis and a CD4 to CD8 ratio above 3.5 are supportive; cardiac MRI is more sensitive than PET for myocardial disease.
• Chest radiograph stages 1 to 4 predict likelihood of spontaneous resolution.
• Treatment is reserved for organ-threatening, progressive or symptomatic disease: prednisone 20 to 40 mg per day with a slow taper, methotrexate as the usual steroid-sparing drug, and infliximab for refractory disease, with cardiac sarcoidosis treated more aggressively.
• Hypercalcaemia responds to corticosteroids; calcium and vitamin D supplementation must be used cautiously.
• In high-tuberculosis, low-resource settings, tuberculosis and lymphoma must be excluded before immunosuppression is given.

• Interstitial lung disease
• Tuberculosis
• Lymphoma
• Hypersensitivity pneumonitis
• Pulmonary function tests
• Chronic cough
• Pulmonary hypertension