Anti-Inflammatory Drugs · Module 4 of 4

Corticosteroid Toxicity, Drug Interactions, and Gout Pharmacology

Organ toxicity, infection prophylaxis, withdrawal, and gout from acute attack to ULT

GIOP greatest bone loss occurs in the first 3–6 months of therapy — early prophylaxis is more effective than late intervention; bisphosphonate indicated for prednisone ≥2.5 mg/day for ≥3 months; calcium and vitamin D required in all patients; AVN can follow even short high-dose courses (including pulse methylprednisolone) and may present months later — any patient who has received high-dose corticosteroids and develops hip, knee, or shoulder pain requires MRI (plain films are often normal in early AVN); steroid myopathy has normal creatine kinase distinguishing it from inflammatory myopathy.
Three entities overlap during corticosteroid tapering and require different management — adrenal insufficiency: morning cortisol <3 mcg/dL, possible hyponatremia and hypoglycemia, requires slower taper and stress dosing; corticosteroid withdrawal syndrome: morning cortisol normal, no electrolyte changes, arthralgia/myalgia/fatigue from physiological GC dependence, requires slower taper and reassurance only (not dose escalation); disease relapse: disease-specific symptoms with rising inflammatory markers, requires increased immunosuppression rather than a taper adjustment.
Mandatory pre-therapy checklist before prednisone ≥10 mg/day for ≥4 weeks: screen for latent TB (IGRA preferred over tuberculin skin test in BCG-vaccinated patients); screen for HBV (surface antigen + total core antibody + surface antibody); update vaccinations (live vaccines ≥4 weeks before immunosuppression if possible; inactivated vaccines at any time); PJP prophylaxis with TMP-SMX when ≥20 mg/day for ≥4 weeks with concurrent immunosuppressants (PJP mortality 30–50% in immunosuppressed).
Colchicine for acute gout must be started within 36 hours of attack onset for maximal efficacy — low-dose protocol: 1.2 mg then 0.6 mg one hour later, equivalent to high-dose but substantially less toxic; mechanism: inhibits microtubule polymerization → impairs neutrophil chemotaxis, phagocytosis, and NLRP3 inflammasome assembly; critical interaction: colchicine is a CYP3A4 and P-glycoprotein substrate — clarithromycin, cyclosporine, and ritonavir can raise levels to life-threatening concentrations causing myopathy, neuromuscular toxicity, and cytopenias.
Never start ULT during an acute gout attack — rapid serum urate changes in either direction mobilize crystals from tissue depots (crystal shedding), triggering or prolonging attacks; wait until 2–4 weeks after full resolution; co-prescribe low-dose colchicine prophylaxis for the first 3–6 months of ULT to prevent paradoxical flares; patients already on ULT who flare should continue ULT without interruption (stopping causes serum urate fluctuation and worsens crystal instability); allopurinol hypersensitivity syndrome risk is substantially reduced by starting at low doses (50–100 mg/day) and titrating slowly.

Abbreviations: GC = glucocorticoid · GIOP = glucocorticoid-induced osteoporosis · AVN = avascular necrosis · PJP = Pneumocystis jirovecii pneumonia · TMP-SMX = trimethoprim-sulfamethoxazole · TB = tuberculosis · IGRA = interferon-gamma release assay · HBV = hepatitis B virus · MSU = monosodium urate · NLRP3 = NOD-like receptor pyrin domain 3 · IL-1β = interleukin-1 beta · XO = xanthine oxidase · ULT = urate-lowering therapy · eGFR = estimated glomerular filtration rate · URAT1 = urate anion transporter 1

Corticosteroid Toxicity by Organ System

Metabolic and Endocrine

Dose-Dependent

Hyperglycemia: postprandial predominant (afternoon/evening after morning dose); fasting glucose underestimates severity; may unmask latent diabetes or convert controlled diabetes to insulin-requiring
Central adipose redistribution: moon face, buffalo hump, truncal obesity with limb wasting; differential GC effects on adipocyte populations in different depots
Dyslipidemia (↑ LDL, ↑ triglycerides), hypertension, atherosclerosis acceleration

Musculoskeletal

Bone, Vasculature, Muscle

GIOP: greatest bone loss in first 3–6 months; start bisphosphonate early — prednisone ≥2.5 mg/day for ≥3 months; calcium + vitamin D for all patients
AVN: fat embolism and endothelial injury in subchondral bone; femoral/humeral heads; can follow even short high-dose courses (pulse methylprednisolone); may present months later; plain films often normal early — MRI required
Steroid myopathy: insidious proximal weakness (hip flexors, shoulder girdle); type II fiber atrophy; normal creatine kinase (distinguishes from inflammatory myopathy); improves with dose reduction

Ophthalmic, Psychiatric, and Other

Multi-Organ Effects

Posterior subcapsular cataracts: dose- and duration-dependent; largely irreversible; annual ophthalmologic review for long-term therapy
Ocular hypertension/open-angle glaucoma: impaired trabecular meshwork drainage; reversible on drug discontinuation
Psychiatric: insomnia, mood elevation, mania, psychosis predominantly at high doses (≥40 mg/day prednisone); depression more common during tapering; prior psychiatric history does not absolutely contraindicate use
GI: corticosteroids alone = low ulcer risk; + NSAID = marked risk → mandatory PPI; skin atrophy, striae, impaired wound healing; growth suppression in children (attenuated by alternate-day dosing)

Infection Risk, Prophylaxis, and Three Tapering Syndromes

Pre-Therapy Mandatory Screening and PJP Prophylaxis

Before ≥10 mg/day for ≥4 Weeks

Latent TB: IGRA preferred (not affected by prior BCG vaccination); positive latent TB without active disease → isoniazid 9 months (can start simultaneously with corticosteroids in urgent cases)
HBV: screen with hepatitis B surface antigen + total core antibody + surface antibody; HBsAg-positive → entecavir or tenofovir prophylaxis continued 6–12 months after immunosuppression ends
Live vaccines contraindicated during ≥20 mg/day for ≥2 weeks; administer ≥4 weeks before immunosuppression when possible; inactivated vaccines safe at any time
PJP prophylaxis (TMP-SMX single-strength daily) when ≥20 mg/day for ≥4 weeks + concurrent immunosuppressants; PJP mortality 30–50% in immunosuppressed patients; also covers toxoplasmosis and nocardiosis

Distinguishing Three Tapering Syndromes

Different Mechanisms, Different Management

Adrenal insufficiency: morning cortisol <3 mcg/dL; possible hyponatremia and hypoglycemia; → slow taper, stress dosing during physiological stress
Withdrawal syndrome: morning cortisol NORMAL; arthralgia, myalgia, fatigue, headache, nausea; no electrolyte changes; caused by physiological GC dependence (tissues adapted to supraphysiological GC); → slower taper, reassurance; do NOT escalate dose
Disease relapse: disease-specific symptoms return; inflammatory markers rise; → increase immunosuppression, not just taper adjustment
Key: all three can cause overlapping symptoms; morning cortisol and electrolytes distinguish the first two; disease-specific features identify the third

Gout — NLRP3 Pathway, Acute Attack Drugs, and ULT

Trigger

MSU crystals precipitate at urate >6.8 mg/dL; cooler peripheral joints (1st MTP, ankles, knees)

→

Inflammasome ← Colchicine

Phagocytosis by macrophages and neutrophils → NLRP3 activation; colchicine blocks microtubule-dependent neutrophil migration and NLRP3 assembly (start ≤36 h)

→

Caspase-1 → IL-1β

NLRP3 → procaspase-1 cleavage → IL-1β secretion → synovial endothelial activation; IL-1 inhibitors (anakinra, canakinumab) block here

→

Cytokine Cascade ← NSAIDs / Steroids

IL-6, IL-8 → neutrophil recruitment → amplifying loop; NSAIDs block PG synthesis; corticosteroids suppress at multiple cascade points; 1st-line: NSAIDs (indomethacin, naproxen) or low-dose colchicine

ULT Agent	Mechanism	Key Points	Cautions
Allopurinol	XO inhibitor (purine analogue)	First-line; start 50–100 mg/day, titrate every 2–4 weeks to urate <6 mg/dL; active metabolite oxypurinol is renally cleared	Dose-adjust in CKD; hypersensitivity syndrome (SJS/TEN, hepatitis, eosinophilia) risk reduced by starting low and slow; HLA-B*5801 (East Asian populations) increases risk
Febuxostat	XO inhibitor (non-purine selective)	No dose adjustment in mild–moderate CKD (≥30 mL/min); hepatically metabolized	CV mortality signal vs. allopurinol in CARES trial; reserve for allopurinol failure or intolerance; caution in established CV disease
Probenecid	URAT1/GLUT9 blocker (uricosuric)	Effective in patients with normal renal function; no urate overproduction; adequate urine flow	Contraindicated: eGFR <30, urate overproduction, urolithiasis history; low-dose aspirin (≤325 mg) blocks uricosuric effect via tubular competition — avoid combination
Pegloticase	Pegylated recombinant uricase (uric acid → allantoin)	Reserved for refractory tophaceous gout failing conventional ULT; IV every 2 weeks	Anti-drug antibodies in ~40–50% → loss of urate-lowering effect + anaphylaxis risk; urate rising >6 mg/dL during treatment = antibodies forming, stop before next infusion; co-administer methotrexate to reduce antibody formation

Chapter Complete — Anti-Inflammatory Drugs (AINF) · Key Rules

NSAIDs block COX only; corticosteroids block PLA2 (annexin A1) and COX-2 gene transcription (NF-κB transrepression), suppressing both COX and LOX branches plus cytokine production — explaining their broader potency and broader adverse effect profile. NSAID gastropathy is a systemic pharmacological effect; enteric coating and parenteral routes do not protect the gastric mucosa; PPI co-prescription is mandatory when NSAIDs and corticosteroids are combined.

Colchicine efficacy in acute gout is window-dependent (within 36 hours); the low-dose protocol (1.2 mg + 0.6 mg) is as effective as historical high-dose regimens with less toxicity; the critical drug interactions are CYP3A4/P-gp inhibitors (clarithromycin, cyclosporine, ritonavir) that raise colchicine to life-threatening concentrations. Never start ULT during an acute gout attack — wait for full resolution, then start allopurinol low and slow with colchicine prophylaxis for the first 3–6 months; patients already on ULT who flare should continue it without interruption.

The pegloticase monitoring rule: loss of the serum urate response (urate rising above 6 mg/dL during treatment) signals anti-drug antibody formation — the next infusion must not be given because it will cause anaphylaxis; co-administering methotrexate substantially reduces antibody formation and improves durable response rates. The probenecid-aspirin interaction: low-dose aspirin (≤325 mg) blocks the uricosuric effect of probenecid by competing for tubular secretion transporters.

Three tapering syndromes overlap in symptoms but differ in mechanism and management: adrenal insufficiency (cortisol low, electrolyte disturbance, slow taper + stress dose), withdrawal syndrome (cortisol normal, no electrolytes, slower taper + reassurance only — do not escalate), and disease relapse (disease-specific features + elevated inflammatory markers, increase immunosuppression). GIOP prophylaxis must begin with corticosteroid initiation, not after bone loss is established — the first 3–6 months carry the greatest loss rate.

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