Sarcoidosis
Non-caseating granulomatous disease affecting multiple organs. Lungs involved in 90%. Bilateral hilar lymphadenopathy on CXR is the hallmark. Young adults, especially African Americans. Lofgren syndrome = excellent prognosis.
🔍 Overview
Overview
Sarcoidosis is a systemic granulomatous disease of unknown etiology characterized by non-caseating granulomas in affected organs. The lungs are involved in ~90% of cases. Other commonly affected organs: skin (erythema nodosum, lupus pernio), eyes (anterior uveitis), liver (granulomatous hepatitis), heart (conduction abnormalities, cardiomyopathy), and nervous system (cranial nerve palsies, especially CN VII). Epidemiology: peaks at age 25-35, higher incidence and more severe disease in African Americans and Scandinavians.
Lofgren Syndrome
A specific acute presentation with an excellent prognosis (>90% spontaneous resolution): bilateral hilar lymphadenopathy + erythema nodosum + polyarthralgia + fever. So characteristic that biopsy is often NOT required for diagnosis. More common in young women.
Scadding CXR Staging
- Stage 0 -Normal CXR
- Stage I -Bilateral hilar lymphadenopathy (BHL) alone. ~60-80% spontaneous remission.
- Stage II -BHL + pulmonary infiltrates. ~50-60% remission.
- Stage III -Pulmonary infiltrates WITHOUT lymphadenopathy. ~30% remission.
- Stage IV -Pulmonary fibrosis. Irreversible. Poor prognosis.
🚨 Management
Treatment Approach
Many patients need NO treatment -sarcoidosis is self-resolving in a large proportion of cases, especially Stage I and Lofgren syndrome. Observation alone is appropriate for asymptomatic patients with stable disease.
Indications for Treatment
- Progressive pulmonary disease -worsening PFTs, increasing infiltrates
- Cardiac involvement -heart block, cardiomyopathy, ventricular arrhythmias
- Neurological involvement -cranial nerve palsies, CNS mass lesions, seizures
- Hypercalcemia -from granulomatous production of 1,25-dihydroxyvitamin D
- Disfiguring skin disease -lupus pernio
- Significant eye disease -posterior uveitis, optic neuritis refractory to topical therapy
- Renal involvement -nephrocalcinosis, nephrolithiasis from hypercalciuria
First-Line Therapy
Prednisone 20-40 mg daily x 4-6 weeks, then slow taper over 6-12 months. Total treatment duration typically 12+ months. Relapse rate is high (~30-50%) when steroids are tapered. NSAIDs can be used for mild arthralgia and erythema nodosum.
Steroid-Sparing Agents
Consider when: unable to taper below prednisone 10 mg/day, steroid side effects, or relapse on taper.
- Methotrexate (Trexall) -most commonly used steroid-sparing agent. 10-15 mg weekly. Supplement with folic acid.
- Azathioprine (Imuran) -alternative to MTX. 50-200 mg daily. Check TPMT before starting.
- Mycophenolate (CellCept) -500-1500 mg BID. Used for refractory disease.
Refractory Disease
Infliximab (Remicade) -anti-TNF-alpha. Reserved for severe disease failing conventional therapy. Evidence strongest for lupus pernio and neurosarcoidosis.
🧪 Workup
Diagnostic Workup
- CXR -Scadding staging (I-IV). Bilateral hilar lymphadenopathy is classic.
- CT chest -better characterization of parenchymal disease, lymphadenopathy pattern
- PFTs -restrictive pattern (decreased FVC, decreased DLCO). Obstructive pattern also possible with endobronchial involvement.
- ACE level -elevated in ~60% but NOT diagnostic. Neither sensitive nor specific (see alert below).
- Calcium -check serum calcium (hypercalcemia from granulomatous 1,25-vitamin D production)
- 24-hour urine calcium -hypercalciuria may be present even with normal serum calcium
- CBC, BMP, LFTs -baseline; elevated alk phos suggests hepatic granulomas
- ECG -screen for heart block (PR prolongation, bundle branch block). If abnormal, consider cardiac MRI or PET.
- Ophthalmology exam -screen for uveitis (anterior > posterior), even if asymptomatic
- Biopsy of accessible tissue -lung (transbronchial), skin, lymph node. REQUIRED for definitive diagnosis.
ACE level is NOT a good diagnostic test for sarcoidosis. Sensitivity ~60%, specificity poor. Many false positives and false negatives. ACE inhibitors lower it (false negative), diabetes can raise it (false positive). Diagnosis requires tissue biopsy showing non-caseating granulomas PLUS exclusion of other causes (TB, fungal infection, lymphoma, berylliosis).
💊 Medications
Medications
| Drug | Dose | Route | Notes |
|---|---|---|---|
| Prednisone 1ST LINE | 20-40 mg daily x 4-6 wk, then taper over 6-12 months | PO | Start at higher dose for severe organ involvement (cardiac, neuro). Monitor glucose, BP, bone density. |
| Methotrexate (Trexall) | 10-15 mg weekly | PO/SQ | Most common steroid-sparing agent. Add folic acid 1 mg daily. Monitor LFTs, CBC q4-8 weeks. Avoid in pregnancy (teratogenic). Vorselaars, Chest 2013 |
| Azathioprine (Imuran) | 50-200 mg daily | PO | Check TPMT before starting (homozygous deficiency = fatal myelosuppression). Monitor CBC regularly. |
| Mycophenolate (CellCept) | 500-1500 mg BID | PO | Alternative steroid-sparing. GI side effects common. Monitor CBC. |
| Infliximab (Remicade) | 3-5 mg/kg IV at weeks 0, 2, 6, then q4-8 weeks | IV | For refractory disease. Screen for TB before starting (anti-TNF reactivates latent TB). Baughman, AJRCCM 2006 |
| Hydroxychloroquine | 200-400 mg daily | PO | Useful for skin sarcoidosis, hypercalcemia, and fatigue. Annual eye exams for retinal toxicity. |
🏥 Rounds
Pimp Questions
❓ Why is ACE level a poor diagnostic test for sarcoidosis?
ACE is produced by epithelioid cells in granulomas. However, it has sensitivity of only ~60% and poor specificity. ACE inhibitors lower the level (false negative), while diabetes, hyperthyroidism, and other granulomatous diseases can raise it (false positive). It should NEVER be used as a sole diagnostic criterion. Diagnosis requires tissue biopsy + exclusion of other causes.
❓ What is Lofgren syndrome and why is it important?
Lofgren syndrome is an acute presentation of sarcoidosis with the triad of: (1) bilateral hilar lymphadenopathy, (2) erythema nodosum, (3) polyarthralgia, often with fever. It has an excellent prognosis (>90% spontaneous resolution) and is so characteristic that biopsy is often not required for diagnosis. Treatment is usually supportive (NSAIDs for symptoms).
❓ How does sarcoidosis cause hypercalcemia?
Activated macrophages within sarcoid granulomas express 1-alpha-hydroxylase, which converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol). This extra-renal production is NOT regulated by PTH, leading to increased intestinal calcium absorption and hypercalcemia. Treatment: corticosteroids suppress macrophage activity. PTH is appropriately suppressed (unlike primary hyperparathyroidism).
❓ What cardiac manifestations should you screen for in sarcoidosis?
Cardiac sarcoidosis can cause: (1) conduction abnormalities -AV block (most common), bundle branch block, (2) ventricular arrhythmias -VT, sudden cardiac death, (3) cardiomyopathy -dilated or restrictive. Screen all patients with an ECG. If abnormal or symptomatic, pursue cardiac MRI (late gadolinium enhancement) or FDG-PET. Cardiac involvement is a leading cause of death in sarcoidosis.
❓ When do you NOT need a biopsy for sarcoidosis diagnosis?
Biopsy may be deferred in two scenarios: (1) Lofgren syndrome -the classic triad of bilateral hilar LAD + erythema nodosum + polyarthralgia is so specific that it is considered virtually diagnostic, (2) Asymptomatic bilateral hilar lymphadenopathy in a young patient with a classic CXR pattern and no concerning features for lymphoma or infection -though many clinicians still prefer biopsy confirmation.
Clinical Examples
📋 Case 1, Stage II Sarcoidosis with Multisystem Disease
Patient: 34-year-old African American woman with 3 months of dry cough, dyspnea, and painful shin nodules. Blurry vision OS.
Key findings: CXR: bilateral hilar LAD + reticular opacities (Stage II). PFTs: FVC 65%, DLCO 58%. Calcium 11.2. Ophthalmology: anterior uveitis. Biopsy: non-caseating granulomas, AFB/fungal negative.
Management:
- Prednisone 40 mg daily × 4-6 weeks, then taper over 6-12 months
- Topical steroids for uveitis (ophthalmology comanagement)
- Methotrexate as steroid-sparing agent for prolonged therapy
- ECG screening for cardiac sarcoidosis
Teaching point: Not all sarcoidosis needs treatment. Indications: progressive pulmonary disease, hypercalcemia, cardiac involvement, neurosarcoidosis, sight-threatening uveitis.
📋 Case 2, Lofgren Syndrome
Patient: 28-year-old Scandinavian woman with acute bilateral ankle pain, fever, and tender erythematous shin nodules × 1 week.
Key findings: CXR: bilateral hilar LAD (Stage I). Classic triad: BHL + erythema nodosum + polyarthralgia. ESR elevated. Calcium normal.
Management:
- Biopsy NOT required, Lofgren syndrome is clinically diagnostic
- > 90% spontaneous resolution within 2 years
- NSAIDs for symptoms. Low-dose prednisone only if refractory.
- Follow-up CXR in 3-6 months to confirm resolution
Teaching point: Lofgren syndrome has the best prognosis in sarcoidosis. Recognize the triad. Rarely needs immunosuppression.
📋 Case 3, Cardiac Sarcoidosis
Patient: 42-year-old man with known pulmonary sarcoidosis presenting with palpitations and near-syncope. ECG: new complete heart block.
Key findings: Cardiac MRI: late gadolinium enhancement in basal septum. LVEF 40% (was 55%). FDG-PET: active myocardial inflammation. No CAD on angiography.
Management:
- Temporary pacing wire; evaluate for permanent pacemaker/ICD
- Prednisone 40-60 mg daily for active cardiac sarcoidosis
- Steroid-sparing agent (methotrexate or mycophenolate)
- ICD if LVEF ≤ 35% or sustained VT
- Guideline-directed HF therapy
Teaching point: Cardiac sarcoidosis is a leading cause of death. Screen ALL sarcoidosis patients with ECG. New AV block or unexplained cardiomyopathy → cardiac MRI or FDG-PET.
Sample Presentation
Ms. Davis is a 34-year-old African American woman presenting with 3 months of dry cough, progressive dyspnea on exertion, and bilateral ankle swelling. She also notes painful red bumps on her shins and bilateral ankle pain. CXR shows bilateral hilar lymphadenopathy with diffuse reticular opacities (Stage II). PFTs: FVC 65% predicted, DLCO 58% predicted. Labs: calcium 11.2, ACE level 85 (elevated), LFTs mildly elevated. Ophtho exam: anterior uveitis OS. Transbronchial biopsy: non-caseating granulomas. AFB and fungal stains negative.
Key Points: Classic Stage II sarcoidosis with multisystem involvement (lungs, skin -erythema nodosum, eyes -uveitis, liver, hypercalcemia). Treatment indicated given progressive pulmonary disease and hypercalcemia. Start prednisone 40 mg daily. Plan for steroid-sparing agent (MTX) given likely need for prolonged therapy.
Monitoring
- PFTs -repeat every 3-6 months while on treatment. FVC and DLCO most useful for tracking disease activity.
- CXR or CT chest -every 6-12 months depending on disease severity.
- Serum calcium and 24h urine calcium -monitor for hypercalcemia/hypercalciuria, especially when tapering steroids.
- Ophthalmology -annual screening even if asymptomatic. More frequent if active uveitis.
- ECG -annual. Low threshold for cardiac MRI or PET if new symptoms (palpitations, syncope, dyspnea).
- LFTs -monitor for hepatic sarcoidosis and drug toxicity (MTX, azathioprine).
- CBC -for steroid-sparing drug monitoring (MTX, azathioprine, mycophenolate).
- Bone density (DEXA) -if on prolonged steroids (>3 months prednisone >= 5 mg/day).
- ACE level -some clinicians follow trends, but NOT useful for diagnosis or as sole marker of disease activity.
📋 Summary
Summary
Recognize It
Non-caseating granulomas in multiple organs, with lungs involved in about 90%. Bilateral hilar lymphadenopathy on chest x-ray is the hallmark. Typically young adults, with higher incidence and more severe disease in African Americans.
Lofgren Syndrome Needs No Biopsy
Erythema nodosum, bilateral hilar lymphadenopathy, arthralgia and fever. The constellation is diagnostic on its own, and the prognosis is excellent with spontaneous remission in most patients, so the treatment is NSAIDs and observation rather than steroids.
Scadding Stage Predicts Remission
Stage I hilar adenopathy alone, 60 to 90% remit. Stage II adenopathy plus infiltrates, 40 to 70%. Stage III infiltrates alone, 10 to 20%. Stage IV fibrosis, which does not reverse. The staging is radiographic, not sequential: patients do not necessarily pass through the stages in order.
ACE Level Does Not Make the Diagnosis
Sensitivity is only about 60% and specificity is poor. ACE inhibitors lower it, giving a false negative; diabetes and other granulomatous disease raise it. Diagnosis requires compatible imaging plus tissue showing non-caseating granulomas, plus exclusion of the mimics, above all tuberculosis and fungal infection, since the histology looks similar and steroids would be disastrous.
Not Everyone Needs Treatment
Asymptomatic stage I disease is observed, because most of it remits on its own. Treat for organ threat or symptoms: cardiac involvement, neurosarcoidosis, ocular disease, hypercalcemia, progressive lung disease with declining function, or disabling symptoms.
First Line and the Taper
Prednisone 20 to 40 mg daily for 4 to 6 weeks, then a taper over 6 to 12 months, with a higher starting dose for cardiac and neurologic disease. Tapering too quickly is the commonest cause of relapse, and courses shorter than 6 months relapse often enough that they mostly waste the steroid exposure.
Steroid-Sparing When the Course Is Long
Methotrexate 10 to 15 mg weekly is the usual second agent, with folic acid and monitoring of liver tests and blood counts. Azathioprine requires TPMT testing first, because homozygous deficiency causes fatal myelosuppression. Infliximab for refractory disease, after screening for latent tuberculosis, since anti-TNF therapy reactivates it.
Two Complications That Are Missed
Cardiac sarcoidosis causes heart block, ventricular arrhythmia and sudden death, and can be the presenting event. Any conduction abnormality or unexplained cardiomyopathy in a sarcoid patient warrants cardiac MRI or FDG-PET. Hypercalcemia comes from granuloma 1-alpha-hydroxylase converting vitamin D, so it is worsened, not helped, by vitamin D supplementation, and these patients should avoid sun and calcium loading.
📄 One Pager
Text version
PULM / RHEUM · One Pager
Sarcoidosis
Non-caseating granulomas in multiple organs, lungs involved in ~90%. The hard part is not making the diagnosis, it is deciding who actually needs steroids, because a large proportion of patients resolve on their own.
Diagnosis and Scadding CXR Staging
- Diagnosis requires two things: tissue biopsy showing non-caseating granulomas plus exclusion of other causes (TB, fungal infection, lymphoma, berylliosis). Biopsy accessible tissue: lung (transbronchial), skin, or lymph node.
- Stage 0: normal CXR.
- Stage I: bilateral hilar lymphadenopathy (BHL) alone. ~60–80% spontaneous remission, which is why observation is a legitimate plan, not neglect.
- Stage II: BHL + pulmonary infiltrates. ~50–60% remission.
- Stage III: pulmonary infiltrates without lymphadenopathy. ~30% remission.
- Stage IV: pulmonary fibrosis. Irreversible, poor prognosis, and the reason you follow PFTs rather than waiting for symptoms.
- Lofgren syndrome: BHL + erythema nodosum + polyarthralgia + fever. > 90% spontaneous resolution, so characteristic that biopsy is often not required. More common in young women.
- Epidemiology that raises suspicion: peaks at age 25–35, higher incidence and more severe disease in African Americans and Scandinavians.
Treat vs Observe
- Many patients need no treatment at all. Sarcoidosis self-resolves in a large proportion of cases, especially Stage I and Lofgren syndrome. Observation alone is appropriate for the asymptomatic patient with stable disease, and steroids carry real harm over 12+ months.
- Progressive pulmonary disease (worsening PFTs, increasing infiltrates): treat, because the endpoint of untreated progression is Stage IV fibrosis, which is irreversible.
- Cardiac involvement (heart block, cardiomyopathy, ventricular arrhythmias): treat. Cardiac involvement is a leading cause of death in sarcoidosis.
- Neurologic involvement (cranial nerve palsies, CNS mass lesions, seizures): treat.
- Hypercalcemia from granulomatous 1,25-dihydroxyvitamin D production: treat.
- Significant eye disease (posterior uveitis, optic neuritis refractory to topical therapy): treat systemically.
- Renal involvement (nephrocalcinosis, nephrolithiasis from hypercalciuria): treat.
- Disfiguring skin disease (lupus pernio): treat.
Workup and Management, Step by Step
1
Image and stage: CXR for Scadding stage, CT chest to better characterize parenchymal disease and the lymphadenopathy pattern. Stage predicts the odds of spontaneous remission and therefore whether you can watch.
2
Quantify the lung: PFTs, typically restrictive with reduced FVC and DLCO (obstruction is also possible with endobronchial involvement). These are the numbers you will track to decide if disease is progressing.
3
Screen the organs that force treatment: ECG on everyone for heart block (PR prolongation, bundle branch block) and cardiac MRI or PET if abnormal; ophthalmology exam for uveitis even if asymptomatic; serum calcium and 24-hour urine calcium (hypercalciuria can be present with a normal serum calcium); CBC, BMP, LFTs, where an elevated alk phos suggests hepatic granulomas.
4
Biopsy accessible tissue for non-caseating granulomas and rule out the mimics. Defer only in Lofgren syndrome, or in asymptomatic BHL in a young patient with a classic CXR and nothing concerning for lymphoma or infection, though many clinicians still prefer confirmation.
5
Decide: observe or treat. If no treatment indication, observe with serial PFTs and imaging. If there is one, start prednisone 20–40 mg daily × 4–6 weeks, then slow taper over 6–12 months, total duration typically 12+ months, because relapse is common (~30–50%) when steroids are tapered. Start higher for severe cardiac or neurologic involvement. NSAIDs cover mild arthralgia and erythema nodosum.
6
Add a steroid-sparing agent when you cannot taper below prednisone 10 mg/day, when steroid side effects accumulate, or when the patient relapses on taper. Methotrexate is the usual choice.
Key Drugs
Prednisone20–40 mg daily × 4–6 wk then taper over 6–12 months; first-line, higher dose for cardiac or neuro involvement
Methotrexate (Trexall)10–15 mg weekly PO/SQ; most common steroid-sparing agent, add folic acid 1 mg daily, avoid in pregnancy (teratogenic)
Azathioprine (Imuran)50–200 mg daily; alternative to MTX, check TPMT first
Mycophenolate (CellCept)500–1500 mg BID; refractory disease, GI side effects common
Infliximab (Remicade)3–5 mg/kg IV at weeks 0, 2, 6 then q4–8 weeks; anti-TNF for severe disease failing conventional therapy, screen for TB first
Hydroxychloroquine200–400 mg daily; useful for skin sarcoidosis, hypercalcemia, and fatigue, annual eye exams for retinal toxicity
Monitoring
- PFTs q3–6 months on treatment. FVC and DLCO are the most useful markers of disease activity and are what tell you whether you are preventing Stage IV fibrosis.
- CXR or CT chest q6–12 months, interval set by disease severity.
- Serum calcium and 24h urine calcium, especially while tapering steroids, since steroid withdrawal can unmask recurrent granulomatous vitamin D activation.
- Ophthalmology annually even if asymptomatic, more often with active uveitis, because sight-threatening disease can be silent.
- ECG annually, with a low threshold for cardiac MRI or FDG-PET on any new palpitations, syncope, or dyspnea.
- LFTs for both hepatic sarcoidosis and drug toxicity (MTX, azathioprine); CBC q4–8 weeks on MTX and for azathioprine or mycophenolate monitoring.
- DEXA if on prolonged steroids (> 3 months of prednisone ≥ 5 mg/day), because the treatment course is measured in years.
Pitfalls
- Using ACE level to diagnose. Sensitivity only ~60% and poor specificity. ACE inhibitors lower it (false negative), diabetes, hyperthyroidism, and other granulomatous diseases raise it (false positive). Never a sole diagnostic criterion.
- Following ACE as a disease-activity marker. Some clinicians trend it, but it is not reliable enough to drive treatment decisions; use PFTs and organ-specific markers.
- Treating everyone. Stage I and Lofgren syndrome mostly resolve without immunosuppression, and 12+ months of steroids is not a benign exposure.
- Skipping the ECG. Cardiac sarcoidosis is a leading cause of death and AV block is often the first sign; screen all patients.
- Skipping the eye exam in someone with no eye complaints, when uveitis is frequently asymptomatic early.
- Missing hypercalciuria by checking only serum calcium, when the 24-hour urine can be abnormal with a normal serum level.
- Calling it sarcoid without excluding the mimics: TB, fungal infection, lymphoma, and berylliosis all produce granulomas or hilar adenopathy.
Escalate / Refer When
- New AV block, palpitations, syncope, or unexplained cardiomyopathy: cardiac MRI (late gadolinium enhancement) or FDG-PET. Consider temporary pacing and evaluation for permanent pacemaker or ICD; ICD if LVEF ≤ 35% or sustained VT. Prednisone 40–60 mg daily for active cardiac sarcoidosis, plus guideline-directed HF therapy.
- Cranial nerve palsy, CNS mass lesion, or seizure: neurosarcoidosis, treat rather than observe, and infliximab has the strongest evidence in refractory disease.
- Cannot taper below prednisone 10 mg/day, steroid toxicity, or relapse on taper: add methotrexate (or azathioprine, mycophenolate).
- Severe disease failing conventional therapy: infliximab, with evidence strongest for lupus pernio and neurosarcoidosis. Screen for TB first, since anti-TNF reactivates latent TB.
- Posterior uveitis or optic neuritis refractory to topical therapy: systemic therapy with ophthalmology comanagement.
Key Evidence and Mechanism
- Vorselaars, Chest 2013: methotrexate versus azathioprine as second-line therapy, the basis for methotrexate being the usual first steroid-sparing choice.
- Baughman, AJRCCM 2006: infliximab in chronic sarcoidosis with pulmonary involvement, supporting anti-TNF for refractory disease.
- Why hypercalcemia happens: activated macrophages in sarcoid granulomas express 1-alpha-hydroxylase, converting 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. This extra-renal production is not regulated by PTH, so intestinal calcium absorption rises and PTH is appropriately suppressed, unlike primary hyperparathyroidism. Corticosteroids work by suppressing macrophage activity.
Related Topics
AsthmaCOPD -Chronic ManagementHemoptysisInterstitial Lung DiseaseObstructive Sleep ApneaPFT Interpretation