Sarcoidosis

Meet the patient

A 34-year-old woman of Afro-Caribbean descent arrives with tender red nodules over both shins, swollen ankles she cannot walk on, a low-grade fever, and a chest X-ray the registrar calls "bat-wing hilar nodes". She has never been in hospital before. The skin plus the film plus the joints is the diagnosis before the biopsy.[3]

Hold the two questions that decide her next two years: is this the good-prognosis face or the bad-prognosis face of sarcoidosis? (the skin and the X-ray answer within a day) and is a vital organ threatened? (the ECG, the slit-lamp, and the calcium answer over the next week). Those two questions sort every sarcoid patient into the two camps that matter — watch and reassure, or treat hard.[1]

One disease, one granuloma, two faces on the skin

Sarcoidosis is one disease read through two questions: what does the skin say, and what does the biopsy say. Every case begins the same way — an unknown antigen triggers an exaggerated Th1 response in a genetically susceptible host, and activated macrophages organise into sterile, non-caseating epithelioid granulomas in one or more organs. The lung and lymph nodes carry 90 percent of the load, but the skin, eyes, heart, nerves, liver, spleen, bones, and kidneys are all in play.[1]

The macrophage is the cornerstone of the whole disease, and everything examinable hangs off it. It expresses 1-alpha-hydroxylase and makes 1,25-dihydroxyvitamin D extrarenally — which is why sarcoid patients turn hypercalcaemic. It secretes angiotensin-converting enzyme (ACE) — the serum marker you must learn to distrust. It produces TNF-alpha — the target of infliximab and adalimumab. And it forms the epithelioid cell and the giant cell of the granuloma itself.[1]

The skin divides sarcoidosis into two camps, and the division is the single most examinable cut on the topic. Specific lesions contain granulomas — biopsy one and you have histological proof of systemic disease. Non-specific lesions are reactive — erythema nodosum shows septal panniculitis, no granulomas, and does NOT confirm sarcoidosis on biopsy. The distinction decides prognosis and treatment.[3][4]

[1]

Specific vs non-specific — the cut that decides everything

Specific means granuloma on biopsy; non-specific means reactive. That single line is the discriminator the examiner wants.[3]

[3]

The one-line discriminator beneath the table: granuloma on biopsy points to specific, chronic, treat; panniculitis on biopsy points to non-specific, acute, reassure.[4]

The 'naked' granuloma — and why you exclude TB first

The 'naked' granuloma is the histological signature of sarcoidosis — compact epithelioid macrophages and giant cells with a sparse lymphocytic cuff and no central necrosis. It is called "naked" precisely because it lacks the dense lymphocytic rim and the caseous centre of the tuberculous granuloma. Inside the giant cells you may find asteroid bodies (star-shaped eosinophilic inclusions) and Schaumann bodies (laminated calcified concretions) — both are non-specific, seen in berylliosis and foreign-body reactions too, so they never clinch the diagnosis.[1]

The histology never stands alone. Diagnosis is a triad: a compatible clinical and radiological picture, histological non-caseating granulomas in at least one tissue, and exclusion of every other granulomatous disease — above all tuberculosis and fungal infection. Send Ziehl-Neelsen for AFB, PAS and GMS for fungi, and PCR for M. tuberculosis off every granulomatous biopsy before you write "sarcoidosis". The diagnosis is one of exclusion dressed as one of inclusion.[1][3]

Sarcoid vs TB — the granuloma face-off

Two granulomas, two questions: is there caseation, and how dense is the lymphocytic cuff? That is the discriminator a pathologist hands back to you.[1]

[1]

The one-line discriminator: caseation and a dense lymphocytic cuff point to TB; naked and sparse point to sarcoid — but send the stains either way.[1]

The classic trap: sarcoidosis mimics TB and TB mimics sarcoidosis, and the trap cuts both ways. A patient with caseating granulomas mislabelled "sarcoidosis" and started on steroids alone will disseminate their tuberculosis. A patient with sarcoidosis mislabelled "TB" will swallow months of unnecessary, toxic anti-tuberculous therapy. The escape from both traps is the same: AFB stain, fungal stain, and TB culture on every granulomatous biopsy, before the diagnosis is locked.[1]

The cutaneous subtypes that bite

Four specific lesions earn their own names because each carries a different prognosis. Memorise the quartet.[3]

• Lupus pernio — chronic, violaceous, indurated plaques on the nose, cheeks, ears, lips, and fingers. The most disfiguring and most treatment-resistant cutaneous form. It is the skin sign of chronic pulmonary fibrosis, upper respiratory tract involvement, and bone cysts — see it and image the chest and sinuses.[3]
• Scar and tattoo sarcoidosis — granulomatous infiltration of old surgical or trauma scars, tattoos, and venepuncture sites. Sarcoidosis literally seeks out scars; a purple, thickening old scar is a diagnostic gift. Never tattoo a sarcoidosis patient — the ink will turn granulomatous.[3]
• Darier-Roussy subcutaneous sarcoidosis — painless firm subcutaneous nodules on trunk and limbs; granulomas in the subcutis; mimics panniculitis and lymphoma.[4]
• Papules and plaques — red-brown to violaceous, on face, neck, shoulders, extensor limbs; apple-jelly colour on diascopy, mirroring cutaneous TB.[4]

Rarer still are mucosal, nail, ulcerative, verrucous, hypopigmented, ichthyosiform, and alopecic variants — name them in the viva, do not dwell on them.[4]

Systemic disease and the two named syndromes

Löfgren syndrome is the good-prognosis face, and it is a triad you must reproduce verbatim: erythema nodosum plus bilateral hilar lymphadenopathy plus ankle arthritis, with or without fever. It is acute, self-limiting, and resolves within two years in roughly 90 percent — usually needs no more than NSAIDs, sometimes colchicine, and reassurance. It carries the HLA-DRB1 star-03 association, which is the genetic marker of the favourable outcome. This is the patient you send home with safety-netting, not steroids.[3][5]

Heerfordt syndrome (uveoparotid fever) is the other named cluster, and it is a tetrad: anterior uveitis plus parotid gland enlargement plus facial nerve (CN VII) palsy plus fever. It is rare but unforgettable — and it is the reason a facial palsy with a swollen parotid and a red eye is sarcoidosis until proven otherwise, not Bell palsy.[1]

The rest of the systemic map is the organ-by-organ survey the examiner wants named in order:[1]

• Pulmonary (90 percent) — bilateral hilar lymphadenopathy is the radiological hallmark; interstitial infiltrates and fibrosis follow, upper-lobe predominant. Scadding chest X-ray stages run 0 to 4: Stage 0 normal; Stage 1 BHL only; Stage 2 BHL plus infiltrates; Stage 3 infiltrates only; Stage 4 pulmonary fibrosis.[1]
• Ocular (10-30 percent) — anterior uveitis is commonest and sight-threatening; conjunctival nodules and dry eye round it out.[1]
• Bone — cystic radiolucent phalangeal lesions, often riding alongside lupus pernio.[3]
• Hepatic and splenic — granulomatous hepatitis, hepatosplenomegaly, abnormal LFTs.[1]
• Salivary and lacrimal glands — bilateral enlargement that mimics Sjögren syndrome.[1]

The killers — heart, calcium, nerve

Three organs kill or maim the sarcoid patient, and none of them is the skin you were referred for. Screen for all three at diagnosis.[2]

• Cardiac sarcoidosis is the leading cause of sarcoidosis-related death — sudden cardiac death from ventricular tachycardia or complete heart block. Granulomas infiltrate the myocardium and conduction system. Every newly diagnosed sarcoid patient gets a 12-lead ECG and a cardiac MRI with late gadolinium enhancement; add Holter monitoring and an echocardiogram. An ICD is considered for sustained VT or an LVEF at or under 35 percent, and a pacemaker for complete heart block. Never dismiss palpitations or syncope in a known sarcoid patient.[2]
• Hypercalcaemia and hypercalciuria — the activated macrophage makes 1,25-dihydroxyvitamin D extrarenally, so calcium rises independent of PTH. Check serum calcium and a 24-hour urinary calcium at baseline. The downstream harm is nephrocalcinosis, nephrolithiasis, and renal impairment — counsel against excess vitamin D and reckless sun exposure.[1]
• Neurosarcoidosis (about 5 percent) — cranial nerve palsies dominate, and CN VII is the commonest, often bilateral ("facial diplegia") and easily mistaken for Bell palsy, Lyme disease, or Guillain-Barré. Aseptic meningitis, hypothalamic-pituitary involvement (diabetes insipidus), seizures, and optic neuropathy complete the picture.[1]

Investigations — the triad and the useless ACE

Diagnosis is the triad: a compatible clinical-radiological picture, non-caseating granulomas in tissue, and exclusion of the mimics. No single test makes the diagnosis — not even the ACE.[1]

• Skin biopsy of a specific lesion — the most accessible tissue and the highest yield; biopsy a papule, plaque, or scar.[3]
• Chest X-ray and HRCT — bilateral hilar lymphadenopathy, interstitial infiltrates, fibrosis; stage with Scadding.[1]
• Pulmonary function tests — restrictive pattern with reduced DLCO.[1]
• Serum calcium and 24-hour urinary calcium — for hypercalcaemia and hypercalciuria.[1]
• FBC, LFTs, renal function, electrolytes — lymphopenia is common; baseline organ function.[1]
• ECG and cardiac MRI — screen the heart in everyone.[2]
• Ophthalmology slit-lamp — screen for uveitis.[1]
• Bronchoalveolar lavage — a CD4:CD8 ratio above 3.5 supports the diagnosis.[1]

What about serum ACE and the Gallium scan?

Serum ACE is elevated in roughly 60 percent of patients but is non-specific — it rises in TB, lymphoma, thyroid disease, diabetes, and even healthy people. Sensitivity about 60 percent, specificity about 70 percent. It is a monitoring tool, not a diagnostic one — and ACE alone never diagnoses sarcoidosis. Do not order it to make the call; order the biopsy.[1]

The Gallium-67 scan is largely historical. Its "panda" sign (bilateral parotid and lacrimal uptake) and "lambda" sign (bilateral hilar plus right paratracheal uptake) are viva gold but are rarely used now that MRI and PET-CT have taken over.[1]

Differential — the great mimicker

Sarcoidosis is the great mimicker, and the differential is long because the granuloma is a final common pathway. Sort it by what the biopsy shows.[1]

[1]

For erythema nodosum (septal panniculitis) the differential is its own list — streptococcal infection, drugs (oral contraceptive pill, sulphonamides), inflammatory bowel disease, Behçet disease, pregnancy, and malignancy — all of which must be weighed alongside sarcoidosis when a patient presents with tender shin nodules.[5]

Management — steroids when an organ is threatened

Treat the organ, not the biopsy. Most cutaneous sarcoidosis needs no systemic therapy; organ-threatening disease needs it urgently and for a long time. The ERS 2021 guidelines stratify therapy exactly this way.[2]

[2]

Corticosteroids are first-line the moment a vital organ is threatened. Oral prednisolone 20-40 mg/day (0.5-1 mg/kg/day) for two to four weeks, then a slow taper toward 5-10 mg by month three, running 6-24 months in total — because relapse on rapid taper runs 30-50 percent. For acute cardiac or neurosarcoidosis, start at the upper end and often precede it with IV methylprednisolone 500-1000 mg daily for three to five days. Add bone protection (calcium, vitamin D, a bisphosphonate) and monitor glucose and blood pressure from day one.[2]

Methotrexate 15 mg once weekly (with folic acid 5 mg the day after) is the most widely used steroid-sparing agent in sarcoidosis; full onset takes 6-12 weeks, the ceiling is 25 mg weekly, and it is teratogenic — both partners need contraception and a washout of at least three months before conception.[7]

Hydroxychloroquine 200-400 mg/day (weight-dosed at or under 6.5 mg/kg ideal body weight) is first-line systemic therapy for chronic cutaneous sarcoidosis — especially lupus pernio — and for sarcoid-related hypercalcaemia; arrange baseline and annual ophthalmology review with spectral-domain OCT and visual fields.[3]

Infliximab 5 mg/kg IV at weeks 0, 2, and 6 then every 4-8 weeks is the biologic of choice for refractory lupus pernio, cardiac sarcoidosis, and neurosarcoidosis; QuantiFERON or IGRA screening for latent TB is mandatory before the first infusion — infliximab reactivates TB. Adalimumab 40 mg subcutaneously every two weeks (weekly for refractory disease) is the principal subcutaneous alternative.[7]

[2]

Second-line and niche agents — name them in the viva

Azathioprine 1-3 mg/kg/day (typically 100-200 mg/day) is the preferred steroid-sparing agent in pregnancy — but TPMT activity must be checked first, because homozygous TPMT deficiency causes life-threatening pancytopenia.[2]

Mycophenolate mofetil 1-1.5 g twice daily is increasingly used for refractory cutaneous and neurosarcoidosis; it is teratogenic and commonly upsets the gut.[2]

Minocycline or doxycycline 100 mg twice daily has small-series evidence in mild cutaneous sarcoidosis — an anti-inflammatory rather than antimicrobial effect. Repository corticotropin (ACTH) gel 40-80 units every 1-2 weeks is FDA-approved but rarely used outside the US. Tetracyclines are avoided in pregnancy and in children under 12 years.[7]

Prognosis — two camps, one decision

Prognosis sorts cleanly along the same line as treatment: Löfgren is good, lupus pernio and fibrosis are bad, and cardiac disease is the killer.[6]

• Löfgren syndrome — excellent; resolves within two years in most; the HLA-DRB1 star-03 allele predicts the good outcome.[3]
• Lupus pernio and chronic pulmonary fibrosis (Stage 4) — chronic, progressive, treatment-resistant; poorer prognosis.[3]
• Cardiac sarcoidosis — the leading cause of sarcoidosis-related death; demands screening and treatment.[2]
• Overall mortality is 1-5 percent; the main causes are respiratory failure, cardiac involvement, and neurosarcoidosis.[6]

[1]

The traps every candidate must name

The classic trap: a granulomatous biopsy labelled "sarcoidosis" without excluding TB, started on steroids alone, that disseminates tuberculosis. The escape is mandatory — AFB stain, fungal stain, and TB culture on every granulomatous biopsy before the diagnosis is locked.[1]

• Never tattoo a sarcoidosis patient — the ink turns granulomatous and the scar reactivates disease.[3]
• Misdiagnosing TB and giving anti-tuberculous therapy — the mirror-image trap; months of unnecessary, toxic treatment for a patient whose granulomas were naked all along.[1]
• ACE alone never diagnoses sarcoidosis — sensitivity 60 percent, specificity 70 percent; it is a monitoring tool, not a diagnostic test. Do not let a registrar order "ACE to confirm".[1]
• A normal chest X-ray does not exclude cardiac sarcoidosis — only about 5 percent have BHL at cardiac presentation; the ECG and cardiac MRI do the work.[2]
• Erythema nodosum does not confirm sarcoidosis on biopsy — it is septal panniculitis, not granuloma; it is the clue that sends you looking for Löfgren syndrome, not the proof.[5]
• Paradoxical sarcoidosis on anti-TNF — new granulomatous disease can emerge when infliximab or adalimumab is used for rheumatoid arthritis or inflammatory bowel disease; recognise the irony, do not dismiss it.[7]

Etymology — one line of viva gold

Sarcoidosis is from the Greek sarkoides, "flesh-like" — the cutaneous papules were mistaken for fleshy tumours when Ernest Besnier first described lupus pernio in 1889. Caesar Boeck added the histology in 1899 and coined "multiple benign sarkoid", and Jörgen Schaumann tied the multisystem disease together in 1917 — hence Besnier-Boeck-Schaumann disease, the eponym still heard in European clinics and on the synonym line of this page.[1]

The mantra, and the honesty line

Naked granuloma, exclude TB first, steroids when an organ is threatened.[1]

Everything else — the hydroxychloroquine for the skin, the methotrexate to spare the steroid, the infliximab for the refractory lupus pernio, the ICD for the failing heart — is a refinement on those three commitments. Hold the three and the page holds together.[1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the woman with the bat-wing hilum (answer)

The 34-year-old with bilateral hilar lymphadenopathy, erythema nodosum, ankle arthritis, and fever. What is the syndrome, the prognosis, and the treatment?[3]

Model: This is Löfgren syndrome — the triad of erythema nodosum, bilateral hilar lymphadenopathy, and ankle arthritis, with or without fever. It is acute and self-limiting, resolving within two years in about 90 percent, carries the HLA-DRB1 star-03 favourable association, and usually needs no corticosteroids — NSAIDs and reassurance, with colchicine for the arthralgia if needed, safety-netting, and follow-up imaging. This is the good-prognosis face of sarcoidosis; do not over-treat it.[3][5]

Stem 2 — the violaceous nose (answer)

A 52-year-old smoker develops chronic violaceous indurated plaques over the nose and cheeks, with nasal crusting and a chronic cough. Biopsy shows naked granulomas. What does the skin sign predict, and what do you screen for?[3]

Model: This is lupus pernio — the most disfiguring and treatment-resistant cutaneous sarcoidosis, and the skin sign of chronic pulmonary fibrosis, upper respiratory tract involvement, and bone cysts. Screen the chest with HRCT (expect Stage 3 to 4 fibrosis), the sinuses and upper airway, and the hands for radiolucent bone cysts. Add an ECG and cardiac MRI in every newly diagnosed patient. Treatment is systemic — hydroxychloroquine first, escalating to methotrexate then a TNF inhibitor for refractory disease; topical therapy alone will not touch lupus pernio.[3]

Stem 3 — the syncope at the sarcoid clinic (answer)

A known sarcoidosis patient on hydroxychloroquine for cutaneous disease mentions two episodes of syncope in a week. What is the first thing you do?[2]

Model: Treat this as presumed cardiac sarcoidosis until proven otherwise — cardiac sarcoid is the leading cause of sarcoidosis-related death, and the mechanism is sudden cardiac death from ventricular tachycardia or complete heart block. Get a 12-lead ECG now, arrange a cardiac MRI with late gadolinium enhancement, Holter monitoring, and an echocardiogram, and refer to cardiology the same day. Never attribute syncope in a sarcoid patient to a vasovagal cause without clearing the heart.[2]

References

1. [1]Sève P, Pacheco Y, Durupt F, et al. Sarcoidosis: A Clinical Overview from Symptoms to Diagnosis Cells, 2021.PMID 33807303
2. [2]Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis Eur Respir J, 2021.PMID 34140301
3. [3]Ezeh N, Caplan A, Rosenbach M, et al. Cutaneous Sarcoidosis Dermatol Clin, 2023.PMID 37236714
4. [4]Abdelghaffar M, Hwang E, Damsky W. Cutaneous Sarcoidosis Clin Chest Med, 2024.PMID 38245372
5. [5]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
6. [6]Rossides M, Darlington P, Kullberg S, et al. Sarcoidosis: Epidemiology and clinical insights J Intern Med, 2023.PMID 36872840
7. [7]Gerke AK. Treatment of Sarcoidosis: A Multidisciplinary Approach Front Immunol, 2020.PMID 33329511