Musculoskeletal

Polyarteritis nodosa: diagnosis and treatment

Clinical Overview and When to Suspect Polyarteritis Nodosa

— Produces transmural inflammation with fibrinoid necrosis, microaneurysms, and segmental stenoses at vessel bifurcations

— ANCA-negative vasculitis (a defining serologic feature on boards)

— Notably spares the lungs; pulmonary involvement should redirect you toward ANCA-associated vasculitis

— Adults 40–60, slight male predominance

— Historically associated with hepatitis B (HBV), though prevalence has fallen with HBV vaccination — still tested

— Hepatitis C, hairy cell leukemia, and DADA2 (adenosine deaminase 2 deficiency) in young/pediatric patients

— Multisystem illness with constitutional symptoms (fever, weight loss, myalgia, malaise) plus organ ischemia

— Mononeuritis multiplex (foot drop + wrist drop) is the single highest-yield clue

— New hypertension + renal infarction without glomerulonephritis (urinalysis often bland — no RBC casts)

— Postprandial abdominal pain ("intestinal angina"), testicular pain, livedo reticularis, tender subcutaneous nodules along arteries

— Skin-limited (cutaneous) PAN exists as a distinct, milder phenotype

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of medium-sized muscular arteries, sparing arterioles, capillaries, and venules

Classic epidemiology

When to suspect PAN on Step 3

Board pearl: The triad that should trigger PAN on a vignette = constitutional symptoms + mononeuritis multiplex + bland urinalysis with renovascular hypertension. The "bland sediment" distinguishes PAN's renal disease (arterial ischemia) from microscopic polyangiitis (glomerulonephritis with RBC casts).

Key distinction: PAN = medium-vessel, ANCA-negative, no lung, no glomerulonephritis. GPA/MPA/EGPA = small-vessel, ANCA-positive, with lung and glomerular involvement. Mixing these up is the single most common Step 3 trap in vasculitis questions.

Untreated PAN has a 5-year mortality near 90%; treated, it approaches 80% survival — early recognition matters.

Presentation Patterns and Key History

— Fever, fatigue, weight loss ≥4 kg, drenching night sweats, diffuse myalgias and arthralgias

— Often mislabeled as fibromyalgia, viral syndrome, or occult malignancy before vasculitis is considered

— Mononeuritis multiplex: asymmetric, painful sensorimotor deficits in named nerves (peroneal, ulnar, median, sural)

— Distal symmetric polyneuropathy later as lesions coalesce

— CNS involvement (stroke, seizures) is less common but heralds severe disease

— New or accelerated hypertension from renin release at ischemic segments

— Renal infarcts cause flank pain, hematuria without casts, rising creatinine

— No glomerulonephritis — urinalysis is characteristically bland

— Postprandial abdominal pain (mesenteric angina), nausea, weight loss

— Mesenteric microaneurysm rupture → acute abdomen, GI bleeding, bowel infarction (surgical emergency)

— Livedo reticularis, tender subcutaneous nodules along course of arteries, digital ischemia/gangrene, purpura, ulcers

— Coronary arteritis → MI in a young patient without atherosclerotic risk factors

— Pericarditis, CHF from hypertensive cardiomyopathy

— Testicular pain/tenderness is a near-pathognomonic clue on boards — caused by testicular artery vasculitis

— HBV risk factors (IVDU, transfusion before 1992, high-risk sexual exposure, endemic country origin)

— Hairy cell leukemia history, recent IV drug use, family history of early-onset stroke (DADA2)

Constitutional prodrome (weeks to months)

Neurologic — present in 50–75%

Renal — most common visceral involvement (~70%)

Gastrointestinal (~50%)

Cutaneous (~50%)

Cardiac

Genitourinary

History to mine

Board pearl: A middle-aged man with fever, weight loss, foot drop, testicular pain, and new hypertension is PAN until proven otherwise — order HBsAg early in the workup.

Step 3 management: On a CCS case, the first three orders should be CBC, CMP, urinalysis, ESR/CRP, and hepatitis B surface antigen — these frame both diagnosis and etiology.

Physical Exam Findings and Hemodynamic Assessment

— Hypertension (often new, moderate-to-severe) is the rule; reflects renovascular ischemia and renin activation

— Low-grade fever, tachycardia from systemic inflammation

— Asymmetric blood pressures or diminished pulses if larger medium vessels are involved

— Livedo reticularis in a net-like pattern on lower extremities and trunk

— Tender subcutaneous nodules 0.5–2 cm along the course of superficial arteries (calves, forearms) — palpate them

— Digital ischemia: splinter hemorrhages, nail-fold infarcts, gangrene of fingertips/toes

— Punched-out ulcers on malleoli, retiform purpura

— Foot drop (peroneal), wrist drop (radial), or isolated median/ulnar deficit — document side and territory

— Asymmetric reflex loss, painful dysesthesias

— Cranial nerve deficits or focal CNS signs warrant urgent imaging

— Diffuse tenderness, postprandial pain reproduced by eating

— Peritoneal signs = microaneurysm rupture or bowel infarction → emergent surgical consult

— Tender testicle without epididymitis or torsion findings on ultrasound — think PAN

— Scrotal exam is frequently omitted and frequently tested

— Lungs clear (lung involvement argues against PAN)

— Pericardial rub, S4 from hypertensive heart disease, signs of CHF in advanced disease

— Establish a baseline BP in both arms, orthostatics, and ankle-brachial indices if claudication is reported

— Document weight, performance status (drives prognostic scoring)

Vitals

Skin exam — high yield

Neurologic exam

Abdominal exam

Genitourinary

Cardiopulmonary

Hemodynamic assessment

Key distinction: Palpable purpura on dependent skin suggests small-vessel vasculitis (IgA vasculitis, cryoglobulinemia, ANCA-associated); livedo + nodules + digital infarcts suggest medium-vessel PAN. Vessel size dictates the differential more than any single symptom.

Board pearl: A bedside exam triad of livedo reticularis, a tender forearm nodule, and unilateral foot drop essentially closes the clinical case for PAN — confirm with imaging or biopsy.

Diagnostic Workup — Initial Labs, Imaging, and Biomarkers

— CBC: normocytic anemia of chronic disease, leukocytosis, thrombocytosis (reactive)

— CMP: elevated creatinine, normal-to-mildly abnormal LFTs unless HBV co-infection

— ESR and CRP: markedly elevated (>50–100); useful for tracking response but nonspecific

— Urinalysis: mild proteinuria and hematuria without RBC casts — bland sediment is the rule

— Spot urine protein/creatinine ratio to quantify proteinuria

— Hepatitis B surface antigen (HBsAg), anti-HBc, HBV DNA — alters treatment dramatically (antivirals + short steroid course rather than cyclophosphamide)

— Hepatitis C antibody with reflex RNA

— HIV screen

— Cryoglobulins (especially if HCV positive)

— ANCA (c-ANCA/PR3, p-ANCA/MPO): should be negative in PAN; positive ANCA redirects to GPA/MPA/EGPA

— ANA, complement (C3/C4): screen for SLE

— RF, anti-CCP: screen for rheumatoid vasculitis

— Blood cultures × 3 to rule out endocarditis, a classic PAN mimic

— CK, aldolase if myalgia is prominent

— Troponin, ECG, echo if chest pain or new heart failure — coronary arteritis is real

— Lipase for mesenteric involvement

— Nerve conduction studies/EMG to map mononeuritis multiplex (also identifies a biopsy target)

— CT abdomen/pelvis with contrast for renal infarcts, mesenteric findings, and incidental aneurysms

— Chest imaging to confirm lung sparing — a key negative finding

— Doppler of symptomatic limbs

Initial laboratory panel

Etiologic serologies — order on every suspected PAN

Vasculitis serologies — to exclude mimics

Markers of organ damage

Initial imaging

Step 3 management: Order HBsAg before initiating immunosuppression — missing HBV-associated PAN leads to fulminant hepatitis on cyclophosphamide.

Board pearl: Eosinophilia >10% points to EGPA, not PAN. Hematuria with RBC casts points to MPA/GPA, not PAN. PAN's labs are characteristically bland-urine + thrombocytosis + sky-high ESR + negative ANCA.

Diagnostic Workup — Advanced and Confirmatory Studies

— Sural nerve + gastrocnemius muscle biopsy is highest yield when mononeuritis multiplex is present (~60–80% sensitivity)

— Skin biopsy of a nodule must be deep/wedge to reach medium-sized vessels in subcutaneous fat — punch biopsy is insufficient

— Testicular biopsy if symptomatic

— Histology: focal, segmental, transmural necrotizing inflammation with fibrinoid necrosis of medium arteries, often with mixed neutrophilic/mononuclear infiltrate; lesions of different ages coexist

— Avoid renal biopsy — risk of bleeding from microaneurysms and low yield (glomeruli typically uninvolved)

— CT angiography or conventional catheter angiography of celiac, mesenteric, and renal arteries

— Findings: multiple microaneurysms (1–5 mm), beading, focal stenoses, and infarcts in medium vessels

— Catheter angiography remains gold standard for small microaneurysms

— MRA is less sensitive for the small medium-vessel lesions

— ≥3 of 10 ACR features: weight loss >4 kg, livedo, testicular pain, myalgias, mono/polyneuropathy, diastolic BP >90, elevated BUN/Cr, HBV, arteriographic abnormality, biopsy showing arteritis

— Use clinically, not as a strict diagnostic gate

— Five-Factor Score (FFS) 2009: age >65, cardiac symptoms, GI involvement, renal insufficiency (Cr >1.7), absence of ENT symptoms — each = 1 point

— FFS ≥1 → add cyclophosphamide to glucocorticoids; FFS = 0 → glucocorticoids alone initially

Two confirmatory paths — choose based on accessible organ involvement

Path 1: Tissue biopsy (preferred when a clinically involved site is safely accessible)

Path 2: Visceral angiography (when no safe biopsy target)

2012 Chapel Hill Consensus & 1990 ACR criteria (for context)

Prognostic scoring

Key distinction: Tissue diagnosis trumps angiographic diagnosis when both are feasible, but either suffices in the right clinical context. Don't delay treatment in a deteriorating patient awaiting biopsy.

Board pearl: "Beads on a string" mesenteric or renal angiogram in a febrile, hypertensive, foot-drop patient = PAN. Commit this image to memory — it appears frequently in question banks.

Risk Stratification and First-Line Management Logic

— +1 each: age >65, cardiac involvement, GI involvement requiring surgery or with bleeding/perforation/pancreatitis/infarction, renal insufficiency (stabilized peak Cr ≥150 µmol/L or ~1.7 mg/dL), absence of ENT symptoms (a granulomatosis marker, hence its absence worsens PAN prognosis)

— FFS 0: 5-year mortality ~9%

— FFS 1: ~21%

— FFS ≥2: ~40%

— FFS = 0 (non–HBV-related, no major organ threat): glucocorticoids alone as induction; add immunosuppressant only if relapse or steroid-dependent

— FFS ≥1 or major organ involvement (mononeuritis multiplex, severe GI, cardiac, CNS, renal): glucocorticoids + cyclophosphamide induction

— HBV-associated PAN: short course steroids + plasma exchange + antiviral therapy (entecavir or tenofovir) — avoid prolonged immunosuppression that perpetuates viral replication

— Cutaneous (skin-limited) PAN: NSAIDs, colchicine, dapsone, or low-dose steroids; escalate only with systemic spread

— DADA2-associated PAN: TNF inhibitors (etanercept) are first-line — disease-defining response

— TB screening (IGRA or PPD), HBV/HCV/HIV serologies, pregnancy test, vaccinations (inactivated only once immunosuppressed), baseline DEXA, PCP prophylaxis plan if high-dose steroids ≥4 weeks

— Counsel about fertility preservation before cyclophosphamide (sperm/oocyte banking, GnRH agonists)

— Aggressive BP control with ACEi/ARB (also renoprotective)

— Statin if vascular risk warrants

— Pain control, PT for mononeuritis multiplex

Goal of stratification — match immunosuppressive intensity to disease severity, minimizing toxicity

Five-Factor Score (FFS, 2009 revision) — drives induction choice

Treatment stratification

Pre-treatment checklist (CCS-style ordering)

Supportive measures

Step 3 management: Always calculate FFS and rule out HBV before choosing induction — these two decisions determine whether the patient gets cyclophosphamide, plasma exchange, or antivirals.

CCS pearl: Order PJP prophylaxis (TMP-SMX), calcium/vitamin D, and a bisphosphonate when starting prednisone ≥20 mg/day expected >4 weeks — these prevention orders score points.

Pharmacotherapy — First-Line Drug Regimen

— Methylprednisolone pulse 500–1000 mg IV daily × 3 days for severe disease (rapidly progressive neuropathy, GI ischemia, cardiac involvement)

— Followed by prednisone 1 mg/kg/day (max 60–80 mg) orally, taper over 9–12 months

— Cyclophosphamide: oral 2 mg/kg/day (cap based on age/renal function) OR IV pulses 15 mg/kg q2 weeks × 3, then q3 weeks × 3–6 (CYCLOPS-style)

— Duration: 3–6 months of cyclophosphamide, then transition to maintenance

— Prednisone 1 mg/kg/day monotherapy with taper

— Add azathioprine or methotrexate if relapse or steroid-dependent at >10 mg/day

— Azathioprine 2 mg/kg/day (check TPMT/NUDT15 activity before starting) — first-line

— Methotrexate 20–25 mg weekly with folic acid — alternative if normal renal function

— Continue 12–18 months beyond remission; longer in relapsing disease

— Short course prednisone (~2 weeks) to control inflammation

— Plasma exchange to remove circulating immune complexes

— Antiviral: entecavir or tenofovir to suppress HBV replication; continue long-term

— Avoid cyclophosphamide if possible — it potentiates viral replication and chronicity

— Rituximab is increasingly used though evidence base is stronger in ANCA vasculitis; reasonable second-line

— IVIG for select cases, especially with infection contraindicating immunosuppression

— TNF inhibitors for DADA2

— MESNA with IV pulses to prevent hemorrhagic cystitis

— Aggressive hydration, morning dosing, monitor CBC weekly–biweekly

— Lifetime cumulative dose <25 g to minimize bladder cancer/MDS risk

— Screen for bladder cancer with urinalysis annually for life after exposure

Induction — non-HBV PAN, FFS ≥1 or organ-threatening

Induction — non-HBV PAN, FFS = 0

Maintenance (after induction remission, ~3–6 months in)

HBV-associated PAN — distinct algorithm

Refractory or relapsing disease

Cyclophosphamide toxicity prophylaxis

Board pearl: HBV-associated PAN reverses the usual playbook — antivirals + plasma exchange + brief steroids, not prolonged cyclophosphamide. This reversal is one of the most testable points in the topic.

Step 3 management: Co-prescribe TMP-SMX (PJP prophylaxis), calcium 1200 mg + vitamin D 800 IU, bisphosphonate, and a PPI with high-dose steroid induction.

Procedures and Expanded Pharmacology

— Indicated in HBV-associated PAN to clear circulating immune complexes

— Typical regimen: ~6–9 sessions over 2–3 weeks, paired with antivirals

— Not routinely indicated in idiopathic PAN (unlike severe ANCA vasculitis with DAH or rapidly progressive GN)

— Entecavir 0.5 mg PO daily OR tenofovir disoproxil 300 mg daily (or tenofovir alafenamide 25 mg)

— Monitor HBV DNA, HBeAg seroconversion, ALT every 3 months

— Continue indefinitely; relapse common with discontinuation

— Renal artery angioplasty/stenting is generally not indicated — PAN lesions are inflammatory, not atherosclerotic; medical control of inflammation reverses stenoses

— Emergent surgery for mesenteric microaneurysm rupture, bowel infarction, or perforation

— Selective transarterial embolization for ruptured visceral microaneurysms in unstable patients

— Avoid elective revascularization during active inflammation — high failure/restenosis

— Gabapentin or duloxetine for neuropathic pain from mononeuritis multiplex

— Ankle-foot orthosis for persistent foot drop; PT/OT for motor recovery (months to years)

— ACE inhibitor or ARB first-line — also renoprotective in renovascular ischemia

— Add calcium channel blocker or thiazide as needed

— Target <130/80 in most adults; monitor creatinine and potassium after ACEi/ARB initiation

— Inactivated influenza annually

— Pneumococcal (PCV20 or PCV15→PPSV23)

— Recombinant zoster (Shingrix) — safe with immunosuppression

— Hepatitis B vaccination if seronegative and not already infected

— Avoid live vaccines (MMR, varicella, yellow fever, live zoster, intranasal flu) while on significant immunosuppression

Plasma exchange (therapeutic plasmapheresis)

Antiviral therapy for HBV-PAN

Vascular procedures

Pain and rehabilitation

Hypertension management

Vaccinations (before or during therapy)

CCS pearl: On a CCS case with acute abdomen + known PAN, order stat CT angiography of the abdomen, type and screen, surgical consult, and transfer to ICU — microaneurysm rupture is time-critical.

Board pearl: Renal artery stenting is wrong in PAN — the correct answer is immunosuppression, which can reverse the inflammatory stenosis.

Special Populations — Elderly and Renal/Hepatic Impairment

— Age >65 is itself an FFS point — automatically upgrades severity stratification

— Higher cumulative toxicity from cyclophosphamide (infection, malignancy, marrow suppression)

— Consider reduced-dose IV cyclophosphamide (e.g., 500 mg flat dose every 2 weeks) or rituximab substitution in frail patients

— Steroid taper should be brisker — older adults are more susceptible to osteoporotic fractures, hyperglycemia, delirium, and infection

— Mandatory fall risk assessment, bone density screening, glucose monitoring

— Adjust cyclophosphamide dose for CrCl — reduce ~25% if CrCl 25–50, ~50% if CrCl <25 or on dialysis

— Methotrexate is contraindicated when CrCl <30 — choose azathioprine for maintenance

— ACEi/ARB initiation: tolerate Cr rise up to ~30%; stop only if higher or hyperkalemia develops

— Renal infarcts can lead to renin-mediated hypertension that persists even after inflammation resolves — long-term BP control essential

— Azathioprine and methotrexate both have hepatotoxicity — monitor LFTs every 2–4 weeks initially

— In HBV-PAN, baseline fibrosis assessment (FibroScan, APRI) guides antiviral monitoring

— Avoid methotrexate in active hepatitis, significant fibrosis, or heavy alcohol use

— Cyclophosphamide is hepatic-metabolized but rarely dose-adjusted for liver disease; monitor closely

— Allopurinol + azathioprine = catastrophic myelosuppression (allopurinol inhibits xanthine oxidase, which clears azathioprine metabolites). If urate-lowering needed, use febuxostat cautiously or dose-reduce azathioprine by 75%

— TMP-SMX + methotrexate raises methotrexate toxicity — consider alternative PJP prophylaxis (dapsone, atovaquone) if both required

— NSAIDs + methotrexate in renal impairment exacerbates marrow suppression

— Glucocorticoid-induced hyperglycemia is near-universal; preemptively adjust insulin/oral agents

— Document A1c at baseline and every 3 months

Elderly (>65)

Chronic kidney disease and renal-limited PAN

Hepatic impairment

Drug interaction watchpoints

Comorbid diabetes

Step 3 management: Before starting azathioprine, check TPMT and NUDT15 genotype/activity — deficiency predicts severe myelosuppression and changes dosing or drug selection.

Board pearl: The allopurinol-azathioprine interaction is among the most tested DDIs on Step 3 — if a vignette mentions both, expect pancytopenia.

Special Populations — Pregnancy, Pediatrics, and DADA2

— Active PAN markedly increases maternal and fetal mortality (hypertensive crisis, eclampsia mimic, mesenteric/renal ischemia)

— Preconception counseling: defer pregnancy until ≥6 months of stable remission off cyclophosphamide

— Safe in pregnancy: prednisone (lowest effective dose), azathioprine, hydroxychloroquine, low-dose aspirin

— Contraindicated: cyclophosphamide, methotrexate, mycophenolate — teratogenic

— ACEi/ARB contraindicated after first trimester (fetal renal/skull defects) — switch to labetalol, nifedipine, or methyldopa for BP control

— Monitor with monthly disease activity assessment; coordinate MFM, rheumatology, nephrology

— Prednisone (<20 mg/day), azathioprine, hydroxychloroquine generally compatible

— Methotrexate, cyclophosphamide, mycophenolate not compatible with breastfeeding

— Rare; presents with fever, rash, arthralgias, hypertension, abdominal pain

— Strong consideration for DADA2 (adenosine deaminase 2 deficiency) — autosomal recessive, ADA2 gene mutations

— DADA2 features: early-onset strokes (often lacunar), livedo racemosa, immunodeficiency, hematologic abnormalities, family history

— Diagnose DADA2 with serum ADA2 enzyme activity and genetic testing

— Treatment of DADA2: TNF inhibitors (etanercept, adalimumab) prevent strokes — disease-modifying. Do not use anti-platelet/anticoagulation alone for stroke prevention in DADA2

— Hematopoietic stem cell transplant for severe DADA2 with cytopenias

— Fertility preservation discussion before cyclophosphamide is mandatory — sperm banking, oocyte/embryo cryopreservation, GnRH agonist (leuprolide) during cyclophosphamide may preserve ovarian function

— Contraception counseling — pregnancy must be avoided on teratogenic agents

Pregnancy

Lactation

Pediatric PAN

Adolescent counseling

Board pearl: Pediatric or young-adult PAN + recurrent stroke + livedo + positive family history = DADA2 until proven otherwise. TNF inhibitor, not cyclophosphamide, is the answer.

Key distinction: ACEi/ARB are first-line for PAN-related hypertension in non-pregnant adults but absolutely contraindicated in pregnancy — swap to labetalol or nifedipine the moment pregnancy is confirmed.

Complications and Adverse Outcomes

— Mesenteric microaneurysm rupture → hemoperitoneum, hemorrhagic shock — surgical/IR emergency

— Bowel infarction and perforation from mesenteric arteritis

— Renal infarction with accelerated hypertension; rare progression to ESRD

— Myocardial infarction from coronary arteritis — consider PAN in young MI without atherosclerotic risk factors

— Ischemic stroke from cerebral arteritis (uncommon but devastating)

— Limb gangrene requiring amputation

— Persistent mononeuritis multiplex with permanent motor deficits despite remission

— Renovascular activation can drive malignant hypertension with encephalopathy or pulmonary edema

— Manage with IV labetalol or nicardipine; avoid abrupt BP drops that worsen ischemia

— Glucocorticoids: osteoporosis/fractures, hyperglycemia/new-onset diabetes, weight gain, cataracts, glaucoma, avascular necrosis of femoral head, mood disturbance, adrenal suppression, infection

— Cyclophosphamide: hemorrhagic cystitis (acute) and bladder cancer (lifetime risk, especially cumulative dose >36 g), MDS/AML, infertility (premature ovarian failure, azoospermia), opportunistic infection (PJP, CMV, fungal), marrow suppression

— Azathioprine: myelosuppression (TPMT/NUDT15-dependent), hepatotoxicity, pancreatitis, increased nonmelanoma skin cancer

— Methotrexate: hepatic fibrosis, pneumonitis, cytopenias, mucositis, teratogenicity

— PJP, herpes zoster, reactivation of latent TB, HBV reactivation, CMV — high incidence during induction

— Annual influenza, pneumococcal series, recombinant zoster, COVID boosters are essential

— Long-term steroid exposure accelerates atherosclerosis — screen lipids, control BP, consider statin

— ~25–40% relapse over 5–10 years; HBV-PAN has lower relapse if viral suppression sustained

— Idiopathic PAN can relapse years after remission — never declare cure prematurely

Disease-related complications

Hypertensive emergencies

Treatment-related complications

Infections

Cumulative cardiovascular risk

Relapse

Board pearl: Hemorrhagic cystitis on cyclophosphamide = stop drug, bladder irrigation, MESNA next time. Painless gross hematuria years after cyclophosphamide = bladder cancer until proven otherwise — order cystoscopy.

Step 3 management: Lifetime annual urinalysis to screen for bladder cancer after any cyclophosphamide exposure is a quality-of-care metric.

When to Escalate — ICU, Consult, and Inpatient Triage

— Hemodynamic instability from mesenteric aneurysm rupture or GI bleeding

— Malignant hypertension with end-organ damage (encephalopathy, pulmonary edema, MI)

— Acute myocardial infarction from coronary arteritis

— Rapidly progressive renal failure requiring dialysis

— Acute stroke from CNS vasculitis

— Bowel ischemia/perforation with peritonitis

— New systemic vasculitis diagnosis requiring IV pulse methylprednisolone

— Initiation of cyclophosphamide induction in a clinically fragile patient

— Uncontrolled pain from mononeuritis multiplex

— Hypertensive urgency requiring IV therapy

— Suspected microaneurysm without rupture — observation and imaging

— Rheumatology — diagnostic confirmation, FFS scoring, treatment plan

— Nephrology if Cr rising or hypertension is severe

— Neurology for mononeuritis multiplex confirmation, EMG/NCS, biopsy targeting

— General surgery + interventional radiology for any GI ischemic syndrome

— Infectious disease if HBV/HCV/HIV positive

— Hepatology for HBV-PAN co-management

— Cardiology for suspected coronary arteritis

— Dermatology for biopsy of skin lesions

— Ophthalmology baseline before chronic steroids

— Reproductive endocrinology/urology before cyclophosphamide for fertility preservation

— Mild constitutional symptoms, no organ threat, FFS = 0 → outpatient workup with urgent rheumatology

— Any major organ involvement → admit for induction and monitoring

— Lack of IR/vascular surgery for ruptured aneurysm

— Lack of rheumatology for complex induction

— Pediatric or DADA2-suspected cases to specialized centers

Immediate ICU indications

Floor-level admission criteria

Consultations to mobilize early (CCS-style)

Outpatient vs inpatient decision

Transfer indications

CCS pearl: On a CCS PAN case, the highest-scoring early orders include NPO, two large-bore IVs, type and screen, stat CT angiography, surgery consult, and rheumatology consult — these reflect both diagnostic urgency and multidisciplinary care.

Board pearl: A PAN patient with acute abdomen and falling hemoglobin = ruptured visceral microaneurysm — escalate to ICU, mobilize IR for embolization or surgery for resection. Do not wait for biopsy results.

Key Differentials — Other Vasculitides

— Small-vessel, p-ANCA/MPO positive

— Pulmonary-renal syndrome: alveolar hemorrhage + pauci-immune glomerulonephritis with RBC casts

— No granulomas (vs GPA)

— Small-to-medium vessel, c-ANCA/PR3 positive

— Upper airway (sinusitis, saddle nose, otitis), lower airway (cavitary nodules), renal (RPGN)

— Granulomatous inflammation on biopsy

— Small-to-medium vessel, p-ANCA in ~40%

— Asthma + peripheral eosinophilia >10% + neuropathy

— Skin nodules and cardiac involvement common

— Small vessel, immune complex (IgA)

— Palpable purpura on lower extremities, arthralgias, abdominal pain, IgA nephropathy

— Predominantly pediatric; usually self-limited

— Small vessel; often HCV-associated

— Palpable purpura, low C4, positive cryoglobulins, glomerulonephritis, neuropathy

— Treat underlying HCV with direct-acting antivirals

— Medium-vessel vasculitis in children <5

— Fever ≥5 days, conjunctivitis, mucositis, rash, extremity changes, cervical lymphadenopathy

— Coronary artery aneurysms are the feared complication

— Treat with IVIG + aspirin

— Large-vessel vasculitis — aortic arch and branches (Takayasu) or temporal/cranial (GCA)

— Different vessel size, different demographic, distinct workup (imaging > biopsy for Takayasu; temporal artery biopsy for GCA)

— Vessel size is the master organizing axis: large (Takayasu, GCA) → medium (PAN, Kawasaki) → small (ANCA-associated, immune complex)

— ANCA status subdivides small/medium category

— Lung involvement and glomerulonephritis flag ANCA-associated disease, not PAN

Microscopic polyangiitis (MPA)

Granulomatosis with polyangiitis (GPA, formerly Wegener)

Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss)

IgA vasculitis (Henoch-Schönlein purpura)

Cryoglobulinemic vasculitis

Kawasaki disease

Takayasu arteritis & GCA

Comparative anchor

Key distinction: PAN spares lung and glomeruli; ANCA-associated vasculitides hit both. Pulmonary nodules or RBC casts essentially rule out PAN.

Board pearl: Asthma + eosinophilia + neuropathy = EGPA, not PAN. Sinusitis + cavitary lung nodules + RPGN = GPA, not PAN. HBV + bland urine + mononeuritis = PAN.

Key Differentials — Non-Vasculitic Mimics

— Fever, weight loss, embolic phenomena (Janeway lesions, Osler nodes, splinter hemorrhages), mononeuritis can occur

— Order blood cultures × 3 and TTE/TEE before committing to immunosuppression

— Immunosuppressing endocarditis is a sentinel safety event

— Constitutional symptoms, embolic phenomena, elevated ESR

— Diagnosed by echocardiography — a routine echo in vasculitis workup catches this

— Post-arterial-instrumentation or anticoagulation in atherosclerotic patient

— Livedo, blue toes, AKI, eosinophilia, hypocomplementemia

— Skin biopsy shows cholesterol clefts in arterioles — distinguishes from PAN's fibrinoid necrosis

— Livedo reticularis, arterial/venous thrombosis, fetal loss

— Positive lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I

— Treat with anticoagulation, not immunosuppression

— Young heavy smoker, distal limb ischemia, migratory superficial thrombophlebitis

— Smoking cessation is the only effective therapy — pathognomonic for the disease

— Young women, renovascular hypertension, "string of beads" on renal angiography

— No inflammation, no constitutional symptoms — bland labs distinguish

— Treat with angioplasty (no immunosuppression)

— Multi-organ disease with cytopenias, glomerulonephritis, serositis

— Positive ANA, low complement, dsDNA — distinct serology

— Can have lupus vasculitis but features SLE multisystem hallmarks

— Lymphoma, paraneoplastic vasculitis — weight loss, fever, lymphadenopathy

— Hairy cell leukemia is uniquely associated with PAN-like vasculitis — check peripheral smear for hairy cells

— Painful livedo and ulcers — distinguished by ESRD context and calcium-phosphate product, biopsy showing vascular calcification

Infective endocarditis

Atrial myxoma

Cholesterol embolization syndrome

Antiphospholipid syndrome (APS)

Thromboangiitis obliterans (Buerger disease)

Fibromuscular dysplasia

Systemic lupus erythematosus

Malignancy mimics

Calciphylaxis (in dialysis patients)

Key distinction: Endocarditis is the highest-stakes mimic — it cures with antibiotics and worsens with steroids. Always rule it out before starting immunosuppression for a febrile multisystem vignette.

Board pearl: Young smoker + distal gangrene + normal labs = Buerger, not PAN. String of beads + young woman + normal ESR = FMD, not PAN. The inflammatory phenotype (ESR, CRP, weight loss, fever) is what makes a vasculitis vs a vasculopathy.

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Azathioprine 2 mg/kg/day (after TPMT/NUDT15 testing) — first-line maintenance

— Methotrexate 20–25 mg weekly + folic acid 1 mg daily — alternative if normal renal function

— Duration: 12–18 months beyond remission for first episode; longer for relapsing disease

— Slow steroid taper to ≤7.5 mg prednisone daily by month 6; off if possible by month 12

— Calcium 1000–1200 mg/day + vitamin D 800–1000 IU/day

— Bisphosphonate (alendronate, risedronate) for any patient on ≥7.5 mg prednisone for >3 months, or those at increased fracture risk

— Baseline and follow-up DEXA

— ACEi or ARB for renovascular hypertension; BP target <130/80

— Statin based on ASCVD risk (chronic steroids raise risk; many adults qualify)

— Low-dose aspirin for digital ischemia or established cardiovascular disease — individualized

— Glycemic monitoring with periodic A1c; preemptive diabetes therapy adjustment

— TMP-SMX for PJP prophylaxis while on prednisone ≥20 mg/day plus another immunosuppressant

— Inactivated influenza annually

— PCV20 (or PCV15 → PPSV23)

— Recombinant zoster (Shingrix) — safe in immunosuppression

— Hepatitis B vaccine if susceptible

— COVID-19 vaccines/boosters per current schedule

— Avoid live vaccines while on significant immunosuppression

— Lifetime annual urinalysis after cyclophosphamide for bladder cancer

— Annual skin exam for nonmelanoma skin cancer (azathioprine, chronic immunosuppression)

— Maintain age-appropriate cervical, breast, colorectal, lung cancer screening

— Lifelong tenofovir or entecavir with HBV DNA every 3–6 months

— Hepatocellular carcinoma surveillance with ultrasound ± AFP every 6 months if cirrhotic or high risk

— Confirmed contraception while on teratogens; counsel timing of conception attempts ≥3–6 months after stopping methotrexate/mycophenolate; ≥3 months for cyclophosphamide

Maintenance immunosuppression

Steroid stewardship and bone protection

Cardiovascular and renal prevention

Infection prevention

Cancer screening

HBV-PAN specifics

Fertility and contraception

Step 3 management: Build the discharge bundle: maintenance immunosuppressant + steroid taper schedule + calcium/vitamin D + bisphosphonate + PJP prophylaxis + vaccines updated + BP/lipid/glucose plan + rheumatology follow-up scheduled.

Board pearl: Forgetting PJP prophylaxis in a vignette where prednisone ≥20 mg/day plus cyclophosphamide is started is a common Step 3 distractor — always include TMP-SMX.

Follow-Up, Monitoring Parameters, and Counseling

— CBC, CMP, urinalysis every 1–2 weeks during cyclophosphamide

— ESR/CRP every 2–4 weeks to track inflammatory burden

— Blood pressure log weekly at home

— Glucose monitoring (fasting and post-prandial) on high-dose steroids

— Symptom diary for neuropathy, abdominal pain, skin lesions

— CBC, CMP, LFTs every 4–8 weeks on azathioprine or methotrexate

— ESR/CRP every 3 months

— BP, weight, glucose, lipids at each visit

— Annual DEXA while on steroids

— Cyclophosphamide-exposed: annual urinalysis and urine cytology indefinitely

— Every 1–2 months in first year, then every 3–6 months during sustained remission

— Sooner with any new symptom — relapse can be subtle (recurrent low-grade fever, rising ESR, new neuropathy)

— Recognize relapse: new fever, weight loss, livedo, weakness, abdominal pain → call promptly

— Infection precautions: hand hygiene, sick contact avoidance, mask in high-risk settings, temperature check with any symptoms

— Sun protection for nonmelanoma skin cancer risk on azathioprine

— Pregnancy planning discussions at every visit during reproductive years

— Smoking cessation — accelerates vascular disease, complicates digital ischemia

— Bone health and weight-bearing exercise

— Mental health screening — chronic illness and steroids both raise depression risk

— PT/OT for residual neuropathy — foot drop bracing, gait training

— Pacing and energy management

— Driving assessment if motor deficits affect pedal use

— Written taper schedule, medication list, sick-day rules for steroids (stress-dose steroids for major illness or surgery)

— Medical alert bracelet for adrenal suppression while on chronic steroids

— Reconcile medications at every transition (admission, discharge, specialty visit)

— Ensure closed-loop communication between rheumatology, primary care, nephrology

Monitoring cadence during induction

Maintenance phase monitoring

Rheumatology follow-up

Counseling priorities

Rehabilitation

Patient education materials

Transitions of care

CCS pearl: Always order "patient education," "smoking cessation counseling," and "schedule rheumatology follow-up in 2 weeks" before ending a CCS case — these are scored advance directives in long-term management.

Board pearl: During major surgery, illness, or trauma, patients on chronic prednisone ≥5 mg/day for >3 weeks need stress-dose hydrocortisone to prevent adrenal crisis — a frequent Step 3 perioperative scenario.

Ethical, Legal, and Patient Safety Considerations

— Cyclophosphamide consent must explicitly cover infertility risk, bladder toxicity/cancer, secondary malignancy (MDS/AML), opportunistic infection, teratogenicity

— Document fertility preservation discussion before initiation — failing to offer sperm/oocyte banking is a malpractice exposure

— For adolescents, parental consent + adolescent assent with developmentally appropriate discussion

— HBV-PAN: hepatitis B is a reportable communicable disease in all U.S. states — public health notification is mandatory

— Partner notification and testing counseling

— Workplace exposure considerations for healthcare workers

— High-risk handoffs: ICU to floor, hospital to home, primary specialist to covering provider

— Medication reconciliation at every transition — missed PJP prophylaxis, missed steroid taper instructions, and missed antivirals in HBV-PAN are sentinel safety errors

— Provide written sick-day rules and stress-dose steroid instructions at discharge

— Confirm follow-up appointments are scheduled before discharge, not just recommended

— Patients on chronic steroids must wear/carry medical identification

— Education on stress-dose steroids for fever, vomiting, surgery, trauma

— Anesthesia and surgical teams must be informed preoperatively

— Discuss risks and benefits of vaccination during immunosuppression; respect autonomy while documenting recommendation

— Live vaccines contraindicated; clarify household member vaccination as alternative protection

— In severe disease with rapid decline, ensure decision-making capacity assessment before high-stakes choices

— Surrogate decision-making framework when capacity is impaired

— Advance directives discussion appropriate for any chronic, potentially life-threatening illness

— Cyclophosphamide and biologics are costly; engage case management, social work, manufacturer assistance programs

— Address transportation, language, health literacy barriers — relapse risk rises when follow-up is missed

— Disclose teratogenicity clearly; respect patient choices around contraception and pregnancy timing without coercion

— Document discussions thoroughly

— Track PJP prophylaxis prescription, bone protection, vaccine completion as PAN-specific quality indicators

Informed consent for high-risk therapies

Mandatory reporting

Transition-of-care safety

Adrenal suppression and emergency identification

Vaccine ethics

Capacity and shared decision-making

Equity and access

Pregnancy and reproductive autonomy

Quality and safety metrics

Board pearl: A patient on prednisone 30 mg/day for 6 months undergoing emergency surgery needs IV hydrocortisone 100 mg + 50 mg q8h × 24 hours to prevent adrenal crisis — perioperative stress-dose steroids are commonly tested.

Step 3 management: Never start cyclophosphamide without documenting the fertility preservation conversation and contraception plan — both are standard-of-care and medico-legally protective.

High-Yield Associations and Rapid-Fire Clinical Facts

— Historically ~30% of PAN cases; falling with universal HBV vaccination

— HBsAg positive + necrotizing arteritis = HBV-PAN → antivirals + plasma exchange + brief steroids; avoid prolonged cyclophosphamide

— More commonly associated with cryoglobulinemic vasculitis, but rare HCV-PAN exists

— Rare but classic association — check peripheral smear in unexplained PAN-like vasculitis

— Cytopenias + splenomegaly + vasculitis triad

— Autosomal recessive, ADA2 gene mutations

— Early-onset stroke (often lacunar) + livedo racemosa + immunodeficiency + cytopenias

— Diagnose with ADA2 enzyme activity + genetic testing

— Treat with TNF inhibitors (etanercept) — disease-modifying, prevents stroke

— Livedo reticularis (net-like) — common

— Tender subcutaneous nodules along arteries — high specificity

— Digital gangrene, retiform purpura, ulcers — severe disease

— Palpable purpura suggests small-vessel disease, not PAN

— Foot drop or wrist drop in mononeuritis multiplex

— Testicular pain or tenderness

— Bland urinalysis with new hypertension in a febrile patient

— "Beads on a string" mesenteric/renal angiogram

— Idiopathic PAN, FFS = 0: steroids alone

— Idiopathic PAN, FFS ≥1: steroids + cyclophosphamide

— HBV-PAN: antivirals + plasma exchange + brief steroids

— DADA2-PAN: TNF inhibitors

— Cutaneous PAN: NSAIDs, colchicine, dapsone, low-dose steroids

— Not ANCA-positive

— Not glomerulonephritic

— Not pulmonary

— Not granulomatous

— Not small-vessel

— Not eosinophilic

— Not atherosclerotic

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

— MESNA with IV cyclophosphamide

— TPMT/NUDT15 before azathioprine

— Allopurinol-azathioprine = pancytopenia trap

— TMP-SMX for PJP on dual immunosuppression

— Bone protection on chronic steroids

Hepatitis B association

Hepatitis C

Hairy cell leukemia

DADA2 (Deficiency of Adenosine Deaminase 2)

Skin findings hierarchy

Classic exam triggers

Treatment fast facts

What PAN is NOT

Five-Factor Score components (memorize)

Pharmacologic must-haves

Board pearl: A single most testable PAN sentence: "ANCA-negative, medium-vessel, lung-sparing, glomerulus-sparing necrotizing vasculitis often associated with hepatitis B, presenting with constitutional symptoms, mononeuritis multiplex, renovascular hypertension, mesenteric ischemia, and testicular pain." Internalize this and most PAN questions answer themselves.

Board Question Stem Patterns

— 50-year-old man with months of fever, weight loss, myalgia, develops sudden right foot drop and BP 180/110. Urinalysis bland. ESR 95.

— Answer path: PAN → check HBsAg → if positive, antivirals + plasma exchange + brief steroids; if negative, steroids + cyclophosphamide

— Patient with known constitutional symptoms develops mesenteric angina, then acute abdomen.

— Answer path: CT angiography → microaneurysm rupture → surgical/IR emergency

— Question juxtaposes two vasculitis vignettes — one with bland urine, one with RBC casts.

— Answer path: bland urine = PAN; RBC casts = MPA/GPA

— Vignette includes ANCA testing.

— Answer path: ANCA negative = PAN-compatible; PR3-ANCA = GPA; MPO-ANCA = MPA/EGPA

— HBsAg-positive patient with vasculitis features.

— Answer path: antivirals (tenofovir/entecavir) + plasma exchange + short-course steroids, NOT prolonged cyclophosphamide

— Child or young adult with recurrent stroke, livedo racemosa, family history of similar.

— Answer path: DADA2 → ADA2 enzyme activity + genetic testing → TNF inhibitor (etanercept)

— Patient on cyclophosphamide develops hematuria.

— Answer path: acute → hemorrhagic cystitis → stop drug, hydrate, MESNA next dose; years later → bladder cancer → cystoscopy

— Patient on azathioprine for PAN develops gout, started on allopurinol; weeks later, pancytopenia.

— Answer path: stop allopurinol or reduce azathioprine 75%; consider febuxostat alternative

— Febrile patient with embolic phenomena and elevated ESR — distractor PAN.

— Answer path: blood cultures + TEE before immunosuppression; positive cultures → endocarditis, not PAN

— PAN patient on chronic prednisone for surgery.

— Answer path: stress-dose hydrocortisone perioperatively

— Pregnant patient with active vasculitis needing therapy.

— Answer path: prednisone + azathioprine; avoid cyclophosphamide, methotrexate, mycophenolate; switch ACEi to labetalol/nifedipine

Pattern 1 — "Foot drop and new hypertension"

Pattern 2 — "Postprandial abdominal pain in a vasculitis vignette"

Pattern 3 — "Bland urinalysis vs RBC casts"

Pattern 4 — "ANCA results given"

Pattern 5 — "Hepatitis B–associated vasculitis treatment"

Pattern 6 — "Pediatric stroke + livedo + family history"

Pattern 7 — "Cyclophosphamide complication"

Pattern 8 — "Allopurinol + azathioprine"

Pattern 9 — "Endocarditis mimic"

Pattern 10 — "Perioperative steroid"

Pattern 11 — "Pregnant patient with PAN"

Board pearl: The single most discriminating data point in PAN vignettes is the urinalysis — bland sediment with arterial-pattern renal disease points squarely to PAN. Train yourself to read the UA line first.

Step 3 management: When in doubt, the most-correct early order on a CCS PAN case is HBsAg + blood cultures + CT angiography + rheumatology consult — covers etiology, mimic, anatomy, and expertise simultaneously.

One-Line Recap

Polyarteritis nodosa is an ANCA-negative, medium-vessel, lung- and glomerulus-sparing necrotizing vasculitis — often hepatitis B–associated — diagnosed by tissue biopsy or visceral angiography, risk-stratified by the Five-Factor Score, and treated with glucocorticoids ± cyclophosphamide (or antivirals + plasma exchange in HBV-PAN, or TNF inhibitors in DADA2).

— Triad to recognize: constitutional symptoms + mononeuritis multiplex + bland-urine renovascular hypertension, often with livedo, nodules, testicular pain, and mesenteric angina

— Confirm with biopsy of an involved site (sural nerve + muscle, deep skin) or visceral angiography showing microaneurysms and beading

— Always order HBsAg, HCV, HIV, ANCA, and blood cultures before immunosuppression

— Negative ANCA, bland urinalysis, clear lungs — the three negatives that fingerprint PAN

— FFS = 0: glucocorticoids alone

— FFS ≥1: glucocorticoids + cyclophosphamide induction → azathioprine or methotrexate maintenance

— HBV-PAN: antivirals + plasma exchange + brief steroids; avoid prolonged cyclophosphamide

— DADA2: TNF inhibitors are disease-modifying and prevent strokes

— Cutaneous PAN: conservative — NSAIDs, colchicine, dapsone, low-dose steroids

— MESNA + hydration with cyclophosphamide; lifelong urinalysis screening for bladder cancer

— TPMT/NUDT15 before azathioprine; beware allopurinol-azathioprine pancytopenia

— PJP prophylaxis on dual immunosuppression; bone protection on chronic steroids; stress-dose steroids perioperatively

— Live vaccines contraindicated; ensure inactivated influenza, pneumococcal, recombinant zoster, COVID, and HBV vaccines

— Bland urine → PAN; RBC casts or pulmonary involvement → ANCA-associated vasculitis; asthma + eosinophilia → EGPA; HCV + low C4 + purpura → cryoglobulinemic vasculitis; pediatric coronary aneurysms → Kawasaki

Diagnostic recap

Treatment recap

Safety recap

Differential recap

Board pearl: Master the vessel-size + ANCA-status + lung-and-glomerulus filter, and you can sort every vasculitis vignette on Step 3 in under thirty seconds — PAN occupies the medium-vessel, ANCA-negative, lung-and-glomerulus-sparing corner of that map, and that single coordinate unlocks the diagnosis and the therapy.