A 22-year-old man comes to the physician for a follow-up evaluation for chronic lower back pain. He has back stiffness that lasts all morning and slowly improves throughout the day. He has tried multiple over-the-counter medications, including ibuprofen, without any improvement in his symptoms. Physical examination shows tenderness over the iliac crest bilaterally and limited range of motion of the lumbar spine with forward flexion. The results of HLA-B27 testing are positive. An x-ray of the lumbar spine shows fusion of the lumbar vertebrae and sacroiliac joints. The physician plans to prescribe a new medication but first orders a tuberculin skin test to assess for the risk of latent tuberculosis reactivation. Inhibition of which of the following is the most likely primary mechanism of action of this drug?

Inosine monophosphate dehydrogenase

A 61-year-old woman comes to the physician because of a 6-month history of left knee pain and stiffness. Examination of the left knee shows tenderness to palpation along the joint line; there is crepitus with full flexion and extension. An x-ray of the knee shows osteophytes with joint-space narrowing. Arthrocentesis of the knee joint yields clear fluid with a leukocyte count of 120/mm3. Treatment with ibuprofen during the next week significantly improves her condition. The beneficial effect of this drug is most likely due to inhibition of which of the following?

Conversion of arachidonic acid to prostaglandin G2

Conversion of hypoxanthine to urate

Conversion of phospholipids to arachidonic acid

Conversion of prostaglandin H2 to thromboxane A2

Conversion of dihydroorotate to orotate

A 46-year-old male presents to his dermatologist for routine follow-up of his psoriasis. He was last seen in the office six months prior, at which time he started undergoing ultraviolet light therapy. He reports that he initially noticed an improvement in his symptoms but the effects were transient. He has also started noticing pain and stiffness in his fingers. His past medical history is notable for obesity and diabetes mellitus. He takes metformin. His temperature is 99°F (37.2°C), blood pressure is 130/80 mmHg, pulse is 80/min, and respirations are 16/min. Multiple plaques with scaling are noted on the extensor surfaces of the upper and lower extremities. The patient’s physician suggests stopping the ultraviolet light therapy and starting an injectable medication that acts as a decoy receptor for a pro-inflammatory cytokine. Which of the following is an adverse effect associated with the use of this medication?

Reactivation of latent tuberculosis

A 23-year-old woman comes to the office because of a 2-day history of right knee pain. She says, "I can't run anymore because my knee hurts." The pain is localized "somewhere under the kneecap" and is achy, rated 5/10, but increases to 8/10 with prolonged sitting. She reports an occasional "popping" sound and sensation when she rises from a seated position. She has no history of trauma to the knee. She had a right clavicular fracture 2 years ago that was treated with a shoulder sling. She takes a daily multivitamin and has no known drug allergies. She does not smoke and drinks up to three glasses of wine weekly. Vital signs: Temperature 37°C (98.6°F), pulse 65/min, respirations 15/min, blood pressure 108/62 mm Hg. Height 173 cm (5 ft 8 in), weight 54 kg (119 lb), BMI 18 kg/m². Physical examination shows no acute distress. Pulmonary examination shows lungs clear to auscultation. Cardiac examination shows regular rate and rhythm with normal S1 and S2; no murmurs, rubs, or gallops. The abdomen is thin with no tenderness, guarding, masses, bruits, or hepatosplenomegaly. Extremities show no joint erythema, edema, or warmth; dorsalis pedis, radial, and femoral pulses are intact. Musculoskeletal examination shows diffuse tenderness to palpation over the right anterior knee, worse with full extension of the knee; no associated effusion or erythema; full, symmetric strength of quadriceps, hip abductors, and hip external rotators; crepitus with knee range of motion; and antalgic gait. Neurologic examination shows the patient is alert and oriented with cranial nerves grossly intact and no focal neurologic deficits. Which of the following is the most appropriate next step in management?

Intraarticular steroid injection

A 36-year-old woman presents with thyroid swelling. She has been healthy until now and follows all the healthcare precautions except for missing a flu shot this year. On physical examination, the thyroid gland is diffusely enlarged and tender to palpation. Laboratory findings show a decreased serum TSH level and elevated erythrocyte sedimentation rate. Which of the following histopathologic findings would most likely be found in the thyroid gland of this patient?

Mixed cellular infiltration with multinuclear giant cells

Extensive fibrosis of the stroma

Lymphocytic infiltration with germinal centers

Orphan Annie nuclei with psammoma bodies

Sheets of polygonal cells in amyloid stroma

A 33-year-old Caucasian female presents to her primary care provider for skin problems and difficulty breathing. She has not sought medical care in over 10 years due to anxiety around physicians. However, she has experienced gradual onset of diffuse pruritus, skin induration, and limited finger mobility over the past 5 years that has negatively impacted her work as an accountant. More recently, she has developed exertional shortness of breath and is concerned that it may impact her ability to care for her 3-year-old son. She reports no prior medical conditions and takes fish oil. She smokes 1 pack of cigarettes per day and drinks socially. Her temperature is 98.6°F (37°C), blood pressure is 145/85 mmHg, pulse is 85/min, and respirations are 22/min. On exam, she appears anxious with minimally increased work of breathing. Dry rales are heard at her lung bases bilaterally. Her fingers appear shiny and do not have wrinkles on the skin folds. A normal S1 and S2 are heard on cardiac auscultation. This patient’s lung disease is caused by increased secretion of which of the following substances within the lungs?

Transforming growth factor beta

Anti-inflammatory therapies for USMLE Step 1: High-Yield Pathology Lessons

NSAIDs - Prostaglandin Party Poopers

Mechanism: Inhibit cyclooxygenase (COX) enzymes, blocking prostaglandin synthesis from arachidonic acid.

NSAID mechanism of action on COX pathway

Classes & Drugs:
- Non-selective (COX-1 & COX-2): Aspirin, Ibuprofen, Naproxen, Indomethacin, Ketorolac.
- Selective (COX-2): Celecoxib (spares gastric mucosa).
Adverse Effects:
- GI: ↓PGE₂ → Gastric ulcers, bleeding (Non-selective).
- Renal: Constriction of afferent arteriole → ↓GFR, AKI.
- CV: ↑Thrombosis risk (COX-2 selective).

⭐ Aspirin is the only NSAID that causes irreversible COX inhibition, leading to a prolonged antiplatelet effect lasting the life of the platelet (~8-10 days).

Corticosteroids - Inflammation's Off Switch

Mechanism: Inhibit Phospholipase A2 (via Lipocortin-1) and suppress the NF-κB transcription factor, leading to ↓ synthesis of virtually all pro-inflammatory cytokines (TNF-α, ILs).
Key Drugs: Prednisone, Prednisolone, Dexamethasone, Hydrocortisone, Fludrocortisone.
Adverse Effects (Chronic Use):
- 📌 CUSHINGOID: Cataracts, Ulcers, Skin thinning, Hypertension, Immunosuppression, Necrosis (avascular), Glucose elevation, Osteoporosis, Impaired wound healing, Depression.

⭐ Abrupt cessation after chronic use can trigger a life-threatening adrenal crisis due to HPA axis suppression. Always taper the dose.

DMARDs - The Chronic Condition Crew

Disease-Modifying Anti-Rheumatic Drugs (DMARDs) are foundational for managing chronic autoimmune disorders like Rheumatoid Arthritis (RA). They aim to slow disease progression, unlike NSAIDs which only manage symptoms. Their onset of action is slow, often taking weeks to months.

Agent	Mechanism of Action (MOA)	Key Use	Major Toxicity / Monitoring
Methotrexate	Inhibits dihydrofolate reductase → ↓folate	RA (1st line), psoriasis	Myelosuppression, hepatotoxicity, pulmonary fibrosis. Monitor LFTs, CBC.
Leflunomide	Inhibits dihydroorotate dehydrogenase → ↓pyrimidines	RA	Hepatotoxicity, teratogen, hypertension.
Hydroxychloroquine	↓ Toll-like receptor (TLR) signaling	SLE, mild RA	Irreversible retinopathy. Requires regular eye exams.
Sulfasalazine	Metabolized to sulfapyridine + 5-ASA	RA, Ulcerative Colitis	Sulfa allergy, hemolysis in G6PD deficiency.

⭐ Methotrexate is the anchor drug for RA, often used in combination with other DMARDs or biologics. Folic acid supplementation is co-administered to reduce common side effects like mucositis and myelosuppression without losing efficacy.

Biologic Agents - Cytokine Assassins

Mechanism: Highly specific agents targeting cytokines or cell surface molecules to halt the inflammatory cascade.
Shared Risk: All cause immunosuppression → ↑ risk of infection.
TNF-α Inhibitors:
- Agents: Adalimumab, Infliximab, Etanercept.
- ⚠️ Classic Risk: Reactivation of latent TB (requires pre-screening).
Other Key Agents:
- IL-1 Inhibitor: Anakinra
- IL-6 Inhibitor: Tocilizumab
- Anti-CD20 (B-cells): Rituximab
- T-cell Blocker: Abatacept

⭐ Etanercept is a decoy TNF receptor (a fusion protein), not a true monoclonal antibody like infliximab.

High-Yield Points - ⚡ Biggest Takeaways

NSAIDs block both COX-1 & COX-2, risking GI ulcers; selective COX-2 inhibitors (celecoxib) spare the gut but increase cardiovascular risk.

Glucocorticoids offer broad anti-inflammatory effects by inhibiting phospholipase A2 (via lipocortin) and suppressing pro-inflammatory genes.

Leukotriene inhibitors (montelukast) block CysLT1 receptors, crucial for treating asthma and allergic rhinitis.

TNF-α inhibitors (infliximab, adalimumab) are potent biologics that risk reactivating latent tuberculosis.

Zileuton inhibits the 5-lipoxygenase enzyme, blocking all leukotriene synthesis.

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