A 60-year-old African American woman presents to her family physician with shortness of breath on exertion. She also describes shortness of breath when she lies down to go to bed at night, as well as recent swelling in her ankles. Past medical history is significant for long-standing hypertension, for which she takes amlodipine and lisinopril. Her temperature is 36.8°C (98.2°F), the heart rate is 90/min, the respiratory rate is 15/min, and the blood pressure is 135/80 mm Hg. The physical exam is significant for JVD, lower extremity pitting edema, laterally displaced PMI, left ventricular heave, bilateral pulmonary crackles, and an S4 heart sound. Chest X-ray demonstrates pulmonary vascular congestion, Kerley B lines, and cardiomegaly. Echocardiogram demonstrates a preserved ejection fraction. Kidney biopsy would likely demonstrate which of the following?

Intimal thickening and medial hypertrophy

Thinning of the intima and media

A 45-year-old woman presents to the clinic with a variety of complaints on different areas of her body, including telangiectasias on both the upper and lower extremities, bluish discoloration of the fingertips when exposed to cold, and burning midsternal chest pain. She is a tobacco smoker and works as a school teacher. After evaluation, an anti-centromere antibody test is ordered, and returns with an elevated titer. Which of the following symptoms are least likely to be seen in this patient's condition?

Spasm of blood vessels in response to cold or stress

Thickening and tightening of the skin on the fingers

A 45-year-old woman comes to the physician's office with her 17-year-old daughter. She tells the physician that she developed Sjögren's syndrome when she was her daughter's age, and that she is concerned about her daughter developing the same condition. The girl appears to be in good health, with no signs or symptoms of the disease or pathology. Which of the following antibodies will most likely be positive if the woman's daughter were to develop Sjögren's syndrome?

Anti-cyclic citrullinated antibodies

Anti-topoisomerase (anti-Scl 70) antibodies

A 27-year-old woman presents with a history of repeated episodes of discoloration of the fingers over the last 3 years. She mentions that the episodes are usually triggered by exposure to cold, which leads to a sequential white, blue, and red discoloration of her fingers, followed by resolution of the symptoms. During an episode, she experiences pain and numbness in the affected fingers. The episodes are usually of short duration and do not interfere with her life, so she did not seek medical advice till now. Which of the following additional clinical features in this patient would most likely support the most likely diagnosis?

Calcinosis on the dorsal surface of the forearm

Bilateral symmetrical involvement of the extremities

A 35-year-old woman comes to the clinic with complaints of joint pain and stiffness for the past few months. Her hands, lower back, and left knee are involved and associated with morning stiffness that improves throughout the day with activities. She also complains that her fingers change color upon exposure to cold. She has also noticed a tightening of the skin on her face and thinning of her lips. She feels tired throughout the day and has taken over-the-counter multivitamins that do not seem to help her much. The patient does not smoke cigarettes and drinks alcohol socially. She was diagnosed with hypertension 1 year ago and has been taking hydralazine for the past year. She lost her parents in a road traffic accident 3 years ago. Temperature is 36.7°C (98°F), blood pressure is 140/85 mm Hg, pulse is 72/min, respirations are 12/min, and BMI is 25 kg/m2. Her skin appears shiny and slightly thickened, especially her face and hands. Laboratory investigation: Complete blood count Hemoglobin 9.5 g/dl Leucocytes 5,500/mm3 Platelets 150,000/mm3 ANA positive Anti-centromere Antibody negative Anti Scl-70 positive Anti Jo-1 negative Anti-histone negative Anti DsDNA negative What is the most likely diagnosis in this patient?

Diffuse cutaneous systemic scleroderma

Limited cutaneous systemic scleroderma

A 32-year-old woman presents with a 3-month history of intermittent blurred vision and problems walking. The patient states that she often feels “pins and needles” in her legs that cause her problems when she’s walking. The patient is afebrile, and her vital signs are within normal limits. An autoimmune disorder is suspected. Which of the following findings would most likely be present in this patient?

Damaged myelin sheath and myelin-producing cells

Destruction of blood-brain barrier

Degeneration of anterior horn cells

Decreased cerebrospinal fluid due to destruction of cells

Systemic sclerosis (scleroderma) for USMLE Step 2 CK: High-Yield Internal Medicine Lessons

Pathophysiology - The Great Hardening

Core Triad: Autoimmunity, non-inflammatory vasculopathy, and collagen deposition with fibrosis.
Mechanism: An unknown trigger initiates endothelial/vascular injury, leading to inflammation.
- Activated T-cells release cytokines (TGF-β, IL-4, PDGF).
- These stimulate fibroblasts to overproduce collagen and extracellular matrix (ECM).
- Results in progressive fibrosis of skin and internal organs, plus vascular damage.

⭐ Anti-Scl-70 (anti-topoisomerase I) antibodies are strongly linked to diffuse cutaneous SSc and pulmonary fibrosis, highlighting the direct role of autoimmunity in organ damage.

Scleroderma Pathophysiology: Endothelial Injury to Fibrosis

Clinical Subtypes - Limited vs. Diffuse

Feature	Limited Cutaneous (lcSSc)	Diffuse Cutaneous (dcSSc)
Skin Fibrosis	Distal to elbows/knees, face	Proximal & distal limbs, trunk
Progression	Slow, insidious	Rapid onset after Raynaud's
Organ Damage	Late, less severe (PAH)	Early, severe (ILD, renal crisis)
Antibodies	Anti-centromere (ACA)	Anti-Scl-70 (topoisomerase I)
Mnemonic	📌 CREST Syndrome	-

⭐ Diffuse scleroderma carries a worse prognosis due to rapid, severe involvement of internal organs like the lungs (interstitial lung disease) and kidneys (scleroderma renal crisis).

Organ Manifestations - An Inside Job

Gastrointestinal (GI): Most common internal organ affected.
- Esophageal dysmotility → dysphagia, GERD.
- Gastric Antral Vascular Ectasia (GAVE) aka "watermelon stomach."
- Wide-mouthed diverticula.
Pulmonary: Leading cause of mortality.
- Interstitial Lung Disease (ILD): Dry cough, dyspnea. NSIP pattern common.
- Pulmonary Arterial Hypertension (PAH): Screen with annual echo.
Renal: Scleroderma Renal Crisis (SRC).
- Abrupt onset of severe hypertension and acute renal failure.
- Associated with anti-RNA polymerase III antibodies.
Cardiac: Myocardial fibrosis, pericarditis, arrhythmias.

⭐ ACE inhibitors are the first-line treatment for Scleroderma Renal Crisis, even with an elevated creatinine.

Systemic Sclerosis: Multi-organ Manifestations

Diagnosis - The Antibody Hunt

ANA: Positive in >95% of cases (sensitive, not specific).
Specific Antibodies (mutually exclusive):
- Anti-Scl-70 (anti-topoisomerase I): Linked to diffuse cutaneous (dcSSc) & severe interstitial lung disease (ILD).
- Anti-centromere: Strongly associated with limited cutaneous (lcSSc) / CREST syndrome.
- Anti-RNA Polymerase III: Tied to dcSSc, scleroderma renal crisis, and rapidly progressive skin thickening.

⭐ High-Yield: The presence of Anti-Scl-70 antibodies is a major red flag for aggressive diffuse disease and a higher likelihood of developing fatal pulmonary fibrosis.

Management - Damage Control

Goal: Organ-specific therapy to halt fibrosis & dysfunction.
Raynaud's: Dihydropyridine CCBs (e.g., Nifedipine).
Scleroderma Renal Crisis (SRC): ACE inhibitors (e.g., Captopril) are critical.
Interstitial Lung Disease (ILD): Mycophenolate mofetil (MMF), Cyclophosphamide.
Pulmonary Arterial Hypertension (PAH): Bosentan, Sildenafil, Epoprostenol.
GI Disease: PPIs for GERD; prokinetics for dysmotility.
Skin Fibrosis: Methotrexate, MMF.

⭐ ACE inhibitors are first-line for Scleroderma Renal Crisis, even if creatinine is elevated. Withholding them is a major cause of mortality.

Systemic Sclerosis: Organ-Specific Treatment Algorithm

High‑Yield Points - ⚡ Biggest Takeaways

Systemic sclerosis is an autoimmune disease causing widespread collagen deposition and fibrosis.

Diffuse cutaneous (dcSSc) involves proximal skin and has a high risk of early interstitial lung disease; associated with anti-Scl-70 antibodies.

Limited cutaneous (lcSSc), or CREST syndrome, primarily affects distal skin; linked to anti-centromere antibodies.

Scleroderma renal crisis presents with malignant hypertension and requires urgent ACE inhibitor therapy.

Pulmonary fibrosis and pulmonary arterial hypertension (PAH) are the leading causes of mortality.

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