Musculoskeletal

ANCA-associated vasculitis: GPA, MPA, EGPA

Clinical Overview and When to Suspect ANCA-Associated Vasculitis

— Granulomatosis with polyangiitis (GPA): granulomatous inflammation of upper and lower respiratory tract + necrotizing glomerulonephritis; classically PR3-ANCA (c-ANCA) positive (~80–90%).

— Microscopic polyangiitis (MPA): pauci-immune necrotizing vasculitis without granulomas; classically MPO-ANCA (p-ANCA) positive (~70%); pulmonary–renal syndrome with alveolar hemorrhage common.

— Eosinophilic granulomatosis with polyangiitis (EGPA, Churg–Strauss): late-onset asthma, eosinophilia, and vasculitis; only ~40% ANCA-positive (usually MPO).

— Middle-aged or older adult with constitutional symptoms (fevers, weight loss, fatigue) plus multisystem involvement.

— Upper airway: chronic sinusitis refractory to antibiotics, saddle-nose deformity, subglottic stenosis, otitis, oral ulcers → GPA.

— Lower airway: nodules/cavities on CXR, hemoptysis, diffuse alveolar hemorrhage.

— Kidney: rapidly progressive glomerulonephritis (rising Cr, hematuria, RBC casts, sub-nephrotic proteinuria).

— Skin: palpable purpura, splinter hemorrhages, livedo, ulcers.

— Nerve: mononeuritis multiplex (foot drop, wrist drop).

— Eye: scleritis, episcleritis, orbital pseudotumor, proptosis.

Board pearl: A patient with chronic sinusitis "not responding to antibiotics" + microscopic hematuria + rising creatinine is GPA until proven otherwise — order ANCA, urinalysis with microscopy, and refer urgently for renal biopsy. Early recognition before dialysis-dependence is the single biggest determinant of long-term renal survival.

ANCA-associated vasculitis (AAV) is a group of small-vessel vasculitides characterized by necrotizing inflammation with few or no immune deposits, often associated with circulating antineutrophil cytoplasmic antibodies.

When to suspect AAV on Step 3:

Epidemiology: peak incidence 50–70 years; MPA more common in older patients; EGPA in adults with adult-onset asthma.

Presentation Patterns and Key History

— Upper airway (often first): persistent purulent or bloody nasal discharge, nasal crusting, recurrent sinusitis/otitis, hearing loss, hoarseness (subglottic stenosis), epistaxis.

— Pulmonary: cough, dyspnea, hemoptysis, pleuritic chest pain; ~30% asymptomatic nodules.

— Renal: often silent until significant; ask about foamy/cola-colored urine.

— Prodromal: adult-onset asthma + allergic rhinitis/nasal polyps (often years prior).

— Eosinophilic: peripheral eosinophilia, eosinophilic pneumonia, gastroenteritis.

— Vasculitic: mononeuritis multiplex, cardiomyopathy (leading cause of death in EGPA), skin lesions, GN (less severe than GPA/MPA).

— Duration and treatment response of "sinusitis" or "asthma."

— Hemoptysis, dyspnea on exertion, urine color changes.

— New numbness/weakness in stocking-glove or asymmetric pattern.

— Medication exposures that mimic or trigger AAV: hydralazine, propylthiouracil, minocycline, levamisole-contaminated cocaine, allopurinol → drug-induced ANCA (usually MPO, often dual MPO+anti-elastase).

— Recent montelukast initiation or steroid taper → can unmask EGPA.

Key distinction: GPA = granulomas + upper airway dominance + PR3; MPA = no granulomas + renal/pulmonary dominance + MPO; EGPA = asthma + eosinophilia + cardiac/neuropathy, only ~40% ANCA+. Recognizing the trigger history (cocaine, hydralazine, montelukast) earns points on Step 3 stems that look like primary AAV but are drug-related.

Prodrome (weeks to months): low-grade fevers, malaise, arthralgias, weight loss, night sweats — often misattributed to viral illness or depression in outpatient setting.

GPA classic triad: upper airway + lower airway + kidney.

MPA pattern: more abrupt; pulmonary–renal syndrome with rapidly progressive GN and diffuse alveolar hemorrhage; less upper airway involvement; no granulomas.

EGPA "three phases":

Key history questions on Step 3 stems:

Physical Exam Findings and Multi-System Assessment

— Saddle-nose deformity from septal cartilage destruction (pathognomonic-feeling on boards).

— Nasal mucosal crusting, ulceration, septal perforation.

— Subglottic stenosis: inspiratory stridor, hoarseness — flexible laryngoscopy.

— Serous otitis media, conductive or sensorineural hearing loss.

— Eye: scleritis (painful red eye, bluish hue), episcleritis, peripheral ulcerative keratitis, orbital pseudotumor with proptosis and diplopia.

— Oral: strawberry gingival hyperplasia (GPA-specific).

Step 3 management: On exam, a saddle nose + foot drop + microscopic hematuria is a near-pathognomonic triad combining airway, nerve, and kidney — immediately order ANCA panel, urinalysis with microscopy, CBC with differential (eosinophils), creatinine, CXR/CT chest, and hospitalize for urgent rheumatology and nephrology consultation if creatinine is rising or hemoptysis is present.

Vital signs: low-grade fever common; hypertension if renal involvement; tachypnea/hypoxia if alveolar hemorrhage; hemodynamic instability suggests massive DAH or sepsis-mimic.

HEENT (especially GPA):

Pulmonary: crackles (alveolar hemorrhage), wheezing (EGPA asthma), decreased breath sounds from effusion; drop in hemoglobin with new infiltrates = DAH until proven otherwise.

Cardiac (EGPA): signs of CHF, pericardial rub, arrhythmias — eosinophilic myocarditis is leading mortality driver.

Abdomen: tenderness from mesenteric ischemia; bloody diarrhea (rare).

Skin: palpable purpura on lower extremities, splinter hemorrhages, nailfold infarcts, livedo reticularis, digital gangrene, pyoderma-like ulcers.

Neuro: mononeuritis multiplex — asymmetric foot drop, wrist drop, sensory deficits in named-nerve distributions; cranial neuropathies (especially EGPA, GPA orbital disease).

MSK: migratory arthralgias, non-erosive arthritis; myalgias.

Diagnostic Workup — Initial Labs, Imaging, and Biomarkers

— Normocytic anemia of chronic disease; drop in Hgb suggests DAH.

— Leukocytosis with neutrophilia common.

— Peripheral eosinophilia >1500/µL or >10% → think EGPA.

— Thrombocytosis (reactive); thrombocytopenia should prompt alternate Dx.

— Rising Cr; sub-nephrotic proteinuria (typically <3 g/day).

— Dysmorphic RBCs and RBC casts = active glomerulonephritis.

— Quantify with spot urine protein:creatinine ratio.

— c-ANCA (cytoplasmic IF) + PR3-ELISA → GPA most likely.

— p-ANCA (perinuclear IF) + MPO-ELISA → MPA or EGPA.

— Atypical p-ANCA without MPO/PR3 → IBD, drug-induced, autoimmune hepatitis (low specificity).

— Sensitivity ~90% in generalized GPA but only ~50% in limited GPA and 40% in EGPA — negative ANCA does NOT exclude AAV.

— CXR: nodules, cavities (GPA), patchy infiltrates (DAH, eosinophilic pneumonia).

— CT chest (high-yield): bilateral nodules with cavitation in GPA; ground-glass DAH; fleeting infiltrates in EGPA.

— CT sinuses for GPA upper airway disease.

— Complement (C3/C4): normal in AAV (helps distinguish from lupus, cryoglobulinemia, post-infectious GN).

— Anti-GBM antibody (overlap syndrome in ~10% with MPO+).

— Hepatitis B/C, HIV (pre-immunosuppression and to rule out mimics).

— ANA, RF (often low-positive nonspecifically).

— Echocardiogram if EGPA suspected (myocarditis).

Board pearl: Normal complement + RBC casts + positive ANCA = pauci-immune crescentic GN. Low complement points away from AAV toward lupus, post-strep GN, or cryoglobulinemic vasculitis.

CBC with differential:

Inflammatory markers: ESR and CRP markedly elevated; useful for tracking activity but nonspecific.

Renal panel + urinalysis with microscopy (must order both):

ANCA serology — order both immunofluorescence (IF) and antigen-specific ELISA:

Imaging:

Additional:

Diagnostic Workup — Confirmatory Studies and Biopsy

— Kidney: pauci-immune necrotizing crescentic glomerulonephritis on light microscopy with few or no immune deposits on IF/EM — diagnostic for AAV-related GN; informs prognosis via Berden histologic classification (focal > crescentic/mixed > sclerotic for renal recovery).

— Skin: leukocytoclastic vasculitis (sensitive but nonspecific).

— Lung (transbronchial or surgical): granulomatous inflammation with necrosis + vasculitis in GPA; eosinophilic infiltrates + extravascular granulomas in EGPA.

— Nasal/sinus: low yield (~20%) but easy access.

— Sural nerve: if mononeuritis multiplex without other accessible site.

— Confirms diffuse alveolar hemorrhage via progressively bloodier returns on serial lavage and hemosiderin-laden macrophages.

— Rules out infection (cultures, PCR, fungal stains) before immunosuppression — critical because superimposed infection mimics flare.

— Cardiac MRI for myocarditis (late gadolinium enhancement).

— Stool studies + IgE level; rule out Strongyloides before steroids in at-risk patients (eosinophilia mimic and reactivation risk).

Step 3 management: When a patient presents with RPGN, start methylprednisolone empirically while awaiting biopsy — do not delay therapy beyond 24–48 h pending pathology, but always obtain BAL or appropriate cultures before high-dose immunosuppression to exclude infection that could be fatal if missed.

Tissue biopsy is the gold standard for definitive diagnosis and is generally required before initiating immunosuppression, except in life-threatening disease where treatment cannot wait.

Biopsy site selection (highest yield, lowest risk):

Bronchoscopy with BAL:

Pulmonary function tests: elevated DLCO is a marker of fresh intra-alveolar hemorrhage (counterintuitive — blood binds CO).

Nerve conduction studies / EMG: confirm axonal mononeuritis multiplex pattern.

EGPA-specific:

Diagnostic criteria: 2022 ACR/EULAR classification criteria (weighted scoring) are now standard; use in patients with confirmed small-/medium-vessel vasculitis.

Risk Stratification and First-Line Management Logic

— Active glomerulonephritis with rising Cr.

— Diffuse alveolar hemorrhage.

— CNS vasculitis, mononeuritis multiplex.

— Cardiac involvement (EGPA myocarditis).

— Mesenteric ischemia, scleritis threatening vision, subglottic stenosis with airway compromise.

→ Aggressive induction with high-dose glucocorticoids + rituximab OR cyclophosphamide; consider plasma exchange in select cases.

— Constitutional symptoms, arthralgias, skin lesions, upper airway disease without erosion, lung nodules without hemorrhage, Cr stable.

→ Glucocorticoids + methotrexate (or rituximab) acceptable.

— Age >65, cardiac involvement, GI involvement, renal insufficiency (Cr >1.7), absence of ENT symptoms.

— FFS ≥1 → cyclophosphamide or rituximab + steroids; FFS = 0 → steroids alone may suffice (with close monitoring).

— Induction (3–6 months): rapidly suppress active inflammation.

— Maintenance (≥18–24 months, often longer): prevent relapse with lower-toxicity agents.

— Relapse management: re-induce; switch class if needed.

— Cr at presentation is the strongest predictor of renal survival.

— PR3-ANCA → higher relapse rate than MPO-ANCA.

— Older age, dialysis dependence, DAH → higher mortality.

Board pearl: Creatinine at presentation predicts long-term renal outcome more than any treatment choice — early diagnosis and induction within days of recognizing RPGN is the single most modifiable factor. Delays of even 1–2 weeks substantially worsen dialysis-free survival.

Disease severity drives induction regimen choice. Use the EULAR/BSR severity framework:

Organ- or life-threatening (severe) disease:

Non–organ-threatening (limited/early systemic) disease:

Five-Factor Score (FFS) for EGPA and PAN — predicts mortality:

Phases of treatment:

Prognostic factors at diagnosis:

Baseline pre-immunosuppression workup: HBV/HCV/HIV/TB screening, vaccinations (pre- or early), pregnancy test, DEXA, lipid panel.

Pharmacotherapy — First-Line Induction and Maintenance

— Glucocorticoids: IV methylprednisolone 500–1000 mg/day × 3 days, then oral prednisone 1 mg/kg/day (max 80 mg) with rapid taper using the PEXIVAS reduced-dose schedule (cuts cumulative steroid ~40% with equivalent efficacy and fewer infections).

— Plus rituximab 375 mg/m² weekly × 4 (preferred) OR cyclophosphamide (IV 15 mg/kg q2–3 wk × 3, then q3 wk × 3; or PO 2 mg/kg/day).

— Rituximab preferred for: relapsing disease, PR3-ANCA, women of reproductive age (fertility sparing), and most newer guidelines.

— Cyclophosphamide preferred for: severe DAH or rapidly worsening GN in some centers; cheaper in resource-limited settings.

— Severe DAH with respiratory failure.

— Coexistent anti-GBM antibodies.

— Cr >5.7 mg/dL with dialysis dependence (individualize).

— Rituximab 500 mg q6 months × ≥2 years (MAINRITSAN trial — superior to azathioprine).

— Azathioprine 2 mg/kg/day (check TPMT before starting).

— Methotrexate 20–25 mg/week (avoid if renal impairment).

— Mycophenolate as alternative.

— PJP prophylaxis with TMP-SMX while on induction.

— Calcium + vitamin D + bisphosphonate for steroid-induced osteoporosis.

— PPI if high-dose steroids + NSAIDs.

— Vaccinations: influenza, pneumococcal, COVID-19 — give before rituximab when possible (rituximab blunts B-cell response for ≥6 months).

Step 3 management: Whenever you start cyclophosphamide or high-dose steroids, co-prescribe TMP-SMX for PJP prophylaxis and a bisphosphonate — these are commonly tested "what did the physician forget to order" items.

Induction — severe disease:

Plasma exchange (PLEX) — per PEXIVAS, not routine; consider for:

Avacopan (C5a receptor antagonist): oral steroid-sparing agent; FDA-approved as adjunct to rituximab/cyclophosphamide → allows much faster steroid taper.

Maintenance therapy:

EGPA-specific add-on: mepolizumab (anti–IL-5, 300 mg SC monthly) for relapsing/refractory EGPA — reduces flares and steroid burden.

Adjunctive prophylaxis (mandatory on Step 3):

Procedures and Advanced/Refractory Management

— Typically 7 sessions over 14 days, replacement with 5% albumin (FFP if active bleeding or recent biopsy).

— Indications (post-PEXIVAS, narrowed): severe DAH, dual anti-GBM positivity, selected dialysis-requiring AAV.

— Complications: hypocalcemia (citrate), coagulopathy, line infection, hypotension.

— Initiate for standard indications; ~20–25% of severe AAV requires dialysis at presentation.

— Even dialysis-dependent patients should receive induction — up to 40% recover renal function within 6 months.

— Transplant feasible after ≥6–12 months remission; recurrence rate ~10–20%.

— Subglottic stenosis: serial endoscopic dilation + intralesional steroid injection; tracheostomy if refractory.

— Ear: tympanostomy tubes for serous OM.

— Nasal: saline irrigation; avoid elective nasal reconstruction during active disease — wait for sustained remission.

— Mechanical ventilation with lung-protective strategy for DAH; ECMO bridge in refractory cases.

— Bronchial artery embolization rarely needed (DAH is diffuse small-vessel, not focal).

— Switch class (rituximab ↔ cyclophosphamide).

— Add IVIG (especially in pregnancy or infection).

— Avacopan for steroid-refractory or steroid-toxic patients.

— Consider clinical trial enrollment.

— Hold immunosuppression timing relative to surgery individualized; stress-dose steroids perioperatively if on chronic prednisone >5 mg.

— Saddle-nose repair, sinus surgery, orbital decompression only during stable remission ≥6 months.

CCS pearl: In a CCS case of suspected DAH with hypoxia, the correct sequence is secure airway → type and cross → CBC/coags/UA → CT chest → bronchoscopy with BAL (cultures!) → IV methylprednisolone 1 g → consult rheum/nephro/pulm → induction with rituximab or cyclophosphamide → consider PLEX. Do not delay empiric steroids while awaiting biopsy in life-threatening disease.

Plasmapheresis (therapeutic plasma exchange):

Renal replacement therapy:

Airway interventions (GPA-specific):

Pulmonary:

Refractory disease management:

Surgical considerations:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher mortality from infection than from vasculitis itself.

— Reduce cyclophosphamide dose by 25% if age >60, additional 25% if age >70; further adjust for GFR.

— Prefer rituximab for fewer cumulative toxicities and easier dosing.

— Use PEXIVAS reduced-dose steroid taper; consider avacopan to shorten steroid exposure.

— Aggressively screen for and treat infections during induction (low threshold for cultures, CT).

— Address deconditioning, falls, polypharmacy at every visit.

— Cyclophosphamide dose reduction: lower dose and extend interval if GFR <30; check trough cell counts.

— Avoid methotrexate if GFR <30 (toxicity, ineffective clearance).

— Rituximab is renally safe — preferred in advanced CKD.

— TMP-SMX prophylaxis: monitor potassium and Cr; reduce dose or use atovaquone/dapsone (check G6PD) if AKI.

— Anticipate dialysis — place AV access early if Cr trajectory unfavorable.

— Adjust antihypertensives; ACEi/ARB for proteinuria after stabilization, but hold during acute AKI.

— Azathioprine: monitor LFTs; reduce dose; check TPMT and consider NUDT15 in Asian patients (severe myelosuppression risk).

— Methotrexate: contraindicated in significant liver disease; absolute in cirrhosis with active EtOH use.

— Hepatitis B reactivation: screen HBsAg and anti-HBc; if positive, prophylactic entecavir or tenofovir before rituximab/cyclophosphamide.

— Hepatitis C: treat if active; coordinate with hepatology.

Board pearl: Always screen for HBV before rituximab or cyclophosphamide — missed occult HBV reactivation causes fulminant hepatic failure and is a classic Step 3 patient-safety vignette. Anti-HBc positivity alone warrants antiviral prophylaxis during and 12 months after immunosuppression.

Elderly patients (>65, common in MPA):

Renal impairment (very common in AAV):

Hepatic impairment:

Bone health: DEXA at baseline; bisphosphonate if prednisone ≥7.5 mg/day for ≥3 months or T-score ≤ -1.5; vitamin D ≥800 IU.

Special Populations — Pregnancy, Pediatrics, and Reproductive Health

— Plan pregnancy during sustained remission ≥6–12 months off teratogens.

— Teratogenic/contraindicated: cyclophosphamide, methotrexate, mycophenolate — discontinue ≥3 months before conception (≥6 weeks for MMF per updated data; longer for MTX).

— Pregnancy-compatible: azathioprine, hydroxychloroquine, low-dose prednisone, certolizumab, IVIG; rituximab generally avoided in pregnancy but no clear teratogenicity (causes transient neonatal B-cell depletion).

— Active disease in pregnancy: low-dose steroids + azathioprine ± IVIG; rituximab if severe (in 2nd trimester after weighing risks); plasmapheresis for life-threatening manifestations.

— Monitor for preeclampsia (overlaps clinically with AAV flare — both cause HTN, proteinuria, AKI); distinguish via ANCA titer, urinary sediment (RBC casts favor AAV).

— Multidisciplinary care: MFM, rheumatology, nephrology.

— Cyclophosphamide → premature ovarian insufficiency risk increases sharply with cumulative dose and age >30.

— Offer GnRH agonist (leuprolide) co-treatment and/or oocyte/sperm cryopreservation before induction.

— Rituximab does not impair fertility — another reason for preference in reproductive-age patients.

— GPA most common pediatric AAV; presents similarly to adults.

— Subglottic stenosis more common in children.

— Treat with similar induction (rituximab now preferred); growth, bone health, and education planning are major longitudinal concerns.

— Transition-of-care planning to adult rheumatology between ages 18–21.

Step 3 management: For a woman of reproductive age newly diagnosed with severe AAV, rituximab + reduced-dose steroids (avoiding cyclophosphamide) preserves fertility and is the modern standard. Always document contraception counseling and fertility preservation discussion in the chart — a high-yield Step 3 patient-safety item.

Pregnancy in AAV:

Fertility preservation:

Contraception: required during cyclophosphamide, methotrexate, mycophenolate exposure; IUDs and progestin methods preferred (estrogen caution if vasculitis-related thromboembolic risk).

Pediatric AAV (rare):

Complications and Adverse Outcomes

— End-stage renal disease: ~20–25% of severe AAV; lifelong nephrology follow-up even after remission.

— Chronic respiratory disease: pulmonary fibrosis (especially MPO-MPA), bronchiectasis, recurrent DAH, restrictive lung disease.

— Permanent sensorineural hearing loss, anosmia, saddle-nose deformity.

— Subglottic stenosis requiring serial dilation.

— Peripheral neuropathy — often incomplete recovery from mononeuritis multiplex.

— Cardiovascular: accelerated atherosclerosis from chronic inflammation; EGPA myocarditis → cardiomyopathy, sudden cardiac death.

— Venous thromboembolism: AAV carries ~7-fold increased VTE risk during active disease — have low threshold for evaluation.

— Infection is the leading cause of death in first year, especially PJP, CMV, invasive fungal, bacterial sepsis — driven by combined steroid + cytotoxic burden.

— Cyclophosphamide-specific: hemorrhagic cystitis (mesna prophylaxis with IV dosing; encourage hydration), bladder cancer (lifetime risk dose-dependent — surveillance UA), myelodysplastic syndrome, infertility.

— Glucocorticoid toxicity: hyperglycemia, hypertension, osteoporosis, avascular necrosis (especially hip), cataracts, glaucoma, myopathy, mood changes, weight gain, skin fragility.

— Rituximab: hypogammaglobulinemia (check IgG; replace with IVIG if recurrent infections + IgG <400), infusion reactions, PML (rare), HBV reactivation.

— Azathioprine: cytopenias, hepatotoxicity, increased SCC of skin and lymphoma.

— Methotrexate: hepatotoxicity, pneumonitis, cytopenias.

— Overall ~50% at 5 years; higher in PR3-ANCA, persistent ANCA positivity, ENT involvement.

— Rising ANCA titer alone is not sufficient to treat — correlate with clinical activity.

Key distinction: Rising creatinine + active urinary sediment = treat as relapse. Rising ANCA alone with stable end-organ function = increase surveillance, do not re-induce. This nuance is heavily tested.

Disease-related complications:

Treatment-related complications:

Relapse:

When to Escalate — ICU, Consults, and Inpatient Triage

— Diffuse alveolar hemorrhage with hypoxia (SpO₂ <90% on supplemental O₂) or respiratory failure.

— Hemodynamic instability, vasopressor requirement.

— Massive hemoptysis (>500 mL/24h).

— Airway compromise from subglottic stenosis or laryngeal edema.

— Severe sepsis on immunosuppression.

— Status epilepticus or stroke from CNS vasculitis.

— Initiation of plasma exchange in unstable patient.

— New AKI with active urinary sediment requiring expedited biopsy and induction.

— Hemoptysis without respiratory failure but with imaging concerning for DAH.

— Severe systemic symptoms with rising inflammatory markers and uncertain diagnosis.

— Need for IV pulse methylprednisolone if outpatient logistics infeasible.

— Neutropenic fever during cytotoxic therapy.

— Rheumatology: every confirmed or strongly suspected case — they direct induction/maintenance.

— Nephrology: any renal involvement, even mild; coordinate biopsy and dialysis planning.

— Pulmonology: pulmonary nodules, hemorrhage, asthma component, bronchoscopy.

— ENT: sinus/airway disease; subglottic stenosis evaluation and dilation.

— Ophthalmology: scleritis, peripheral ulcerative keratitis, orbital pseudotumor.

— Cardiology: EGPA with cardiac involvement; echo and cardiac MRI.

— ID: opportunistic infection workup before/during high-dose immunosuppression.

— Hematology/Oncology: stem cell rescue or lymphoma surveillance.

— Stable limited GPA without renal, pulmonary, or neuro threat.

— Established remission on maintenance therapy.

CCS pearl: A patient with hemoptysis, dropping Hgb, bilateral ground-glass opacities, and rising Cr belongs in the ICU, not the floor — order ABG, type and cross 4 units, secure large-bore IV access, methylprednisolone 1 g IV, urgent rheumatology/nephrology/pulmonology, and prepare for bronchoscopy and possible PLEX. Hesitation kills.

ICU admission indicators:

Inpatient (floor) admission:

Specialty consultation (early!):

Outpatient management appropriate when:

Transfer criteria: refer to a tertiary center with PLEX capability and AAV expertise if local resources cannot deliver rituximab/cyclophosphamide protocols, biopsy, or PLEX.

Key Differentials — Other Vasculitides

— Pulmonary–renal syndrome mimicking MPA; linear IgG on renal biopsy IF (vs. pauci-immune in AAV).

— Anti-GBM antibody positive; ~10–15% are dual-positive with MPO-ANCA — these behave aggressively, treat as anti-GBM (PLEX + cyclophosphamide + steroids).

— Medium-vessel vasculitis, ANCA-negative, often HBV-associated.

— Renal involvement: renovascular (microaneurysms on angiogram), not glomerular — no RBC casts.

— Skin: nodules, livedo, ulcers; spares lungs.

— Treat HBV + steroids ± cyclophosphamide; antivirals key if HBV+.

— Children > adults; palpable purpura on legs/buttocks, arthritis, abdominal pain, IgA nephropathy.

— IgA deposits on biopsy; ANCA-negative.

— HCV association; palpable purpura, arthralgias, GN, neuropathy.

— Low C4, positive cryoglobulins, positive RF — distinguishes from AAV (normal complement).

— Large-vessel; older adults (GCA) or young women (Takayasu); jaw claudication, visual loss, limb pulse deficits — different syndrome.

— Oral and genital ulcers, uveitis, pathergy; variable-vessel; ANCA-negative.

— Hydralazine, propylthiouracil, minocycline, levamisole-laced cocaine, allopurinol.

— Often high-titer MPO + anti-elastase + ANA + anti-histone; tends to remit on drug withdrawal but may need immunosuppression.

Key distinction: Pauci-immune (AAV) vs. immune-complex (cryo, lupus, post-infectious, IgA) vs. anti-GBM (linear) glomerulonephritis is the foundational frame — every RPGN stem on Step 3 forces you to choose among these three buckets based on complement levels, serologies, and biopsy IF pattern.

Anti-GBM disease (Goodpasture):

Polyarteritis nodosa (PAN):

IgA vasculitis (HSP):

Cryoglobulinemic vasculitis:

Giant cell arteritis / Takayasu:

Behçet disease:

Drug-induced ANCA vasculitis:

Key Differentials — Non-Vasculitic Mimics

— Infective endocarditis: fever, splinter hemorrhages, glomerulonephritis, low complement, positive blood cultures, ANCA can be falsely positive — always get blood cultures and TTE before immunosuppression.

— Tuberculosis: cavitary lung lesions mimic GPA nodules; screen with IGRA/PPD + CXR/CT before steroids.

— Fungal (aspergillosis, mucor): especially in immunosuppressed; cavitary lung disease.

— HIV with opportunistic infections.

— Disseminated gonococcal infection: skin lesions + arthritis.

— Lung cancer: cavitary lesions; obtain biopsy.

— Lymphoma: systemic symptoms, organ infiltration.

— Multiple myeloma / cast nephropathy: AKI in older adult.

— Lymphomatoid granulomatosis: EBV-driven; mimics GPA pulmonary nodules — requires biopsy.

— SLE: positive ANA, dsDNA, low complement, multisystem; can overlap with AAV.

— Sarcoidosis: granulomas without necrosis; hilar adenopathy; ACE elevation; lacks vasculitis on biopsy.

— IgG4-related disease: orbital pseudotumor, retroperitoneal fibrosis, pancreatitis; elevated IgG4, storiform fibrosis on biopsy.

— Hypereosinophilic syndrome: distinguish from EGPA — lacks vasculitis and asthma; FIP1L1-PDGFRA mutation.

— Cholesterol embolization syndrome: post-catheterization, livedo, AKI, eosinophilia, low complement — mimics AAV.

— Atrial myxoma, antiphospholipid syndrome: multi-organ ischemia.

— Cocaine/levamisole: nasal destruction mimics GPA; atypical p-ANCA + anti-elastase + agranulocytosis clues.

Board pearl: Always blood-culture and echo a patient with new "vasculitis" before pulling the immunosuppression trigger — missed endocarditis treated with steroids is a classic Step 3 patient-safety vignette and a board favorite.

Infections (the can't-miss mimics):

Malignancy:

Other immune-mediated:

Thrombotic and embolic:

Toxic/environmental:

Secondary Prevention, Discharge Medications, and Long-Term Plan

— TMP-SMX single-strength daily or DS 3×/week — PJP prophylaxis throughout induction and ≥6 months after.

— Antiviral prophylaxis (acyclovir/valacyclovir) if VZV/HSV history.

— HBV antiviral prophylaxis if anti-HBc+.

— Annual influenza, COVID-19 boosters.

— Pneumococcal (PCV20 or PCV15→PPSV23).

— Recombinant zoster (Shingrix) — safe and recommended.

— Hepatitis B series if non-immune.

— No live vaccines (MMR, varicella, yellow fever) while immunosuppressed.

— Statin for high CV risk given inflammatory burden and steroid effects.

— BP control to <130/80 (CKD).

— ACEi/ARB for proteinuria once stable; dose for tolerability.

— Bisphosphonate, calcium, vitamin D while on chronic steroids.

— Skin exam annually (SCC risk with azathioprine).

— Cervical cancer screening at usual intervals (HPV may be more persistent).

— Bladder surveillance (UA q6–12 months) lifelong if cumulative cyclophosphamide exposure.

— Smoking cessation (worsens GPA outcomes).

— Sun protection.

— Exercise, nutrition for steroid weight gain and sarcopenia.

Step 3 management: At every discharge from an AAV admission, the order set must include PJP prophylaxis, bone protection (calcium/vitamin D ± bisphosphonate), PPI if indicated, vaccination plan, maintenance immunosuppression scheduled, and rheum/nephro follow-up within 2–4 weeks.

Maintenance immunosuppression continues ≥18–24 months past remission; many guidelines now favor ≥4 years for PR3-ANCA GPA given high relapse risk. Options: rituximab q6 months, azathioprine, methotrexate, mycophenolate.

Steroid taper: target prednisone ≤5 mg/day by 6 months; avacopan facilitates earlier withdrawal. Stress-dose for surgery/infection if on ≥5 mg chronically.

Infection prophylaxis (discharge essentials):

Vaccinations (administer when on lowest possible immunosuppression; inactivated only while immunosuppressed):

Cardiovascular and bone prevention:

Cancer surveillance:

Lifestyle:

Follow-Up, Monitoring, and Counseling

— Induction phase: rheumatology every 2–4 weeks; nephrology in parallel if renal disease.

— Early remission: every 1–3 months.

— Stable remission on maintenance: every 3–6 months indefinitely.

— PCP visits between specialty visits for BP, glycemic control, vaccinations, mood.

— Every visit: CBC with differential, CMP (Cr, LFTs), urinalysis with microscopy, urine protein:creatinine ratio, CRP/ESR.

— ANCA titer every 3–6 months: rising titer is a relapse predictor but not a treat-on-its-own indicator — increase surveillance.

— CD19/CD20 B-cell count before redosing rituximab (if B-cell-guided dosing used).

— IgG levels every 6–12 months on rituximab — hypogammaglobulinemia <400 mg/dL with infections → consider IVIG.

— TPMT before azathioprine; weekly CBC × 1 month, then monthly.

— Bladder UA + cytology annually if prior cyclophosphamide.

— CT chest if new pulmonary symptoms or to follow nodules.

— Sinus CT for ENT symptoms.

— DEXA every 1–2 years on chronic steroids.

— Echo annually in EGPA with prior cardiac involvement.

— Recognize early relapse: new sinusitis, hemoptysis, foamy urine, numbness, rash — call early.

— Sick-day rules: fever or signs of infection → seek evaluation; do not abruptly stop steroids (adrenal crisis).

— Medication adherence: missed rituximab doses precipitate relapse.

— Mental health: depression, anxiety, body-image issues from steroid effects and disfigurement — screen routinely (PHQ-9).

— Reproductive planning with each maintenance visit for premenopausal women.

— Pulmonary rehab for fibrotic or post-DAH lungs; PT/OT for neuropathy and steroid myopathy.

Board pearl: A rising ANCA titer without clinical activity warrants closer monitoring, not retreatment — this is one of the most-tested nuances of AAV maintenance.

Follow-up cadence:

Laboratory monitoring:

Imaging surveillance:

Counseling pillars:

Ethical, Legal, and Patient Safety Considerations

— Document discussion of infertility risk (cyclophosphamide), infection risk, malignancy risk, alternative regimens (especially rituximab vs. cyclophosphamide for reproductive-age patients).

— Offer fertility preservation referral before cyclophosphamide; missing this is a legal and ethical lapse.

— Discharge after induction: ensure PJP prophylaxis, steroid taper schedule, follow-up appointments, vaccination plan, and refill of maintenance agent are all in writing with teach-back.

— Inter-hospital transfer: communicate biopsy status, infection workup results, current immunosuppression, and steroid dose (adrenal suppression risk if dropped).

— Hand-off from pediatric to adult rheumatology: structured transition program reduces lapses.

— TB screening positive → report and treat latent TB before/during immunosuppression.

— Cocaine-induced vasculitis: address substance use disorder; document counseling and referral.

— Suspected occupational silica exposure (associated with AAV) → occupational medicine referral.

— Counsel that household contacts should be up to date on vaccines; avoid live oral polio in household contacts during patient's immunosuppression; rotavirus precautions for infants.

— Avoid abrupt discontinuation after >3 weeks of physiologic-equivalent dosing — adrenal crisis risk; provide stress-dose instructions and a medical alert bracelet.

— Foot drop or visual impairment may require DMV reporting (state-specific) and occupational accommodations.

— In dialysis-dependent elderly AAV patients, discuss goals of care, dialysis withdrawal options, and palliative integration.

— Refractory disease — discuss trial enrollment as part of shared decision-making.

Step 3 management: A 28-year-old woman started on cyclophosphamide without prior documented contraception counseling and fertility preservation discussion represents a high-yield patient-safety/ethics failure — the correct answer on Step 3 vignettes is to pause, document the discussion, and consider rituximab as fertility-sparing alternative.

Informed consent for immunosuppression:

Transitions of care — high-risk junctions:

Mandatory reporting and public health:

Vaccination ethics:

Steroid-related safety:

Driving and disability:

Advance care planning:

Research and clinical trials:

High-Yield Associations and Rapid-Fire Facts

Key distinction: "c-ANCA + cavitary lung nodules + saddle nose + microhematuria" = GPA; "p-ANCA + DAH + RPGN, no granulomas" = MPA; "asthma + eosinophilia + foot drop" = EGPA. Memorize these triads cold.

PR3-ANCA (c-ANCA) → GPA; more relapses, more upper airway, more granulomas.

MPO-ANCA (p-ANCA) → MPA and EGPA; more renal fibrosis, more pulmonary fibrosis (especially MPA).

Pauci-immune crescentic GN on renal biopsy = AAV until proven otherwise.

Normal complement in AAV distinguishes from lupus, post-infectious, cryoglobulinemic GN.

Saddle-nose deformity = think GPA (also relapsing polychondritis, cocaine use, congenital syphilis).

Strawberry gingival hyperplasia = GPA-specific finding.

Subglottic stenosis with stridor in young woman = GPA.

Mononeuritis multiplex + asthma + eosinophilia = EGPA.

Five-Factor Score components: age >65, cardiac, GI, renal (Cr >1.7), absent ENT.

PEXIVAS trial: PLEX not routinely beneficial; reduced-dose steroids equivalent to standard taper.

MAINRITSAN trial: rituximab > azathioprine for maintenance.

Mepolizumab (anti–IL-5) is FDA-approved for EGPA maintenance.

Avacopan (C5aR antagonist) — steroid-sparing adjunct, approved 2021.

Drug-induced AAV: hydralazine, PTU, minocycline, levamisole-laced cocaine, allopurinol — often dual MPO + anti-elastase.

Silica exposure and smoking are environmental AAV risk factors.

Anti-GBM dual positivity (~10% of MPO+) = treat as anti-GBM (PLEX-required).

Elevated DLCO = active alveolar hemorrhage (counterintuitive).

Cyclophosphamide pearls: mesna + hydration → prevents hemorrhagic cystitis; monitor for bladder cancer and infertility.

TMP-SMX = PJP prophylaxis + may reduce GPA upper-airway relapses (independent benefit).

Vaccinate before rituximab when possible; B-cell depletion blunts response ≥6 months.

VTE risk ~7× higher in active AAV.

EGPA cardiac involvement drives mortality.

ACR/EULAR 2022 criteria are the current classification standard.

Berden histopathologic class (focal, crescentic, mixed, sclerotic) predicts renal recovery.

Board Question Stem Patterns

— Best initial test: ANCA panel + UA + creatinine.

— Definitive: renal biopsy (pauci-immune crescentic GN).

— Treatment: pulse methylprednisolone + rituximab + PJP prophylaxis.

— ICU admission, type and cross, methylprednisolone 1 g IV × 3, bronchoscopy with BAL, rituximab or cyclophosphamide; consider PLEX for severe DAH.

— Echo + cardiac MRI; high-dose steroids; cyclophosphamide or rituximab if FFS ≥1; mepolizumab maintenance.

— Stop hydralazine; immunosuppression only if organ-threatening.

— Counsel on cessation; treat severe organ involvement; primary intervention is drug discontinuation.

— Get blood cultures and TTE before steroids — do not miss IE.

— Switch off methotrexate to azathioprine ≥3 months before conception; counsel on flare risk and MFM co-management.

— Increase monitoring, do not re-induce.

— Identify prophylaxis omission; treat with TMP-SMX, add steroids for PJP, restart prevention bundle.

Board pearl: Most AAV Step 3 questions hinge on a single management omission — PJP prophylaxis, bone protection, fertility counseling, missed endocarditis workup, or HBV screening. Pattern-match the gap before choosing.

Stem 1 — GPA classic: 55-year-old with 4 months of "sinusitis" unresponsive to antibiotics, hemoptysis, new microhematuria. UA shows RBC casts; CXR shows cavitary nodules.

Stem 2 — MPA pulmonary–renal: 65-year-old with hemoptysis, falling Hgb, bilateral ground-glass opacities, Cr 3.2.

Stem 3 — EGPA: 45-year-old with long-standing asthma, new foot drop, eosinophils 22%, elevated troponin.

Stem 4 — Drug-induced: Patient on hydralazine for HTN develops palpable purpura, arthralgias, hematuria; high-titer MPO + anti-histone.

Stem 5 — Cocaine mimic: Young patient with nasal destruction, neutropenia, atypical p-ANCA, anti-PR3 + anti-elastase.

Stem 6 — Mimic endocarditis: Fever + splinter hemorrhages + RPGN + low complement.

Stem 7 — Pregnancy: 30-year-old with GPA in remission planning pregnancy.

Stem 8 — Relapse vs. titer rise: Patient in remission on maintenance with rising ANCA titer but normal Cr/UA.

Stem 9 — Steroid forgotten Rx: Patient on prednisone 40 mg/day without bisphosphonate or TMP-SMX presents with PJP.

One-Line Recap

ANCA-associated vasculitis (GPA, MPA, EGPA) is a small-vessel pauci-immune necrotizing vasculitis defined by ANCA serology, multisystem involvement (upper airway/lung/kidney/nerve), and a treatment paradigm of rapid induction with high-dose steroids plus rituximab or cyclophosphamide followed by long-term maintenance — and Step 3 mastery hinges on recognizing the triads early, avoiding mimics, and never forgetting prophylaxis.

Board pearl: The most-tested Step 3 AAV concepts are (1) recognizing RPGN early, (2) choosing rituximab in reproductive-age patients, (3) ANCA titer rise ≠ retreatment, and (4) the prophylaxis bundle omission — master these four and the topic is yours.

Recognize the triads: GPA = upper airway + lung + kidney with PR3/c-ANCA; MPA = pulmonary–renal RPGN with MPO/p-ANCA, no granulomas; EGPA = asthma + eosinophilia + neuropathy/cardiac, only ~40% ANCA+.

Workup essentials: ANCA panel, UA with microscopy (RBC casts), creatinine, CBC with differential, CXR/CT chest, complement (normal in AAV), HBV/HCV/HIV/TB screening, and tissue biopsy (renal preferred) for definitive diagnosis — but do not delay empiric steroids in life-threatening disease while awaiting results.

Treatment skeleton: PEXIVAS reduced-dose steroids + rituximab (preferred) or cyclophosphamide for induction; rituximab maintenance for ≥2 years; PLEX only for severe DAH or dual anti-GBM; avacopan as steroid-sparing adjunct; mepolizumab for EGPA maintenance.

Never forget the prophylaxis bundle: TMP-SMX for PJP, bisphosphonate + calcium + vitamin D, HBV screen with antiviral prophylaxis if anti-HBc+, vaccinations before rituximab, fertility preservation counseling before cyclophosphamide, and always rule out endocarditis and TB before immunosuppression.