A 47-year-old woman comes to the physician because of a 3-week history of a dry cough. She does not smoke or use illicit drugs. Physical examination shows mild conjunctival hyperemia. Chest auscultation shows fine crackles in both lung fields. Laboratory studies show a total calcium concentration of 10.8 mg/dL. The results of spirometry are shown (dashed loop shows normal for comparison). Further evaluation of this patient is most likely to show an increase in which of the following?

Angiotensin-converting enzyme activity

A 35-year-old African-American female presents to the emergency room complaining of chest pain. She also complains of recent onset arthritis and increased photosensitivity. Physical examination reveals bilateral facial rash. Which of the following is most likely to be observed in this patient?

Pain relieved by sitting up and leaning forward

A 27-year-old Asian woman presents to her primary care physician with joint pain and a headache. She has had intermittent joint and muscle pain for the past several months in the setting of a chronic headache. She states that the pain seems to migrate from joint to joint, and her muscles typically ache making it hard for her to sleep. The patient's past medical history is non-contributory, and she is currently taking ibuprofen for joint pain. Physical exam is notable for an asymmetrical pulse in the upper extremities. The patient has lost 10 pounds since her previous visit 2 months ago. Laboratory values are notable for an elevated C-reactive protein and erythrocyte sedimentation rate. Which of the following is the best next step in management?

Recommend exercise and optimize the patient's sleep regimen

A 34-year-old woman comes to the physician because of a 6-week history of fever and productive cough with blood-tinged sputum. She has also had a 4-kg (8.8-lb) weight loss during the same time period. Examination shows enlarged cervical lymph nodes. An x-ray of the chest shows a 2.5-cm pulmonary nodule in the right upper lobe. A biopsy specimen of the lung nodule shows caseating granulomas with surrounding multinucleated giant cells. Which of the following is the most likely underlying cause of this patient's pulmonary nodule?

Delayed T cell-mediated reaction

Combined type III/IV hypersensitivity reaction

IgE-mediated mast cell activation

Antibody-mediated cytotoxic reaction

An otherwise healthy 27-year-old man presents to his dermatologist because of a rash over his knees. The rash has been present for 5 weeks and is moderately itchy. Physical examination reveals erythematous plaques covered with silvery scales over the extensor surface of the knees as shown in the image. Which of the following is the best initial step in the management of this patient’s condition?

Topical corticosteroids and/or topical vitamin D analog

A 61-year-old construction worker comes to the physician because of a 3-month history of progressively worsening cough and shortness of breath. He has had a 7.5-kg (16.5-lb) weight loss during this period. He smokes occasionally and does not drink alcohol. Physical examination shows clubbing of the fingers. End-inspiratory crackles are heard in both lower lung fields. X-ray of the chest shows bilateral reticulonodular densities with interstitial fibrosis. Histologic examination of a lung biopsy specimen shows noncaseating granulomas in the interstitium. Which of the following is the most likely underlying mechanism of this patient's condition?

Silica-induced macrophage activation

Aspergillus-induced eosinophil release

Elastase-mediated parenchymal destruction

IgG-mediated immune complex deposition

A 49-year-old man comes to the physician because of tender, red nodules that appeared on his chest 3 days ago. Three weeks ago, he had similar symptoms in his right lower limb and another episode in his left foot; both episodes resolved spontaneously. He also has diarrhea and has had a poor appetite for 1 month. He has a history of dry cough and joint pain, for which he takes albuterol and aspirin as needed. He has smoked 2 packs of cigarettes daily for 15 years. He does not drink alcohol. Physical examination shows a linear, erythematous lesion on the right anterior chest wall, through which a cord-like structure can be palpated. The lungs are clear to auscultation. The abdomen is soft, nontender, and non-distended. Examination of the legs is normal. An ultrasound of the legs shows no abnormalities. Which of the following is the most appropriate next step in diagnosis of the underlying condition?

Serum angiotensin-converting enzyme level

A 33-year-old African-American female presents to her physician with complaints of a persistent, dry cough. She states that the cough has gone on for some time now. Three weeks ago, during her last general checkup, she was started on lisinopril and metformin for concerns regarding an elevated blood pressure and fasting blood glucose. Past medical history is notable for eczema, asthma, and seasonal allergies. At this visit the patient has other non-specific complaints such as fatigue and joint pain as well as a burning sensation in her sternum when she eats large meals. Her physical exam is only notable for painful bumps on her lower extremities (figure A) which the patient attributes to "bumping her shins," during exercise, and an obese habitus. Which of the following is most likely true for this patient's chief concern?

Non-caseating granulomas are found on biopsy of mediastinal lymph nodes

Omeprazole is an appropriate next step in management

Loratadine would best treat her chief complaint

Serum levels of bradykinin will be elevated

Beta agonists would relieve this patient's symptoms

Sarcoidosis for USMLE Step 3: High-Yield Internal Medicine Lessons

Pathophysiology - Granulomas Gone Wild

Trigger: Unknown inhaled antigen in genetically susceptible individuals.
Core Defect: Exaggerated, cell-mediated immune response driven by CD4+ Th1 cells.
Mechanism: Antigen-presenting cells (APCs) activate CD4+ T-cells, leading to a cytokine cascade (↑ IL-2, ↑ IFN-γ, ↑ TNF-α).
- This recruits and activates macrophages, which differentiate into epithelioid cells and multinucleated giant cells, forming the hallmark non-caseating granulomas.

Asteroid body in multinucleated giant cell in sarcoidosis

⭐ High-Yield: Bronchoalveolar lavage (BAL) fluid characteristically shows a CD4/CD8 ratio > 3.5, reflecting the intense T-helper cell activity in the lungs.

Clinical Features - The Great Masquerader

General: Often asymptomatic (incidental CXR finding). Can present with fever, weight loss, fatigue.
Pulmonary (~90%): Dry cough, dyspnea, chest pain. The most common presentation.
- Classic finding: Bilateral hilar lymphadenopathy (BHL).

Chest X-ray: Bilateral hilar lymphadenopathy in sarcoidosis

Skin (25%):
- Erythema Nodosum: Painful red nodules on shins; associated with acute disease & good prognosis.
- Lupus Pernio: Violaceous plaques on nose, cheeks, ears; specific for chronic sarcoidosis.
- Papules, nodules, plaques.
Ocular (~25%): Anterior uveitis is most common; posterior uveitis, conjunctivitis, dry eyes.
Cardiac: Arrhythmias (heart block), cardiomyopathy, sudden death.
Neurologic: Cranial nerve palsies (esp. CN VII), aseptic meningitis.

⭐ Löfgren's Syndrome: An acute, high-prognosis triad of fever, bilateral hilar lymphadenopathy, and erythema nodosum/polyarthritis.

Diagnostics - Cracking the Case

Initial Labs:
- ↑ Serum Angiotensin-Converting Enzyme (ACE) levels (in >75% of patients)
- ↑ Serum calcium (hypercalcemia) due to granulomatous production of $1,25-(OH)_2D_3$
- Pancytopenia on CBC
Imaging:
- Chest X-Ray: The cornerstone. Bilateral hilar lymphadenopathy is the classic finding.
- Gallium-67 Scan: Panda sign (lacrimal/salivary glands) & Lambda sign (hilar/paratracheal nodes).
Definitive Diagnosis:
- Biopsy: Transbronchial biopsy is the preferred method. Shows non-caseating granulomas.

⭐ Löfgren's Syndrome: An acute, highly specific form of sarcoidosis presenting with fever, bilateral hilar lymphadenopathy, and erythema nodosum. Excellent prognosis.

Management - Taming Inflammation

Asymptomatic/Stage I: Observation; high rate of spontaneous remission.
Symptomatic Disease: Oral corticosteroids are first-line.
- Indicated for worsening respiratory symptoms, cardiac, neuro, or ocular disease, or severe hypercalcemia.
- Start prednisone 20-40 mg/day for 4-6 weeks, then slow taper.
Steroid-Sparing Agents: For refractory cases or to limit steroid toxicity.
- Methotrexate (most common), azathioprine, leflunomide.

⭐ Infliximab, a TNF-α inhibitor, is reserved for severe, refractory sarcoidosis, especially neurosarcoidosis.

High-Yield Points - ⚡ Biggest Takeaways

Non-caseating granulomas are the pathognomonic finding on biopsy, essential for diagnosis.

Classic chest imaging reveals bilateral hilar lymphadenopathy and pulmonary reticular opacities.

Expect elevated serum ACE levels and hypercalcemia from extra-renal vitamin D activation by macrophages.

Key extrapulmonary signs include erythema nodosum, lupus pernio, and anterior uveitis.

Asymptomatic patients are often monitored; systemic corticosteroids are first-line for symptomatic disease.

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Sarcoidosis