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Sarcoidosis

Definition and Epidemiology

Sarcoidosis is a chronic multisystem granulomatous disease of unknown etiology, characterized by the formation of non-caseating (non-necrotizing) granulomas in affected tissues. It occurs worldwide, in patients of every age, ethnicity, and socioeconomic class, though patterns of prevalence vary considerably.

Prevalence: Highest in Scandinavia (Sweden: 64/100,000). In the United States: 10.9/100,000 in White persons vs. 35.5/100,000 in African Americans.
Sex: Women are slightly more affected, particularly African American women aged 30-39. Late-onset disease (ages 65-69) is 5x more common in women.
Lifetime risk: 0.85% (White U.S. residents) vs. 2.4% (Black U.S. residents).
Onset: Most commonly between ages 20-40, with a second peak at ages 65-69.
Andrews' Diseases of the Skin, p. 1321

Pathophysiology

The disease is driven by a Th1/Th17 immune response in which activated macrophages and CD4+ helper T cells form granulomas. IL-2 and IFN-γ secreting CD4+ Th cells play a key role, along with TNF and other Th1/Th17 cytokines.

Circulating cytokines, chemokines, and other mediators not only cause direct granulomatous organ damage but also produce systemic symptoms (fatigue, fever, weight loss, depression) through non-tissue-damaging mechanisms - called parasarcoidosis syndromes.

Key genetic associations:

HLA-DRB1 variants increase risk
HLA-DQB1*0201 and HLA-DRB1*0301 associate with acute disease and good prognosis
HLA-B8/DR3 associated with Löfgren syndrome
TNF promoter polymorphisms linked to erythema nodosum
ANXA11, BTNL2, CCR5 polymorphisms also identified

A notable metabolic effect: active sarcoidosis upregulates 1-alpha-hydroxylase, converting inactive 25-OH vitamin D to active 1,25-OH vitamin D, causing hypercalcemia.

Fishman's Pulmonary Diseases and Disorders, pp. 470-475

Organ Involvement

Sarcoidosis earns its reputation as a "great imitator" - it can affect virtually any organ.

Organ System	Prevalence	Key Manifestations
Pulmonary	>90%	Restrictive/obstructive disease, reduced DLCO, bilateral hilar adenopathy, pulmonary fibrosis, pulmonary hypertension
Constitutional	>50%	Fever, night sweats, fatigue, weight loss
Skin	20-30%	Lupus pernio, papules/plaques/nodules, erythema nodosum, scar/tattoo granulomas
Eyes	20-30%	Anterior/posterior uveitis, optic neuritis, chorioretinitis
Hematologic	20-30%	Lymphadenopathy, splenomegaly, anemia, lymphopenia
Cardiac	5-20%	Arrhythmias, heart block, dilated cardiomyopathy, sudden death
Liver/abdominal	10-20%	Hepatomegaly, granulomatous hepatitis, portal hypertension
Joints/MSK	10-20%	Arthralgia, polyarthritis, Achilles tendinitis, dactylitis
Neurologic	5-10%	Bell's palsy (most common), basilar meningitis, optic neuropathy, small fiber neuropathy
Renal	<10%	Nephrocalcinosis, renal calculi, interstitial nephritis

Fishman's Pulmonary Diseases and Disorders, Table 53-2

Key Specific Syndromes

Löfgren Syndrome: Acute triad of erythema nodosum + bilateral hilar adenopathy + periarthritis/arthritis, typically with fever. Generally carries a good prognosis.

Lupus Pernio: Indurated plaques/nodules on the nose and central face - a marker of chronic sarcoidosis strongly associated with upper airway granulomatous infiltration, pulmonary fibrosis, and persistent pulmonary involvement.

Cardiac Sarcoidosis: Clinically apparent in <10% of U.S. cases, but autopsy studies show myocardial involvement in >20% (U.S.) and >50% (Japan). Ventricular arrhythmias and high-degree heart block can cause sudden death.

Neurosarcoidosis: Cranial neuropathies dominate; VII nerve (Bell's) palsy is most common. Hypothalamic involvement can cause diabetes insipidus, hypogonadism, or hyperprolactinemia.

Chest Radiographic Staging (Scadding)

Stage	Finding	Prognosis
0	Normal	-
I	Bilateral hilar adenopathy only	>80% resolve at 2-5 years
II	Hilar adenopathy + parenchymal infiltrates	Intermediate
III	Parenchymal infiltrates only (no adenopathy)	<30% resolve
IV	Pulmonary fibrosis	Does not resolve

Diagnosis

The diagnosis is never fully secure and requires:

Compatible clinical and radiologic presentation
Histologic demonstration of non-necrotizing granulomas (ideally in two or more organs)
Exclusion of other causes (especially tuberculosis, fungal infections, other granulomatous diseases)

Useful workup:

Chest radiograph and HRCT
Pulmonary function tests (FVC, DLCO - DLCO is the most sensitive early marker)
Serum ACE (angiotensin-converting enzyme) - elevated in ~60%, neither sensitive nor specific
24-hour urinary calcium (hypercalciuria)
LFTs, renal function, serum calcium
Ophthalmologic examination (slit-lamp)
ECG (screening for cardiac involvement)
Serum LDH, lysozyme
BAL: CD4:CD8 ratio >3.5 is suggestive
FDG-PET/CT: useful for detecting active inflammation in cardiac and neurologic sarcoidosis and identifying the best biopsy site
Cardiac MRI with gadolinium: reveals myocardial inflammation and scarring in a non-coronary distribution

Biopsy sites (least invasive first): skin lesions, peripheral lymph nodes, transbronchial lung biopsy (high yield ~70-90%), EBUS-guided mediastinal biopsy.

The historical Kveim test (intradermal inoculation of sarcoid splenic tissue) is now essentially obsolete.

Murray & Nadel's Textbook of Respiratory Medicine, pp. 3565-3575

Treatment

There are no FDA-approved systemic therapies for sarcoidosis. Treatment is indicated for threatened organ function, not just for the presence of disease.

Indications for Treatment

Severe ocular, cardiac, or neurologic disease
Progressive, persistent, or symptomatic pulmonary disease
Disfiguring cutaneous disease (especially lupus pernio)
Persistent hypercalcemia
Renal or hepatic dysfunction
Symptomatic myopathy, painful lymphadenopathy
Severe fatigue and weight loss

Treatment Ladder

1. Corticosteroids (first-line)

Prednisone 20-40 mg/day, tapered slowly to maintenance 5-15 mg/day
Duration: minimum 6-24 months (premature taper leads to relapse)
Inhaled corticosteroids have limited effectiveness alone
Löfgren syndrome: NSAIDs first; corticosteroids if arthritis is disabling

2. Steroid-sparing agents (second-line)

Hydroxychloroquine (200-400 mg/day): particularly for skin and hypercalcemia
Methotrexate (7.5-15 mg/week): most widely used second-line agent
Azathioprine: alternative immunosuppressant

3. Biologics (refractory disease)

Infliximab (anti-TNF): evidence-based for pulmonary and cutaneous sarcoidosis; a recent 2025 systematic review and meta-analysis (PMID: 40393718) confirmed efficacy of biologic and targeted synthetic therapies in sarcoidosis
Adalimumab: alternative anti-TNF
Caution: anti-TNF agents are contraindicated in active infections (especially TB - screening required)

Cutaneous disease specifically:

Intralesional corticosteroid injections (first-line for localized lesions, repeated every 2-4 weeks)
Topical steroids often inadequate (poor penetration of thick granulomas)
Hydroxychloroquine or methotrexate for refractory/widespread disease
Fishman's Pulmonary Diseases and Disorders, pp. 597-619
Textbook of Family Medicine 9e, p. 489

Prognosis

Stage I disease: excellent prognosis; most resolve spontaneously
Stage II/III: ~50-70% improve with treatment
Stage IV (fibrotic): irreversible
Chronic progressive disease occurs in >20% overall
Monitoring for at least 3 years after apparent remission is recommended; longer for serious pulmonary or extrapulmonary disease
Special concern: aspergilloma can develop in cavitary/fibrotic upper lobe lesions and is a serious complication

Recent evidence: A 2025 systematic review and meta-analysis in Thorax (PMID: 40393718) confirmed the efficacy of biologics (particularly anti-TNF agents) in sarcoidosis - relevant for refractory cases where standard immunosuppression has failed.

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Here is a complete MPMSU-pattern CNS Pharmacology Q&A, organized exactly as the exam expects.

What's Covered (All Major MPMSU CNS Topics):

Long Answer Questions (10 marks each):

Antiepileptic drugs - classification + Phenytoin (mechanism, uses, adverse effects)
Antipsychotics - classification + Chlorpromazine in full detail
Opioid analgesics - classification + Morphine + Morphine vs Pethidine comparison table

Short Answer Questions (5 marks each):

Benzodiazepines/Diazepam - GABA-A mechanism, frequency of Cl⁻ opening, uses
Levodopa + Carbidopa - why L-DOPA is used, on-off phenomenon, adverse effects
Sedative-hypnotics - classification + Barbiturate mechanism (duration of Cl⁻ channel opening)
Status Epilepticus - stepwise treatment ladder (lorazepam → fosphenytoin → thiopental)
Antidepressants - all classes (SSRI, TCA, MAOI, SNRI) with mechanisms

Short Notes / Viva (2-3 marks):

General anesthesia stages (Guedel's stages I-IV)
Nitrous oxide
Drug of Choice table (must-memorize for MPMSU)
Methanol poisoning treatment

Key Mnemonics: NMS vs Serotonin Syndrome, Opioid tolerance "CAD", CPZ side effects "ABCDE"

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