Sarcoidosis

Meet the patient

A 32-year-old woman of African ancestry arrives with three weeks of painful red lumps on her shins, swollen ankles, a low-grade fever, and a dry cough. Her chest X-ray shows bilateral hilar lymphadenopathy. She has never been ill before, and she is alarmed.[1][11]

The two questions that decide her next month are the two that decide every sarcoid case: is this Löfgren syndrome — the acute, benign triad that needs no biopsy and no steroids? (the picture answers at the bedside), and have I excluded tuberculosis before I even think about a corticosteroid? (the histology and the stains answer that). Hold those two questions and everything below slots into place.[1]

What sarcoidosis is — and the one word that separates it from TB

Sarcoidosis is a multisystem granulomatous disorder of unknown cause defined by non-caseating granulomas. The granuloma is an organised aggregate of epithelioid macrophages, multinucleated Langhans giant cells and a rim of CD4+ T-lymphocytes, in the absence of any infection or malignancy that could explain them. The cause is unknown, but the dominant model is an exaggerated antigen-driven Th1 immune response in a genetically susceptible host.[1][7]

The one word that earns the marks is non-caseating. Tuberculosis builds caseating granulomas with central cheesy necrosis; sarcoid builds hard, non-necrotising granulomas. That distinction — plus the negative AFB stain, the negative Xpert MTB/RIF, and the negative mycobacterial culture — is what lets you give a corticosteroid in safety. The principle "exclude TB before starting steroids" is non-negotiable, because corticosteroids can accelerate undiagnosed TB.[1]

The clinical spectrum is exceptionally broad. At one end is the patient with incidental bilateral hilar lymphadenopathy on a chest X-ray, entirely well, who may never need treatment. At the other is the young patient who presents in complete heart block, ventricular tachycardia, or with rapidly progressive pulmonary fibrosis. The disease is named for the skin — Boeck's sarkoid, "flesh-like" lesions — though its modern identity rests on the multisystem granuloma.[3]

The two syndromes that anchor the bedside

Two clinical syndromes anchor the diagnosis, and the examiner rewards you for naming both.[3]

Löfgren syndrome is the acute triad of bilateral hilar lymphadenopathy, erythema nodosum and bilateral ankle arthritis (periarthritis) with fever. It carries an excellent prognosis — 80 to 90 per cent resolve within two years without specific therapy — and when the picture is classical, biopsy is not required. HLA-DRB1*03 positivity predicts resolution.[1][11]

Heerfordt syndrome (uveoparotid fever) is the combination of uveitis, parotid enlargement, fever and cranial nerve VII palsy — a multisystem acute sarcoid that signals more extensive disease and requires systemic corticosteroids. The facial palsy often resolves with treatment.[3]

The Scadding stages — read the CXR, predict the prognosis

The Scadding radiographic staging system (1961) is the universal language of pulmonary sarcoidosis and is reproduced verbatim below. Stage does not tightly track symptoms — a stage II patient may be asymptomatic and a stage I patient may have disabling uveitis — but it does predict prognosis: stages I and II resolve more often than stages III and IV.[7]

[1] [4]

Who gets it — and the smoking paradox

Sarcoidosis is a worldwide disease with a striking distribution. The peak incidence is in adults under 40, with a second smaller peak in women over 50. Lifetime risk is about 0.85 per cent in white Americans but approaches 2.4 per cent in African-Americans, who also have more severe, more chronic and more extrathoracic disease. Scandinavians, Irish and African ancestry populations are most affected; the disease is uncommon in Indians and East Asians, although Japanese patients have a notably high rate of cardiac sarcoidosis despite a low overall incidence.[4]

The classic trap: tobacco smoking is inversely associated with sarcoidosis — smokers are less likely to develop it. The examiner may test exactly that counterintuitive fact. The landmark ACCESS study (Newman 2004) found modest environmental and occupational associations (mould, insecticides, agricultural employment) and concluded that sarcoidosis is the common endpoint of several environmental triggers in a susceptible host.[5]

The genetics are increasingly mapped. The strongest associations sit in the MHC on chromosome 6: HLA-DRB1*03 defines Löfgren syndrome and a resolving course; HLA-DRB1*15 predicts chronicity. BTNL2, ANXA11 and CCR2 variants each modestly raise susceptibility.[4]

The granuloma and the four cytokines

The granuloma is the unit of sarcoidosis. A non-caseating granuloma is a tightly organised collection of activated epithelioid macrophages and multinucleated Langhans giant cells (formed by macrophage fusion, with peripheral horseshoe nuclei), surrounded by a cuff of CD4+ Th1 lymphocytes and a thin outer rim of CD8+ cells and B cells. Unlike TB, there is no central caseous necrosis.[7]

The cytokine cascade is examinable because each cytokine maps to a drug. IL-12 and IL-18 polarise the T cell toward Th1; IL-2 expands the CD4+ clone (driving the BAL CD4:CD8 ratio over 3.5); interferon-gamma activates macrophages; TNF-alpha sustains the granuloma and is the rationale for anti-TNF (infliximab) therapy in refractory disease.[3]

Why the calcium rises in summer

Activated granuloma macrophages express the 25-hydroxyvitamin D-1-alpha-hydroxylase (CYP27B1) — the same enzyme normally confined to the kidney proximal tubule. They therefore convert 25-hydroxyvitamin D into active 1,25-dihydroxyvitamin D (calcitriol) in an unregulated, substrate-driven way. The result is increased intestinal calcium absorption and bone resorption, producing hypercalcaemia and (more often) hypercalciuria, with the risks of nephrocalcinosis, nephrolithiasis and chronic kidney disease.[15]

The bedside pearl examiners love: a sarcoid patient's calcium rises in summer (sunlight generates vitamin D substrate) and falls with corticosteroids (which switch off the granuloma's 1-alpha-hydroxylase). That single mechanism explains both the seasonal pattern and the treatment.[15]

Granulomas then follow one of two fates. They may resolve by apoptosis, leaving no scar — the favourable outcome of Löfgren syndrome. Or they may persist and drive fibrosis under TGF-beta and fibroblast activation, producing the upper-lobe-predominant pulmonary fibrosis of Scadding stage IV with traction bronchiectasis, honeycombing, volume loss, and eventually pulmonary hypertension and cor pulmonale.[3]

Clinical presentation by organ — the dangerous four

A focused multisystem history and examination is mandatory at the first encounter, not a respiratory review alone. The lung is the commonest organ but not the most dangerous — the danger lives in the heart, nerves, eyes and calcium.[3]

Pulmonary disease (over 90 per cent) is often detected incidentally as bilateral hilar lymphadenopathy. Symptomatic disease produces a dry cough, exertional dyspnoea and vague retrosternal chest discomfort; pleuritic pain and haemoptysis are uncommon and suggest an alternative or a complication (aspergilloma in a fibrotic cavity).[3][7]

Cutaneous disease is the most visible extrathoracic manifestation, and the skin lesion often predicts prognosis. Erythema nodosum — tender, erythematous subcutaneous nodules on the shins — is a non-specific (reactive) lesion, the hallmark of acute sarcoid and Löfgren syndrome, and signals a good prognosis. Lupus pernio — chronic, violaceous, indurated plaques on the nose, cheeks, ears and lips — is a specific (granulomatous) lesion that signals chronic disease, upper-respiratory involvement, bone cysts and pulmonary fibrosis, and a poor prognosis.[12][14]

Ocular sarcoidosis affects about a quarter of patients and may precede other manifestations by years. Anterior uveitis presents with a painful red eye, photophobia and blurred vision; untreated it causes synechiae, glaucoma, cataract and blindness, so every patient needs a slit-lamp examination.[3]

Cardiac sarcoidosis is the leading cause of sarcoid-related death. It presents with palpitations, syncope, conduction disease (bundle branch block, AV block, complete heart block), ventricular arrhythmia, cardiomyopathy and heart failure, and may declare itself as sudden cardiac death.[9]

Neurosarcoidosis occurs in 5 to 15 per cent and most often involves the cranial nerves (especially the facial nerve, which may be bilateral), the basal leptomeninges, the hypothalamic-pituitary axis (diabetes insipidus), the spinal cord and the cerebral parenchyma (seizures). Heerfordt syndrome with its facial palsy is the classic neurocutaneous presentation.[3]

The differential — exclude TB and fungal before any steroids

The differential of sarcoidosis is the differential of the granulomatous diseases and of bilateral hilar lymphadenopathy. The examiner expects you to list the mimics and the features that distinguish each.[1][7]

[1] [7]

The discriminator line: chronic beryllium disease is histologically identical to sarcoid — only the occupational exposure and the beryllium lymphocyte proliferation test tell them apart.[5]

Fungal infections — histoplasmosis, coccidioidomycosis, blastomycosis, cryptococcosis — produce granulomatous disease radiographically indistinguishable from sarcoid; distinguish them by endemic exposure, fungal serology and special stains. Lymphoma and metastatic malignancy cause mediastinal lymphadenopathy and B-symptoms; biopsy shows malignant cells. Hypersensitivity pneumonitis is distinguished by exposure history (bird fancier's, farmer's lung) and loose, poorly formed granulomas around bronchioles.[1]

For Löfgren syndrome, the differential is that of erythema nodosum itself — streptococcal pharyngitis, drugs (oral contraceptives, sulfonamides), inflammatory bowel disease, pregnancy, histoplasmosis and coccidioidomycosis. When the triad is classical, a clinical diagnosis without biopsy is endorsed by the ATS 2020 guideline.[1][13]

Investigations — three pillars

The diagnosis rests on three pillars: a compatible clinical and radiological picture, histological non-caseating granulomas in at least one tissue, and exclusion of the mimics (TB, fungal, berylliosis, lymphoma). Löfgren syndrome is the principal exception where biopsy is not required.[1][7]

Imaging. The chest X-ray stages the disease (Scadding 0 to IV); the classical appearance is bilateral hilar and right paratracheal lymphadenopathy (the "1-2-3 sign" or garland triad). High-resolution CT shows perilymphatic nodules (along bronchovascular bundles, fissures and subpleural regions), the galaxy sign, and the reversed-halo sign. Stage IV shows upper-lobe fibrosis with traction bronchiectasis.[1]

Pulmonary function tests show a restrictive defect with reduced FVC and total lung capacity and a disproportionately reduced DLCO. The FVC is the single best measure to follow over time; a fall of 10 per cent or more in FVC or 15 per cent or more in DLCO is a recognised threshold to initiate or escalate therapy.[8]

Histology. Demonstrate non-caseating granulomas from the most accessible involved tissue: skin lesion first (highest yield, lowest risk); then EBUS-TBNA of mediastinal and hilar nodes (yield 80 to 90 per cent, the modern preferred bronchoscopic technique); then transbronchial lung biopsy; and, failing those, surgical (VATS) biopsy. All material must be stained for AFB (Ziehl-Neelsen) and fungi (Grocott methenamine silver, PAS).[1]

Bloods and BAL. A full blood count may show anaemia, leukopenia or lymphopenia. Serum ACE is elevated in about 60 per cent of active cases but is non-specific (also raised in TB, lymphoma, asbestosis) and non-diagnostic — its main role is following disease activity over time. Serum and 24-hour urinary calcium are essential; hypercalciuria often precedes hypercalcaemia. BAL shows a lymphocytic alveolitis with a CD4:CD8 ratio over 3.5 — supportive, not diagnostic in isolation. The tuberculin skin test is typically negative (anergy), a useful contrast with TB.[7]

[1]

Management ladder — observe, steroid, spare, anti-TNF

[1]

The ladder is observe, corticosteroid, steroid-sparing, anti-TNF for refractory disease, then organ-specific measures. The thresholds for stepping up are as important as the drugs themselves.[2][8]

Step 1 — Observe. Asymptomatic pulmonary sarcoidosis (Scadding 0 to II with stable lung function and no dangerous organ involvement) is observed without therapy, because the disease resolves spontaneously in the majority. A reasonable surveillance schedule is clinical and spirometric review every 3 to 6 months for the first two years.[2]

Step 2 — Corticosteroids (first-line when treatment is needed). Oral prednisolone 20 to 40 mg per day (0.3 to 0.6 mg/kg/day for 4 to 6 weeks, then a taper over 6 to 24 months to the lowest effective maintenance dose of 5 to 15 mg/day) is started for symptomatic pulmonary disease, ocular disease not controlled by topical therapy, cardiac, neurologic or renal involvement, symptomatic hypercalcaemia, and disfiguring cutaneous disease. Löfgren syndrome usually needs only NSAIDs.[2]

Step 3 — Steroid-sparing agents. Added when disease is chronic or relapsing on steroid taper, when steroid toxicity is unacceptable, or for specific organs. The ERS 2021 guideline names methotrexate as the first steroid-sparing agent of choice — methotrexate 10 to 25 mg once weekly with folic acid 5 mg once weekly, monitoring FBC, liver and renal function every 4 to 8 weeks. Azathioprine 1 to 3 mg/kg/day (check TPMT activity first to avoid fatal myelosuppression) is a near-equivalent alternative. Hydroxychloroquine 200 to 400 mg/day is preferred for cutaneous disease.[2][6]

Step 4 — Anti-TNF for refractory disease. For refractory pulmonary, cardiac or neurosarcoidosis unresponsive to corticosteroids and two steroid-sparing agents, infliximab 3 to 5 mg/kg at weeks 0, 2 and 6, then every 8 weeks is the agent with the best evidence (the Baughman 2006 RCT showed a modest but significant FVC gain). Screening for latent TB (IGRA) and hepatitis B before anti-TNF is mandatory.[6][10]

[2] [6] [10]

Cardiac sarcoid — the one that kills

Cardiac sarcoidosis deserves its own paragraph because it kills. The presenting rhythm disturbances range from first-degree AV block, bifascicular block and complete heart block through sustained monomorphic ventricular tachycardia to sudden cardiac death. Diagnosis rests on cardiac MRI (basal, subepicardial or mid-wall late gadolinium enhancement of the septum or lateral wall) or FDG-PET (focal uptake), with the Heart Rhythm Society 2014 criteria.[9]

Treatment combines corticosteroids (0.5 to 1 mg/kg/day) to suppress active inflammation, an early steroid-sparing agent, and device therapy: a permanent pacemaker for symptomatic AV block, and an implantable cardioverter-defibrillator (ICD) for sustained ventricular arrhythmia, prior cardiac arrest, or an ejection fraction under 35 per cent despite optimised therapy. Every newly diagnosed sarcoid patient needs an ECG — any conduction disease mandates echocardiography and cardiac MRI.[9]

When it goes wrong — the preventable list

• Missing cardiac sarcoid — every new sarcoid patient needs an ECG; any conduction disease needs echocardiography and cardiac MRI. Sudden death is the leading mortality.[9]
• Steroids before excluding TB and fungal — caseating granuloma, positive AFB, Xpert MTB/RIF or fungal culture must redirect the diagnosis.[1]
• Over-treating asymptomatic disease — observe Scadding 0 to II with stable lung function; not every granuloma needs a steroid.[2]
• Missing hypercalcaemia — send a 24-hour urinary calcium at baseline; hypercalciuria precedes hypercalcaemia and silently causes nephrocalcinosis.[15]
• Neglecting drug toxicity — methotrexate (liver, lungs), azathioprine (TPMT, marrow), hydroxychloroquine (eye), infliximab (latent TB reactivation).[6][10]
• Missing uveitis — every patient needs a slit-lamp; untreated uveitis blinds.[3]

Prognosis and disposition

The prognosis is good for the majority and grave for the minority, and the job is to identify which patient sits at which end of the curve. Overall, 60 to 70 per cent of patients resolve within two years. Löfgren syndrome has the best outlook — 80 to 90 per cent resolve within two years, especially HLA-DRB1*03-positive patients, and the disease does not recur.[1][4][11]

The poor-prognosis features are lupus pernio; Scadding stage III and especially stage IV (fibrosis); chronic uveitis; hypercalcaemia; African ancestry; age of onset over 40; nasal mucosal involvement; bone cysts; and neurologic, cardiac or renal involvement. The leading causes of sarcoid-related death are respiratory failure from pulmonary fibrosis, sudden cardiac death, and neurologic disease.[4][15]

Most patients are managed as outpatients with respiratory or general medicine follow-up. Admission is reserved for suspected or confirmed cardiac sarcoid with arrhythmia, severe symptomatic hypercalcaemia, acute respiratory failure, and rapidly progressive neurosarcoidosis.[1]

Special populations

In pregnancy, sarcoidosis usually improves during the third trimester as the maternal immune system shifts toward Th2, and may flare postpartum. Corticosteroids are safe and remain first-line; azathioprine is relatively safe. Methotrexate and mycophenolate are absolutely contraindicated (teratogenic) and must be stopped before conception.[6]

African ancestry patients have about three times the incidence of white Americans, more often present with extrathoracic disease (cardiac, lupus pernio, bone cysts, ocular), and have more chronic, severe, steroid-dependent disease — warrant closer surveillance and earlier steroid-sparing therapy.[4]

The elderly present more insidiously; cardiac sarcoidosis is more common than in the young, and hypercalcaemia may be occult and mistaken for malignancy. The threshold for cardiac MRI and Holter monitoring should be lower. Immunocompromised patients and those on immune checkpoint inhibitors may develop a sarcoid-like granulomatous reaction; biopsy and exclusion of infection remain essential.[3]

[1] [4]

The evidence — ATS, ERS, ACCESS, infliximab

The two governing modern guidelines are the ATS 2020 Clinical Practice Guideline on Diagnosis and Detection (Crouser) and the ERS 2021 Clinical Practice Guideline on Treatment (Baughman). The ATS endorses tissue confirmation of non-caseating granulomas in most cases but accepts a clinical diagnosis of Löfgren syndrome without biopsy when the triad is classical, and supports EBUS-TBNA as the preferred bronchoscopic technique. The ERS codifies corticosteroids as first-line, methotrexate as the first steroid-sparing agent.[1][2]

The Delphi consensus treatment algorithm (Rahaghi 2020) operationalises the ladder: observe asymptomatic disease; start prednisolone 20 to 40 mg/day for symptomatic or worsening disease; add methotrexate at steroid taper or relapse; switch to or add infliximab for refractory disease; consider transplant for end-stage fibrosis.[8]

Landmark evidence includes the ACCESS study (Newman 2004) mapping the gene-environment model, the Baughman 2006 RCT of infliximab (the first positive anti-TNF trial in sarcoidosis, a modest FVC gain), and the Heart Rhythm Society 2014 expert consensus providing the criteria for cardiac sarcoidosis.[5][9][10]

The mantra, and the mnemonic

[1] [2]

The mantra: non-caseating granuloma, exclude TB first, observe the asymptomatic, steroid the symptomatic or organ-threatened, methotrexate to spare, infliximab for the refractory — and never miss the heart.[1]

[1] [2] [9]

Ward-round test — three stems, thirty seconds each

Stem 1 — the patient from the top of the topic (answer)

The 32-year-old with erythema nodosum, ankle arthritis, fever and bilateral hilar lymphadenopathy. What is the diagnosis, and what do you NOT need to do? Model: This is Löfgren syndrome — the acute triad of bilateral hilar lymphadenopathy, erythema nodosum and ankle arthritis with fever. When the picture is classical, biopsy is not required and management is NSAIDs and rest; 80 to 90 per cent resolve within two years. Review to exclude the mimics of erythema nodosum (streptococcal infection, drugs, inflammatory bowel disease). HLA-DRB1*03 predicts resolution. A short course of corticosteroids is reserved for severe arthritis or persistent symptoms.[1][11]

Stem 2 — the young man with syncope and bifascicular block (answer)

A 38-year-old with known pulmonary sarcoidosis presents with syncope and is found to have bifascicular block on ECG. What is the diagnosis, the investigation, and the treatment? Model: This is cardiac sarcoidosis — the leading cause of sarcoid-related death. Get a cardiac MRI (basal, subepicardial or mid-wall late gadolinium enhancement) or FDG-PET, plus echocardiography and a 24-hour Holter. Treat with corticosteroids (prednisolone 0.5 to 1 mg/kg/day) to suppress active inflammation, an early steroid-sparing agent, and device therapy — a permanent pacemaker for symptomatic AV block, an ICD for sustained ventricular arrhythmia or low ejection fraction. This is why every new sarcoid patient needs an ECG at diagnosis.[9]

Stem 3 — the histologically identical mimic (answer)

A 45-year-old aerospace machinist has non-caseating granulomas on lung biopsy, identical to sarcoidosis. What is the one test that distinguishes the diagnosis, and why does it matter? Model: This is chronic beryllium disease (berylliosis) — histologically identical to sarcoidosis. The distinguishing test is the beryllium lymphocyte proliferation test (BeLPT) on blood or BAL, plus the occupational exposure history (aerospace, nuclear, electronics, dental industries). It matters because treatment begins with removal from beryllium exposure alongside corticosteroids, and because it proves an inorganic metal antigen can generate a sarcoid-like granuloma.[5]

References

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2. [2]Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis Eur Respir J, 2021.PMID 34140301
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8. [8]Rahaghi FF, Baughman RP, Saketkoo LA, et al. Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis Eur Respir Rev, 2020.PMID 32198218
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10. [10]Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement Am J Respir Crit Care Med, 2006.PMID 16840744
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12. [12]Ezeh N, Caplan A, Rosenbach M, et al. Cutaneous Sarcoidosis Dermatol Clin, 2023.PMID 37236714
13. [13]Pérez-Garza DM, Chavez-Alvarez S, Ocampo-Candiani J, et al. Erythema Nodosum: A Practical Approach and Diagnostic Algorithm Am J Clin Dermatol, 2021.PMID 33683567
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