Polyarteritis nodosa is a systemic necrotizing vasculitis affecting medium-sized muscular arteries, leading to segmental transmural inflammation, aneurysm formation, and ischemic damage to multiple organs, notably sparing the lungs.

Exam domain	One-glance essentials
Definition / diagnosis	PAN is necrotising vasculitis of medium/small muscular arteries ^[1] *No glomerulonephritis, no capillary/venular vasculitis and no ANCA association* ^[2]
Epidemiology / risks	Most cases are idiopathic; HBV association is the classic secondary cause ^[1]^[2] Incidence has fallen with HBV vaccination ^[3]
Core mechanism	Transmural fibrinoid necrosis → wall weakness and microaneurysm/rupture ^[2] Luminal thrombosis → downstream ischaemia and infarction ^[3]
Clinical picture	Think skin–gut–kidney–nerve–testis: livedo/nodules, abdominal ischaemia, renovascular HTN, mononeuritis multiplex and orchitis ^[2]^[3] *Lungs are spared* and renal disease is vascular rather than glomerular ^[1]
Investigations	*ANCA negative; test HBsAg; urinalysis lacks RBC casts* ^[1]^[2] Angiography: visceral microaneurysms; biopsy: necrotising medium-vessel arteritis with fibrinoid necrosis ^[2]
Management	Non-severe idiopathic PAN: glucocorticoid ± AZA/MTX; severe organ disease: glucocorticoid + cyclophosphamide ^[2] HBV-PAN: antiviral-centered therapy, brief steroid and plasma exchange when severe; generally avoid prolonged CYC ^[3]
Complications	Mesenteric infarction/perforation, renal infarction/failure, MI, stroke and digital gangrene ^[3] Aneurysm rupture causes renal, mesenteric or cerebral haemorrhage ^[3]
Prevention / follow-up	HBV vaccination and treatment reduce HBV-associated PAN ^[1] Control renovascular BP; monitor CBC/renal/liver function and provide infection/bone prophylaxis during immunosuppression ^[2]
Exam traps	*PAN spares glomeruli and lungs—GN or diffuse alveolar haemorrhage points to MPA ^[1] ANCA negativity alone is not diagnostic; confirm with compatible angiography or biopsy* ^[2]

References

^[1] Lecture slides: GC 053. Fingers turn white and blue.pdf (PAN and PAN-versus-MPA, pp.80, 91, 93) ^[2] Senior notes: Maksim Medicine Notes.pdf (Medium-vessel vasculitis, p.331) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Polyarteritis Nodosa, p.159)

Polyarteritis Nodosa (PAN)

Polyarteritis nodosa (PAN) — let's break the name down from its Latin/Greek roots:

"Poly" = many
"Arter" = artery
"itis" = inflammation
"Nodosa" = nodular (referring to the nodular inflammatory lesions along affected arteries that were first described grossly at autopsy — the inflamed vessel segments form palpable "knots" or nodules)

So the name literally tells you: inflammation of many arteries forming nodules.

PAN is defined as a necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules, and is NOT associated with anti-neutrophil cytoplasmic antibodies (ANCAs). ^[1]^[2]^[3]

This is the 2012 Revised International Chapel Hill Consensus Conference (CHCC) definition and remains the accepted standard ^[1]^[2].

Key Definitional Points — High Yield

Three definitional hallmarks that separate PAN from other vasculitides:

Medium-vessel necrotizing vasculitis (not capillaries/venules → therefore no glomerulonephritis, no pulmonary capillaritis/alveolar haemorrhage)
ANCA-negative (this distinguishes PAN from microscopic polyangiitis [MPA], which also affects small/medium vessels but is ANCA-positive and causes GN)
Necrotizing — transmural fibrinoid necrosis of the arterial wall is the histological hallmark

Common Exam Pitfall

Students often confuse PAN with MPA (microscopic polyangiitis). The critical distinguishing features:

PAN: medium vessel, NO GN, NO lung haemorrhage, ANCA usually negative, abnormal angiogram with microaneurysms, HBV-associated in ~50%
MPA: small vessel (with medium vessel overlap), RPGN, pulmonary haemorrhage, p-ANCA positive (50–80%), normal angiography

PAN has renal involvement via vasculitis with infarcts/microaneurysms (NOT glomerulonephritis). MPA has renal involvement via rapidly progressive glomerulonephritis. ^[4]

2. Epidemiology

Prevalence: 2–33 per million population ^[3]
Incidence: 4.4–9.7 per million per year ^[3]
The incidence has been declining over recent decades, largely attributable to:
- Widespread HBV vaccination (reducing HBV-associated PAN)
- Better antiviral therapy for chronic HBV
- Reclassification — many cases previously labelled "PAN" are now correctly diagnosed as MPA since the Chapel Hill Consensus

Peak age: 6th decade of life (40–60 years), though can occur at any age ^[3]
Sex: Male predominance, M:F ≈ 1.5:1 ^[3]

In Hong Kong and East/Southeast Asia, chronic hepatitis B remains more prevalent than in Western populations (despite declining rates thanks to universal HBV vaccination since 1988). This means HBV-associated PAN, while rare, is still a relevant entity to consider in older unvaccinated cohorts.
The overall incidence of PAN in Hong Kong is very low, but it appears in differential diagnosis lists for multi-system vasculitis, mononeuritis multiplex, and unexplained mesenteric ischaemia.

Risk Factor	Mechanism
Hepatitis B infection (most important)	Immune complex–mediated vessel wall damage; HBsAg–anti-HBs complexes deposit in arterial walls
Hepatitis C infection (less common)	Similar immune complex mechanism; also overlaps with cryoglobulinaemic vasculitis
Hairy cell leukaemia	Uncertain; possibly immune dysregulation from the malignancy
Inflammatory bowel disease	Immune dysregulation / cross-reactive autoimmunity
Streptococcal infection	Molecular mimicry / post-infectious immune complex formation
Advancing age	Accumulated immune dysregulation
Male sex	Unknown mechanism; possibly hormonal or genetic susceptibility

4. Anatomy and Function of Affected Vessels

PAN targets medium-sized muscular arteries — these are the arterial branches that supply individual organs. Think of the arterial tree:

Aorta → Large arteries (e.g. renal artery trunk) → Medium arteries (e.g. arcuate, interlobar arteries) → Arterioles → Capillaries → Venules

PAN sits squarely at the medium artery level — from the main organ-supplying arteries down to the arcuate/interlobar branches. It does not go down to arterioles, capillaries, or venules (that's the domain of small-vessel vasculitis like MPA, GPA, IgA vasculitis).

The anatomy dictates the clinical picture:

Anatomical Feature	Clinical Consequence
Medium arteries supply individual organs segmentally	Segmental infarction of organs (kidney, bowel, heart, testes)
Transmural inflammation weakens the arterial wall	Microaneurysm formation (the "nodosa" — these are visible on angiography)
No capillary/venular involvement	No glomerulonephritis (GN requires capillary-level inflammation in glomeruli)
No pulmonary capillary involvement	No diffuse alveolar haemorrhage
Medium arteries have a muscular media + internal elastic lamina	Necrotizing inflammation destroys the media → aneurysm; or causes luminal thrombosis → downstream ischaemia/infarction
Vasa nervorum (small arteries supplying peripheral nerves) are medium-vessel calibre	Mononeuritis multiplex — nerve infarction from vasculitis of vasa nervorum

PAN can affect virtually any organ's medium arteries, but has a predilection for:

Renal arteries (most common organ involvement)
Mesenteric arteries (GI involvement)
Hepatic arteries
Coronary arteries (cardiac involvement)
Vasa nervorum (neurological involvement — peripheral nerves)
Testicular arteries (orchitis — relatively specific for PAN)
Dermal arteries (cutaneous involvement)
Musculoskeletal arteries (myalgia)
CNS arteries (rare, 5–10%)

High Yield

PAN characteristically spares the lungs (because it does not affect pulmonary arterioles/capillaries — the bronchial arteries are rarely involved). If a patient with suspected medium-vessel vasculitis has pulmonary haemorrhage or RPGN, think MPA, not PAN.

5. Etiology

The majority of PAN cases are idiopathic — no identifiable trigger ^[3]
Presumed to involve a dysregulated immune response against arterial wall antigens

PAN can be idiopathic or secondary, e.g. HBV (HBsAg is included in ACR criteria). ^[2]

PAN is classified as medium/small vessel disease and is viral hepatitis B related. ^[4]

Cause	Notes
Hepatitis B virus (HBV)	Historically the most important secondary cause. ~30–50% of PAN cases in older series were HBV-associated. Now declining due to vaccination. HBV infection is present in ~50% of PAN cases ^[5]. The association is strong enough that HBsAg was included in the original 1990 ACR classification criteria.
Hepatitis C virus (HCV)	Less common; often overlaps with cryoglobulinaemic vasculitis
Streptococcal infection	Post-streptococcal immune complex–mediated; rare
Inflammatory bowel disease (IBD)	Extraintestinal manifestation
Hairy cell leukaemia	Rare paraneoplastic association

Hong Kong–Specific Considerations

Universal HBV vaccination has been in place since 1988 → younger generations are largely protected
However, older unvaccinated individuals (born before ~1988) may still harbour chronic HBV and are at risk
HCV prevalence in HK is low (~0.3–0.5%) but should still be screened for

Rarely, certain drugs have been implicated: minocycline, hydralazine, propylthiouracil (though these more commonly cause ANCA-associated vasculitis)

6. Pathophysiology

6.1 Overview of the Pathogenetic Cascade

The pathophysiology of PAN differs depending on whether it is idiopathic or HBV-associated:

Immune complex formation: HBsAg combines with anti-HBs antibodies in the circulation
Deposition: These immune complexes deposit in the walls of medium-sized arteries (Type III hypersensitivity reaction)
Complement activation: The classical complement pathway is triggered → C3a, C5a (anaphylatoxins) recruit neutrophils
Neutrophilic infiltration: Neutrophils release proteolytic enzymes (elastase, collagenase) and reactive oxygen species
Fibrinoid necrosis: The transmural inflammation causes death of the smooth muscle cells in the media, with deposition of fibrin ("fibrinoid necrosis") — this is the pathological hallmark
Consequences:
- Weakened wall → aneurysmal dilatation (microaneurysms)
- Intimal proliferation + thrombosis → luminal narrowing → downstream ischaemia and infarction

The mechanism is less well understood but is thought to involve:

Cell-mediated immunity (T-cell–driven) against arterial wall antigens
Possible role of endothelial dysfunction and innate immune activation
The end result is the same: transmural necrotizing inflammation → fibrinoid necrosis

PAN lesions are characteristically segmental and at different stages of evolution in the same patient (unlike the uniform inflammation seen in some other vasculitides). This is a classic exam point.

Stage	Description
Acute	Transmural neutrophilic infiltration with fibrinoid necrosis of the media; destruction of internal elastic lamina
Subacute	Mixed inflammatory infiltrate (lymphocytes, macrophages); early fibrosis; microaneurysm formation
Chronic (Healed)	Fibrosis of vessel wall; intimal proliferation → luminal narrowing/occlusion; loss of normal vessel architecture

Segmental and Pleomorphic Lesions

The hallmark pathological feature of PAN is the coexistence of acute, subacute, and chronic lesions in different segments of the same artery or in different arteries. This reflects ongoing, recurrent waves of inflammation — the disease doesn't "hit everywhere at once" but rather attacks vessel segments sequentially.

Understanding why each organ is affected requires understanding the consequences of medium artery occlusion/aneurysm in that organ:

Pathological Process	Organ	Clinical Manifestation
Renal artery branch occlusion/microaneurysm	Kidney	Renal infarction → haematuria, proteinuria, renal insufficiency, renovascular hypertension (↓renal perfusion → RAAS activation)
Mesenteric artery vasculitis	GI tract	Mesenteric ischaemia → postprandial abdominal pain ("intestinal angina"), nausea/vomiting, GI bleeding, bowel infarction
Coronary artery vasculitis	Heart	Myocardial ischaemia/infarction, ischaemic cardiomyopathy, heart failure
Vasa nervorum occlusion	Peripheral nerves	Mononeuritis multiplex (asymmetric, painful, stepwise neuropathy); less commonly polyneuropathy
Testicular artery vasculitis	Testes	Orchitis (testicular pain and swelling — relatively specific for PAN)
Dermal medium arteries	Skin	Tender subcutaneous nodules (the "nodosa"), livedo reticularis, digital ulcers/gangrene, palpable purpura
Cerebral artery vasculitis	CNS	Stroke, seizures (rare, 5–10%)
Muscle artery vasculitis	Skeletal muscle	Myalgia, muscle weakness

7. Classification

PAN: Necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries or venules. NOT associated with ANCAs. ^[1]^[2]

Classification of primary vasculitis ^[4]:

Large vessel disease: Giant cell arteritis, Takayasu's arteritis Medium / small vessel disease: Polyarteritis nodosa (PAN) (Viral hepatitis B related), Kawasaki disease ANCA-related: GPA (Wegener's), EGPA (Churg-Strauss), MPA IgA vasculitis (Henoch-Schönlein Purpura)

PAN is categorized as a medium vessel vasculitis alongside Kawasaki disease.

Subtype	Description
Systemic PAN	Classic multi-organ involvement as described above
Cutaneous PAN	Limited to the skin (subcutaneous nodules, livedo reticularis, ulcers) without systemic involvement; generally better prognosis; may be a separate entity
HBV-associated PAN	Secondary to chronic HBV; tends to be more severe; treatment includes antivirals
Childhood PAN	Rare; more commonly single-organ (e.g. cutaneous)

The Five-Factor Score (FFS, Guillevin 2011) is used to assess severity and guide treatment:

Factor	Points
Proteinuria > 1 g/day	+1
Renal insufficiency (Cr > 140 μmol/L)	+1
Cardiomyopathy	+1
GI involvement (e.g. bowel perforation, bleeding, pancreatitis)	+1
CNS involvement	+1

FFS = 0: Mild disease → glucocorticoids ± steroid-sparing agent (MTX or AZA)
FFS ≥ 1: Moderate–severe disease → glucocorticoids + cyclophosphamide

Polyarteritis and microscopic polyangiitis comparison ^[5]:

Feature	PAN	MPA
Renal involvement	Vasculitis with infarcts / microaneurysms — Yes	RPGN — Yes
Glomerulonephritis	No	Yes
Lung involvement / Pulmonary haemorrhage	No	Yes
HBV infection	Yes (~50%)	No
pANCA	< 20%	50–80%
Abnormal angiogram with microaneurysms	Yes	No
Relapses	Rare	Common

ANCA related vasculitis — ANCA prevalence by disease entity ^[6]:

Disease entity	Anti-PR3 (c-ANCA)	Anti-MPO (p-ANCA)
Polyarteritis nodosa	5%	15%
Granulomatosis with polyangiitis	85%	10%
Eosinophilic granulomatosis with polyangiitis	10%	66%
Microscopic polyangiitis	15–45%	45–80%

High Yield — ANCA in PAN

While PAN is defined as "ANCA-negative" by Chapel Hill criteria, in clinical practice up to ~20% of PAN patients may have low-titre ANCA ^[6]. The key point is that ANCA is not pathogenically linked to PAN (unlike in GPA/MPA where ANCA directly activates neutrophils). If a patient has high-titre ANCA + GN + pulmonary haemorrhage, reclassify as MPA, not PAN.

8. Clinical Features

8.1 Symptoms

PAN is a systemic disease — patients typically present with constitutional symptoms plus organ-specific complaints. The clinical presentation can be insidious or fulminant.

Symptom	Pathophysiological Basis
Fever	Systemic inflammation → IL-1, IL-6, TNF-α → hypothalamic thermoregulatory set-point elevation
Weight loss	Chronic inflammation → catabolic state from cytokines (TNF-α, IL-6); also mesenteric ischaemia → reduced nutrient absorption ("intestinal angina" leads to food avoidance)
Fatigue / malaise	Cytokine-mediated; also contribution from anaemia of chronic disease
Arthralgia / myalgia	Vasculitis of small arteries supplying muscles and joints → ischaemia and inflammation of musculoskeletal tissues

Symptom	Pathophysiological Basis
Painful subcutaneous nodules (the "nodosa")	Inflamed segments of dermal/subcutaneous medium arteries form palpable lumps. Biopsy shows necrotizing vasculitis in deep dermis or between fat lobules ^[3]
Livedo reticularis (net-like purplish discolouration)	Vasculitis of dermal arterioles at the dermal-subcutaneous junction → sluggish/obstructed blood flow in a reticular pattern. The unaffected areas between the involved vessels appear as pale centres surrounded by cyanotic borders
Digital ulcers / gangrene	Occlusion of digital arteries → critical ischaemia → tissue necrosis
Skin rash / purpura	Extravasation of blood from damaged vessel walls

Skin disease is more frequently found over lower extremities ^[3]

Symptom	Pathophysiological Basis
Asymmetric limb pain + weakness + numbness (mononeuritis multiplex)	Vasculitis of vasa nervorum → nerve infarction. Affects individual named nerves sequentially and asymmetrically (e.g. right common peroneal → left ulnar → right radial). Mononeuritis multiplex occurs in up to 70% of PAN patients ^[3]. This is because the vasa nervorum are medium-calibre vessels — exactly the size PAN targets. The patient typically describes sudden onset of pain in a nerve distribution followed by foot drop, wrist drop, or numbness
Headache, confusion, seizures (CNS involvement, rare)	Vasculitis of cerebral medium arteries → ischaemia/infarction of brain parenchyma. CNS involvement occurs in 5–10% ^[3]

Symptom

Pathophysiological Basis

Asymmetric limb pain + weakness + numbness (mononeuritis multiplex)

Vasculitis of vasa nervorum → nerve infarction. Affects individual named nerves sequentially and asymmetrically (e.g. right common peroneal → left ulnar → right radial). Mononeuritis multiplex occurs in up to 70% of PAN patients ^[3]. This is because the vasa nervorum are medium-calibre vessels — exactly the size PAN targets. The patient typically describes sudden onset of pain in a nerve distribution followed by foot drop, wrist drop, or numbness

Headache, confusion, seizures (CNS involvement, rare)

Vasculitis of cerebral medium arteries → ischaemia/infarction of brain parenchyma. CNS involvement occurs in 5–10% ^[3]

Mononeuritis Multiplex — High Yield

Causes of mononeuritis multiplex: Wegener's granulomatosis, Amyloidosis, Rheumatoid arthritis, Diabetes mellitus, SLE, Polyarteritis nodosa, Leprosy, Carcinomatosis and Churg-Strauss syndrome ^[7]

In PAN, mononeuritis multiplex is the most common neurological manifestation and one of the most common presenting features overall. If it progresses, the confluent involvement of many nerves can mimic a symmetric polyneuropathy.

Symptom	Pathophysiological Basis
Hypertension (often severe, sometimes malignant)	Renal artery branch vasculitis → renal ischaemia → activation of RAAS (renin-angiotensin-aldosterone system) → renovascular hypertension
Flank pain	Renal infarction from arterial occlusion
Haematuria (usually microscopic)	Renal infarction → tissue necrosis → blood in urine. Note: this is from renal infarction, NOT from glomerulonephritis (there is no GN in PAN by definition)
Oliguria / uraemic symptoms (in severe disease)	Bilateral renal artery branch vasculitis → progressive renal insufficiency

Renal involvement: variable renal insufficiency, hypertension, renal infarctions, subnephrotic proteinuria/haematuria (no glomerular inflammation) ^[3]

Why No Glomerulonephritis in PAN?

Glomerulonephritis (GN) requires inflammation at the capillary level — the glomerulus is a capillary tuft. PAN, by definition, does not involve capillaries or venules. The renal damage in PAN occurs at the level of the arcuate and interlobar arteries (medium arteries) → renal infarction, not glomerular inflammation. This is why PAN causes proteinuria and haematuria from infarction but NOT nephritic sediment with red cell casts (which would indicate GN).

Symptom	Pathophysiological Basis
Postprandial abdominal pain ("intestinal angina")	Mesenteric arteritis → inability to meet increased oxygen demand during digestion → ischaemic pain. Similar concept to angina pectoris in the heart — demand exceeds supply
Nausea and vomiting	Mesenteric ischaemia → impaired gut motility
GI bleeding (haematemesis, melaena)	Mucosal ischaemia → ulceration → bleeding
Diarrhoea	Ischaemic colitis → impaired absorption and mucosal irritation
Acute abdomen (bowel perforation/infarction)	Full-thickness bowel wall ischaemia from arterial occlusion → gangrene and perforation — a surgical emergency
Weight loss	Combination of food fear (sitophobia due to postprandial pain) and malabsorption

GI: mesenteric arteritis leading to postprandial angina, weight loss, N/V, GIB, diarrhoea, bowel infarction ^[3]

Symptom	Pathophysiological Basis
Chest pain	Coronary arteritis → myocardial ischaemia/MI
Dyspnoea, orthopnoea	Ischaemic cardiomyopathy → heart failure
Palpitations	Ischaemic arrhythmias

Cardiac: myocardial ischaemia, ischaemic cardiomyopathy, heart failure ^[3]

PAN is listed as a cause of non-atherosclerotic CAD via vasculitis ^[8]

Symptom	Pathophysiological Basis
Testicular pain (orchitis)	Vasculitis of testicular artery → ischaemia and inflammation of the testis. This is relatively specific for PAN among the vasculitides and is included in ACR criteria. Why? Because the testicular artery is a classic medium-sized muscular artery ^[2]^[3]

Symptom	Pathophysiological Basis
Myalgia	Vasculitis of muscle-supplying arteries → muscle ischaemia
Muscle weakness	Ischaemic damage to skeletal muscle
Arthralgia (non-erosive)	Vasculitis near joints → inflammation; not a true synovitis

8.2 Signs

Sign	Significance
Fever	Active vasculitis; exclude infection
Cachexia / weight loss	Chronic inflammation + mesenteric ischaemia
Hypertension (often severe)	Renovascular hypertension from renal artery vasculitis (RAAS activation) — may be the presenting sign

Sign	Pathophysiological Basis
Livedo reticularis	Net-like mottled cyanotic discolouration of skin, predominantly on lower limbs. Caused by vasculitis of dermal arteries → sluggish blood flow in a reticular network pattern
Tender subcutaneous nodules	Inflamed arterial segments palpable through the skin — the "nodosa"
Digital ulcers / gangrene	End-artery occlusion in digital arteries → critical ischaemia → necrotic tissue
Palpable purpura	Extravasation from damaged vessel walls; less common than in small-vessel vasculitis but can occur
Bullous / vesicular eruptions	Severe dermal ischaemia → blistering

Skin: livedo reticularis, digital ulcers / gangrene, subcutaneous nodules ^[2]

Sign	Pathophysiological Basis
Foot drop (common peroneal nerve palsy)	Vasa nervorum vasculitis → infarction of the common peroneal nerve at the fibular neck
Wrist drop (radial nerve palsy)	Infarction of radial nerve
Asymmetric sensory loss in named nerve distributions	Patchy nerve infarction
Absent reflexes in affected territories	Loss of afferent/efferent arc from nerve infarction
Muscle wasting in affected territories (late)	Denervation atrophy

CNS: mononeuritis multiplex, polyneuropathy ^[2]

Sign	Pathophysiological Basis
Abdominal tenderness (diffuse or localised)	Mesenteric ischaemia
Absent bowel sounds	Ileus from bowel ischaemia/infarction
Peritonism (guarding, rigidity, rebound)	Bowel perforation — surgical emergency
Hepatomegaly	Hepatic artery vasculitis; also seen in HBV-associated PAN from chronic hepatitis

Sign	Pathophysiological Basis
Hypertension (may be malignant with retinopathy)	Renovascular hypertension
Signs of heart failure (raised JVP, S3, basal crackles, pedal oedema)	Ischaemic cardiomyopathy from coronary vasculitis
New murmur	Rarely, aortic regurgitation if aortic root involvement (very uncommon)

CVS: MI ^[2]

Sign	Pathophysiological Basis
Tender, swollen testis	Testicular artery vasculitis → orchitis. Important to distinguish from torsion or tumour

GU: orchitis (testicular pain) ^[2]

PAN can cause:

Peripheral ulcerative keratitis (PUK): immune complex deposition in the corneal periphery → corneal thinning and ulceration ^[9]
Retinal vasculitis: rare; cotton-wool spots, retinal haemorrhages
Scleritis / episcleritis: nodular or diffuse

Systemic association of PUK: RA (34–42%), collagen vascular disease (SLE, relapsing polychondritis), polyarteritis nodosa, IBD, ANCA vasculitides (GPA, EGPA) ^[9]

Sign	Pathophysiological Basis
Hypertension	As above — renovascular
Renal bruit (rare)	Turbulent flow through stenosed renal arteries
Elevated creatinine	Progressive renal insufficiency from arterial occlusion

Renal (most common): variable renal insufficiency, hypertension, renal infarctions, subnephrotic proteinuria/haematuria (no glomerular inflammation) ^[3]

Organ System	Frequency	Key Features
Constitutional	> 90%	Fever, weight loss, malaise
Neurological	60–70%	Mononeuritis multiplex (most common), CNS (5–10%)
Renal	60–70%	Hypertension, renal insufficiency, infarctions. No GN
Musculoskeletal	50–60%	Myalgia, arthralgia
GI	40–50%	Mesenteric ischaemia, GI bleed, bowel infarction
Skin	40–50%	Nodules, livedo reticularis, digital ischaemia
Cardiac	10–30%	MI, cardiomyopathy, HF
Testicular	10–20%	Orchitis (relatively specific for PAN)
CNS	5–10%	Stroke, seizures
Ophthalmic	Rare	PUK, scleritis, retinal vasculitis

Distinguishing characteristics of vasculitis subtypes ^[1]:

Feature	PAN	ANCA-associated
Renal	Microaneurysm	GN
Pulmonary	Rare	Frequent
Peripheral neuropathy	√	√
GI	√	√
Skin	√	√
Granuloma	X	√ (except MPA)
Other	Mesenteric aneurysm / Testicular involvement	GPA: ENT; EGPA: Asthma

Red Flags in PAN

The following features indicate severe disease and should prompt urgent aggressive treatment (FFS ≥ 1):

Renal insufficiency (creatinine > 140 μmol/L)
Heavy proteinuria ( > 1 g/day)
GI involvement (bowel perforation, GI bleeding, pancreatitis)
Cardiomyopathy
CNS involvement (stroke, seizures)

Major sources of mortality: renal failure, mesenteric/cardiac/cerebral infarction ^[3]

PAN is listed among the intrinsic causes of pulmonary eosinophilia:

Intrinsic: idiopathic AEP, Churg-Strauss syndrome, polyarteritis nodosa ^[10]

This is a somewhat confusing association because PAN classically does not cause pulmonary haemorrhage or RPGN. However, systemic PAN can rarely be associated with eosinophilic infiltration, and PAN may coexist with eosinophilic conditions. In practice, if there is significant pulmonary eosinophilia, one should consider EGPA (Churg-Strauss) as the primary diagnosis rather than PAN.

PAN appears in several differential diagnosis lists across medicine:

Context	Role of PAN
Cause of petechiae (small vessel disease)	Polyarteritis nodosa, Henoch-Schönlein purpura ^[11]
Cause of non-atherosclerotic coronary artery disease	Vasculitis: Takayasu arteritis, PAN, Kawasaki disease, EGPA ^[8]
Cause of mononeuritis multiplex	PAN, DM, SLE, RA, Wegener's, Churg-Strauss, Leprosy ^[7]
Cause of secondary nephrotic/nephritic disease	PAN causes subnephrotic proteinuria from renal infarction (not GN) ^[12]
Peripheral ulcerative keratitis	PAN is a recognized systemic association ^[9]
Cryoglobulinemia	PAN is listed as an autoimmune cause of cryoglobulinemia ^[13]

High Yield Summary

Definition: Necrotizing vasculitis of medium/small arteries; NO GN, NO capillary/venular involvement, ANCA-negative.

Epidemiology: Rare (incidence 4.4–9.7/million/year); peak 6th decade; M > F (1.5:1); declining due to HBV vaccination.

Key Etiology: Idiopathic (majority) or HBV-associated (~50% historically); also HCV, streptococcal, IBD, hairy cell leukaemia.

Pathophysiology: Immune complex deposition (in HBV-PAN) or cell-mediated → transmural fibrinoid necrosis → microaneurysms + luminal thrombosis → organ ischaemia/infarction.

Anatomy: Targets medium muscular arteries (arcuate, interlobar, mesenteric, coronary, vasa nervorum, testicular, dermal).

Clinical Features (Think: SKIN-GUT-KIDNEY-NERVE-TESTIS):

Systemic: Fever, weight loss, malaise
Skin: Tender subcutaneous nodules, livedo reticularis, digital ulcers/gangrene
Neuro: Mononeuritis multiplex (up to 70%); CNS (5–10%)
Renal: Hypertension (renovascular), renal insufficiency, infarction — NOT GN
GI: Mesenteric ischaemia, bowel infarction, GI bleeding
Cardiac: MI, cardiomyopathy, HF
Testis: Orchitis (relatively specific)
Lungs: Spared (no pulmonary haemorrhage)

PAN vs MPA: PAN = no GN, no lung, ANCA-negative, microaneurysms on angio, HBV; MPA = GN, lung haemorrhage, pANCA+, no microaneurysms.

Active Recall - Polyarteritis Nodosa (PAN)

^[1] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf — Rheumatological Diseases, Vasculitis chapter (pp. 1763–1768) ^[2] Senior notes: Maksim Medicine Notes.pdf — Rheumatology, Medium vessel vasculitis section (p. 331) ^[3] Senior notes: Ryan Ho Rheumatology.pdf — Section 4.7.3 Polyarteritis Nodosa (p. 159) ^[4] Lecture slides: GC 053. Fingers turn white and blue.pdf (p. 80, 93) ^[5] Lecture slides: GC 053. Fingers turn white and blue.pdf (p. 93 — PAN vs MPA comparison table) ^[6] Lecture slides: GC 053. Fingers turn white and blue.pdf (p. 91 — ANCA prevalence table) ^[7] Senior notes: Ryan Ho Neurology.pdf — Section 10.2.2 Mononeuropathy Multiplex (p. 180) ^[8] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf — CAD Etiology, Non-atherosclerotic CAD (p. 395) ^[9] Senior notes: Ryan Ho Ophthalmology.pdf — Section 7.2 Rheumatological Disease and the Eye (p. 131) ^[10] Senior notes: Ryan Ho Respiratory.pdf — Section 3.5.3.1 Pulmonary Eosinophilia (p. 139) ^[11] Senior notes: Ryan Ho Haematology.pdf — Causes of petechiae (p. 5) ^[12] Senior notes: Ryan Ho Urogenital.pdf / Ryan Ho Fundamentals.pdf — Glomerulonephritis classification ^[13] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf — Cryoglobulinemia section (p. 1780)

Differential Diagnosis of Polyarteritis Nodosa (PAN)

Before diving into the list, let's understand why PAN has such a broad differential. PAN is a multi-system disease that can present with almost any combination of constitutional symptoms, skin lesions, neuropathy, renal impairment, GI ischaemia, and cardiac disease. No single feature is pathognomonic. The differential therefore depends on which presenting complaint brings the patient to you — and you need to systematically work through mimics organized by:

Other vasculitides (the most important differential — "which vasculitis is this?")
Non-vasculitic mimics organized by dominant presenting feature (e.g. mononeuritis multiplex, livedo reticularis, mesenteric ischaemia, renal impairment with hypertension)

The overall clinical reasoning can be structured as follows:

2. Differential Diagnosis by Category

2.1 Other Systemic Vasculitides (Primary Differentials)

This is the most critical category. The key question is: "Is this PAN, or is it actually another vasculitis that mimics PAN?"

This is, bar none, the single most important differential for PAN. Historically, many cases of MPA were misclassified as PAN before the Chapel Hill Consensus Conference separated them.

Polyarteritis and microscopic polyangiitis comparison ^[4]:

Feature	PAN	MPA
Renal involvement	Vasculitis with infarcts / microaneurysms — Yes	Rapidly progressive glomerulonephritis — Yes
Lung involvement / Pulmonary haemorrhage	No	Yes
HBV infection	Yes (~50%)	No
pANCA	< 20%	50–80%
Abnormal angiogram with microaneurysms	Yes	No
Relapses	Rare	Common

Why the confusion? Both PAN and MPA can cause mononeuritis multiplex, constitutional symptoms, skin vasculitis, and renal impairment. The distinguishing pivot points are:

Glomerulonephritis → if present, it's MPA (or another small-vessel vasculitis), not PAN. PAN causes renal infarction via medium artery occlusion, not glomerular capillary inflammation.
Pulmonary haemorrhage / diffuse alveolar haemorrhage (DAH) → MPA, not PAN. PAN spares the lung.
ANCA positivity (especially p-ANCA/anti-MPO at high titre) → strongly favours MPA.
Microaneurysms on mesenteric/renal angiography → PAN. MPA does not cause these because MPA affects capillaries/venules, not medium-artery walls.

Exam Pitfall — PAN vs MPA

If the stem describes a patient with constitutional symptoms + mononeuritis multiplex + rapidly progressive GN with red cell casts + pulmonary haemorrhage → this is MPA, not PAN. The presence of GN and/or DAH by definition excludes PAN per Chapel Hill criteria ^[1]^[4].

GPA can also cause multi-system vasculitis with renal and neurological involvement.

Feature	PAN	GPA
ENT involvement	No	Upper airway: rhinosinusitis, recurrent epistaxis, nasal crusting/ulcers, saddle nose deformity ^[2]
Lung involvement	No	Lower airway: pulmonary infiltrates / nodules / cavities ^[2]
Renal	Infarction, no GN	Pauci-immune GN (RPGN) ^[2]
ANCA	Usually negative	c-ANCA +ve (80%), p-ANCA (20%) ^[2]
Granulomas	No ^[1]	Yes — necrotizing granulomatous vasculitis ^[2]
Eye	Rare (PUK)	Scleritis, retro-orbital mass ^[2]
Ear	No	Otitis media, otorrhoea ^[2]

Key distinguishing clue: GPA characteristically involves the upper airway (ENT) — if there is sinusitis, nasal crusting, saddle nose deformity, or subglottic stenosis, think GPA, not PAN ^[2].

A useful clinical pearl: "Triad of sinusitis, pulmonary infiltrates and nephritis suggests Wegener's" ^[14]^[15]

Feature	PAN	EGPA
Asthma	No	Three phases: (1) Asthma and atopic allergies, (2) Eosinophilic infiltrative disease, (3) Vasculitis ^[2]
Eosinophilia	No	Marked peripheral eosinophilia
ANCA	Usually negative	p-ANCA +ve (anti-MPO, 66%) ^[6]
Granulomas	No	Eosinophil-rich necrotising vasculitis ^[2]
Cardiac	MI from coronary vasculitis	Myocarditis (leading cause of death) ^[2]

Key distinguishing clue: EGPA patients almost always have a history of adult-onset asthma with peripheral eosinophilia — this is absent in PAN.

HSP is a small-vessel vasculitis with IgA immune complex deposition. It can mimic PAN in children (palpable purpura + abdominal pain + renal involvement + arthralgia).

Feature	PAN	HSP
Vessel size	Medium	Small (capillaries, venules)
Age	Adults (peak 6th decade)	Children (peak 6–7y) ^[16]
Purpura distribution	Lower extremities, may ulcerate	LL and buttocks, non-ulcerating ^[16]
Renal	Infarction, no GN	IgA GN — haematuria, proteinuria, may → RPGN ^[16]
GI	Mesenteric ischaemia, bowel infarction	Submucosal haemorrhage/oedema, intussusception ^[16]
Testicular	Orchitis (from arterial vasculitis)	Scrotal pain (from small-vessel inflammation, normal USS) ^[16]
ANCA	Negative	Negative
Complement	Normal C3/4 ^[14]	Normal C3/4 (IgA does not activate complement) ^[14]
Pathology	Necrotizing arteritis, fibrinoid necrosis	Leukocytoclastic vasculitis with IgA deposition on IF

Key distinguishing clue: HSP has the classic tetrad of palpable purpura + arthralgia + abdominal pain + renal disease in a child following a URTI. Skin biopsy with IgA on direct IF is diagnostic ^[16]^[17].

Both KD and PAN are medium-vessel vasculitides per Chapel Hill classification ^[1]^[4]. In paediatric patients, this is an important differential.

Feature	PAN	KD
Age	Adults (usually)	Infants and young children (6m–5y, peak 2–3y) ^[18]
Mucocutaneous features	Absent	Conjunctivitis, strawberry tongue, cracked lips, polymorphous rash, desquamation ^[18]
Cervical lymphadenopathy	Absent	Unilateral, ≥ 1.5 cm ^[18]
Coronary involvement	Possible (coronary vasculitis → MI)	Coronary artery aneurysms (up to 25% if untreated) ^[18]
Self-limiting	No	Yes (average 12 days without treatment) ^[18]

Key distinguishing clue: KD is a clinical diagnosis in children with ≥ 5 days of fever + ≥ 4/5 mucocutaneous criteria ^[18]. PAN does not cause mucocutaneous lymph node syndrome.

These rarely enter the differential for PAN because the clinical presentation is fundamentally different:

GCA: age > 50, temporal headache, jaw claudication, visual loss, ↑↑ESR, polymyalgia rheumatica — targets temporal/cranial arteries ^[19]
Takayasu: age < 50, usually young women, limb claudication, absent pulses ("pulseless disease"), aortic arch involvement

Both are large-vessel vasculitides without the multi-organ ischaemia/infarction pattern seen in PAN. However, Takayasu can overlap: if renal artery stenosis is present, it can cause renovascular hypertension similar to PAN — but Takayasu affects the main renal artery trunk (large vessel), while PAN affects branch arteries (medium vessels) ^[1].

Variable vessel vasculitis: Behçet's syndrome — can affect arteries or veins; characterized by recurrent oral and/or genital aphthous ulcers accompanied by cutaneous, ocular, articular, gastrointestinal or CNS inflammatory lesions ^[1]

Behçet's can mimic PAN when it presents with mesenteric vasculitis, skin lesions, and neurological involvement. The key differentiator is the presence of recurrent oral and genital ulcers + pathergy test positivity.

Cryoglobulinaemia can cause palpable purpura, mononeuritis multiplex, renal impairment, and arthralgia — similar to PAN.

Feature	PAN	Cryoglobulinaemic vasculitis
Vessel size	Medium	Small (immune complex)
Association	HBV	HCV ^[1]
Renal	Infarction, no GN	GN (MPGN pattern)
Complement	Normal	↓C4 (classical pathway activation)
Cryoglobulins	Absent	Present
RF	Usually negative	Often positive

Key distinguishing clue: Cryoglobulinaemic vasculitis is strongly associated with HCV (not HBV), causes GN (MPGN pattern), and has low C4 with positive cryoglobulins and rheumatoid factor.

Secondary vasculitis differential includes: SLE, RA, Sjögren's syndrome, Behçet's disease, essential mixed cryoglobulinaemia ^[4]

2.2 Non-Vasculitic Mimics (Organized by Dominant Presentation)

Causes of mononeuritis multiplex: Wegener's granulomatosis, Amyloidosis, Rheumatoid arthritis, Diabetes mellitus, SLE, Polyarteritis nodosa, Leprosy, Carcinomatosis and Churg-Strauss syndrome ^[7]

Differential	How to Distinguish from PAN
Diabetes mellitus	Most common cause of mononeuritis multiplex in clinical practice; occurs via atherosclerosis of vasa nervorum. No systemic vasculitis features. HbA1c elevated, no microaneurysms on angiography
Rheumatoid arthritis	Known RA with rheumatoid vasculitis; RF/anti-CCP positive; joint erosions
SLE	ANA/anti-dsDNA positive; lupus vasculitis; typically younger women with photosensitivity, malar rash
Amyloidosis	Carpal tunnel syndrome common; Congo red stain on biopsy; paraprotein screen
Leprosy	Thickened peripheral nerves on palpation; skin lesions with anaesthesia; acid-fast bacilli on biopsy
Sarcoidosis	Non-caseating granulomas; bilateral hilar lymphadenopathy; ↑ACE; ↑Ca²⁺

Differential	How to Distinguish from PAN
Cholesterol crystal embolism (atheroembolism)	Occurs after vascular procedures/anticoagulation; blue toe syndrome; livedo reticularis; eosinophilia; renal failure. No ANCA, no microaneurysms — cholesterol clefts on biopsy
Antiphospholipid syndrome (APS)	Livedo reticularis, thrombosis (venous and arterial), pregnancy losses; aPL antibodies (anticardiolipin, anti-β2GPI, lupus anticoagulant)
Thrombotic thrombocytopenic purpura (TTP)	Microangiopathic haemolytic anaemia (schistocytes), thrombocytopenia, neurological symptoms, fever, renal impairment. ADAMTS13 activity < 10%
Livedoid vasculopathy	Painful ulcers on lower legs with atrophie blanche; primarily a thrombotic vasculopathy, not true vasculitis
Cutaneous PAN	Limited to skin without systemic involvement; tender subcutaneous nodules + livedo; considered a separate entity with better prognosis ^[3]
Erythema nodosum	Painful nodules on shins; septal panniculitis (not necrotizing arteritis); a/w TB, streptococcal infection, OCP, IBD, Behçet's. Does not ulcerate ^[3]

Normal C3/4 with renal disease: D/dx includes PAN, Goodpasture, HSP/IgAN, ANCA-related renal vasculitis ^[14]^[15]

Differential	How to Distinguish from PAN
Renovascular disease (atherosclerotic)	Older patients with atherosclerotic risk factors; renal artery stenosis on Doppler/CTA; no systemic vasculitis features
Fibromuscular dysplasia (FMD)	Young women; "string of beads" on renal angiography; no inflammation/vasculitis
Thrombotic microangiopathy (TMA)	HUS/TTP; schistocytes on blood film; low platelets; LDH elevated
Scleroderma renal crisis	Sudden-onset hypertension + AKI in scleroderma patient; anti-RNA polymerase III antibody

Differential	How to Distinguish from PAN
Atherosclerotic mesenteric ischaemia	Older patients with established atherosclerosis; no microaneurysms; CT angiography shows calcified stenosis
SLE mesenteric vasculitis	Young woman with known SLE; positive ANA/anti-dsDNA; complement low
Mesenteric venous thrombosis	CT shows venous filling defects; associated with hypercoagulable states
ANCA-associated vasculitis (GPA/MPA)	Concurrent GN / DAH; ANCA positive

Differential	How to Distinguish from PAN
Testicular torsion	Acute onset; abnormal Doppler (absent blood flow); no systemic vasculitis. Surgical emergency
Epididymo-orchitis (infection)	Fever, dysuria; positive urine culture; responds to antibiotics
Testicular tumour	Painless mass; elevated AFP / β-hCG / LDH; USS shows solid lesion
HSP	Scrotal pain/swelling mimicking torsion but with normal USS ^[16]; child with classic tetrad

CNS inflammatory disorders in the differential of demyelinating disease include: SLE, CNS vasculitis, polyarteritis nodosa, Sjögren's disease ^[20]

Differential	How to Distinguish from PAN
Primary CNS vasculitis (PCNSV)	Isolated CNS involvement without systemic features; diagnosed by cerebral angiography + brain/meningeal biopsy
Multiple sclerosis	Demyelinating lesions disseminated in space and time on MRI; CSF oligoclonal bands; younger patients
Neurosyphilis	VDRL/RPR positive; CSF VDRL; history of syphilis
SLE cerebritis	Known SLE; ANA/anti-dsDNA positive; low complement

The following algorithm represents a systematic clinical approach when PAN is suspected:

High Yield — Serum Complement in Narrowing DDx

Serum complement level is important in helping narrow the differential diagnosis ^[14]^[15]:

↓C3/4 generally indicates immune complex–mediated GN: MPGN, PSGN, lupus, cryoglobulinaemia, IE, shunt nephritis
Normal C3/4 generally indicates non-IC–mediated GN (except IgAN): PAN, Goodpasture, HSP/IgAN, ANCA-related renal vasculitis

So if complement is normal and there is no GN, and you see microaneurysms on angiography → think PAN.

Feature	PAN	MPA	GPA	EGPA	HSP	Cryo
Vessel size	Medium	Small/Medium	Small/Medium	Small/Medium	Small	Small
ANCA	< 20% ^[4]	50–80% (pANCA) ^[4]	85% (cANCA) ^[6]	66% (pANCA) ^[6]	Negative	Negative
GN	No	Yes (RPGN)	Yes (RPGN)	Possible	Yes (IgA)	Yes (MPGN)
Lung	No	DAH	Nodules/cavities	Infiltrates	Rare	Rare
ENT	No	No	Yes ^[2]	Allergic rhinitis ^[2]	No	No
Asthma	No	No	No	Yes ^[2]	No	No
Microaneurysms	Yes ^[4]	No ^[4]	No	No	No	No
HBV	Yes (~50%) ^[4]	No ^[4]	No	No	No	No
HCV	Possible	No	No	No	No	Yes
Complement	Normal	Normal	Normal	Normal	Normal	↓C4
Granulomas	No ^[1]	No ^[2]	Yes ^[2]	Yes ^[2]	No	No
Testicular	Yes ^[1]	Rare	Rare	Rare	Possible (children)	No
Relapses	Rare ^[4]	Common ^[4]	Common	Common	Self-limited	Variable

When renal involvement is the presenting feature, the immunofluorescence (IF) pattern on biopsy is critical for narrowing the differential:

RPGN classification based on IF staining pattern ^[15]^[21]:

Type I (linear staining): anti-GBM disease

Type II (granular staining): immune complex RPGN (SLE, IgAN, PSGN)

Type III (negative staining): pauci-immune RPGN (most are ANCA-positive, may be associated with extrarenal ANCA vasculitis)

PAN does not cause RPGN (no crescents, no glomerular inflammation), so if you see crescents on renal biopsy, the diagnosis is not PAN — reconsider MPA, GPA, EGPA, anti-GBM disease, or immune complex GN ^[1]^[3]^[15].

6. Special Considerations by Presentation Context

Causes of petechiae from small vessel disease include: Polyarteritis nodosa, Henoch-Schönlein purpura ^[11]

The differential of purpura is broad and includes:

Vasculitis (PAN, HSP, ANCA-associated, infective endocarditis, meningococcaemia)
Thrombocytopenia (ITP, TTP/HUS, DIC, marrow failure)
Platelet dysfunction (acquired/congenital)
Coagulation disorders ^[22]

The key to identifying PAN within this differential is the systemic multi-organ pattern with normal platelet count and coagulation, plus the presence of medium-vessel pathology (subcutaneous nodules, microaneurysms, mononeuritis multiplex).

Polyarteritis nodosa: primary vasculitis of septal vessels of subcutaneous fat; a/w streptococcal infection, IBD, hepatitis B and C; p/w tender subcutaneous nodules, often ulcerates and a/w livedo racemose ^[3]

The differential of subcutaneous nodules/panniculitis includes erythema nodosum, lipodermatosclerosis, lupus panniculitis, and erythema induratum — distinguished by biopsy pattern (PAN = necrotizing arteritis of septal vessels; EN = septal panniculitis without arteritis) ^[3].

High Yield Summary — Differential Diagnosis of PAN

The #1 differential is MPA — distinguished by: (1) GN present in MPA, absent in PAN; (2) DAH in MPA, absent in PAN; (3) pANCA 50–80% in MPA vs < 20% in PAN; (4) microaneurysms on angiography in PAN, absent in MPA; (5) HBV in PAN, not in MPA; (6) relapses rare in PAN, common in MPA.

GPA is distinguished by ENT involvement + c-ANCA + granulomas.

EGPA is distinguished by asthma + eosinophilia + p-ANCA.

HSP is distinguished by IgA deposition + pediatric age + self-limiting tetrad.

Non-vasculitic mimics include atheroembolism, APS, FMD, and diabetic vasculopathy.

Complement levels help narrow the differential: PAN has normal C3/C4.

Biopsy IF pattern: PAN does NOT cause GN → no IF pattern on renal biopsy. If RPGN with crescents → reclassify as MPA/GPA/anti-GBM/IC-mediated.

Active Recall - Differential Diagnosis of PAN

References

^[1] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf — Rheumatological Diseases, Vasculitis chapter (pp. 1763–1768) ^[2] Senior notes: Maksim Medicine Notes.pdf — Rheumatology, ANCA-associated vasculitis section (p. 331) ^[3] Senior notes: Ryan Ho Rheumatology.pdf — Section 4.7.3 Polyarteritis Nodosa and Section 4.7.1 Panniculitis (pp. 155, 159) ^[4] Lecture slides: GC 053. Fingers turn white and blue.pdf (pp. 80, 93) ^[6] Lecture slides: GC 053. Fingers turn white and blue.pdf (p. 91 — ANCA prevalence table) ^[7] Senior notes: Ryan Ho Neurology.pdf — Section 10.2.2 Mononeuropathy Multiplex (p. 180) ^[11] Senior notes: Ryan Ho Haematology.pdf — Causes of petechiae (p. 5) ^[14] Senior notes: Adrian Lui Pediatrics Notes.pdf — Evaluation of nephritic syndrome (p. 325) ^[15] Senior notes: Ryan Ho Fundamentals.pdf — Evaluation of nephritic syndrome and RPGN (pp. 360–361) ^[16] Senior notes: Adrian Lui Pediatrics Notes.pdf — HSP section (p. 460) ^[17] Senior notes: Maksim Surgery Notes.pdf — Henoch-Schonlein purpura (p. 336) ^[18] Senior notes: Adrian Lui Pediatrics Notes.pdf — Kawasaki Disease (pp. 242–243) ^[19] Senior notes: Ryan Ho Neurology.pdf — Giant Cell Arteritis (p. 65) ^[20] Senior notes: Ryan Ho Neurology.pdf — Differential diagnosis of MS / CNS inflammatory disorders (p. 137) ^[21] Senior notes: Ryan Ho Urogenital.pdf — RPGN classification and ANCA-associated GN (pp. 64, 69) ^[22] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf — Differential diagnosis of purpura (p. 699)

Diagnostic Criteria, Algorithm, and Investigations for PAN

1. Diagnostic Criteria

There are no universally accepted "diagnostic criteria" for PAN in the strict sense (unlike, say, the Jones criteria for rheumatic fever). What we use in practice are classification criteria — designed to classify patients who already have vasculitis into the correct category for research purposes. Nevertheless, the 1990 American College of Rheumatology (ACR) criteria remain widely used clinically and are examined frequently.

PAN can be idiopathic / secondary e.g. HBV (HBsAg included in ACR criteria) ^[2]

The 1990 ACR Classification Criteria for PAN — diagnosis requires ≥ 3 of 10 criteria (sensitivity 82.2%, specificity 86.6%):

#	Criterion	Rationale / Explanation
1	Weight loss ≥ 4 kg	Reflects the catabolic state of systemic vasculitis (TNF-α, IL-6) + mesenteric ischaemia → malabsorption/food avoidance
2	Livedo reticularis	Net-like cyanotic mottling from vasculitis of dermal medium arteries
3	Testicular pain or tenderness	Orchitis from vasculitis of testicular artery — relatively specific for PAN among vasculitides
4	Myalgias, weakness, or leg tenderness	Ischaemia of muscle-supplying arteries
5	Mononeuropathy or polyneuropathy	Infarction of vasa nervorum → mononeuritis multiplex
6	Diastolic BP > 90 mmHg (new onset)	Renovascular hypertension from renal artery branch vasculitis → RAAS activation
7	Elevated BUN or creatinine (BUN > 40 mg/dL or Cr > 1.5 mg/dL, not due to dehydration)	Renal insufficiency from arterial infarction
8	Hepatitis B virus (positive HBsAg or anti-HBs in serum)	Immune complex–mediated mechanism; included because of the strong HBV–PAN association
9	Arteriographic abnormality (aneurysms or occlusions of visceral arteries, not due to atherosclerosis/FMD)	Abnormal angiogram with microaneurysms — this is a hallmark finding ^[4]
10	Biopsy of small or medium artery showing PMN infiltration	Histological confirmation of necrotizing arteritis

High Yield — ACR Criteria Mnemonic: 'PAN WHELMS BIO'

A memory aid for the 10 ACR criteria:

Polyneuropathy / mononeuropathy Arteriographic abnormality New diastolic BP > 90

Weight loss ≥ 4 kg Hepatitis B Elevated BUN/Cr Livedo reticularis Myalgias / weakness / leg tenderness Scrotal (testicular) pain/tenderness

BIOpsy — PMN in artery wall

≥ 3 of 10 = classified as PAN.

Exam Pitfall — Classification vs Diagnostic Criteria

The ACR 1990 criteria were designed to classify a patient who already has confirmed vasculitis into the PAN category — they were NOT designed to diagnose vasculitis in the first place. In clinical practice, PAN diagnosis requires:

Clinical suspicion (multi-system disease with constitutional symptoms + organ ischaemia/infarction)
Exclusion of other vasculitides and mimics (especially MPA — must be ANCA-negative, no GN, no DAH)
Histological confirmation (biopsy showing necrotizing medium-vessel arteritis) OR angiographic confirmation (microaneurysms)
ACR criteria help support the classification once vasculitis is established

Diagnosis: clinical + compatible underlying cause + Bx showing necrotizing medium-sized vasculitis ^[3]

The CHCC provides a descriptive definition (not point-based criteria) that serves as the conceptual framework:

Necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries or venules. NOT associated with ANCAs. ^[1]

This definition is used to conceptually separate PAN from MPA and other small-vessel vasculitides.

In 2022, the ACR and EULAR jointly published updated weighted classification criteria for PAN (replacing the 1990 criteria for research classification). These use a points-based scoring system applied to patients who have already been diagnosed with medium- or small-vessel vasculitis:

Entry criterion: Diagnosis of medium- or small-vessel vasculitis (excluding large-vessel vasculitis and other mimics)

Criterion	Points
Positive for HBV infection	+1
Arteriographic/radiologic evidence of typical abnormalities (aneurysms, stenoses of medium arteries)	+6
Mononeuritis multiplex	+4
Myalgia	+2
Skin involvement (livedo reticularis, nodules, ulcers, infarction)	+2
Absence of ANCA (negative anti-MPO AND anti-PR3)	+3
Absence of pulmonary involvement (no haemorrhage, no nodules)	+2
Absence of glomerulonephritis	+3
Absence of eosinophilia	+1

≥ 5 points classifies as PAN.

Note how the 2022 criteria explicitly reward the absence of features that would suggest other vasculitides (absence of ANCA, GN, lung involvement, eosinophilia) — this reflects the key clinical reasoning that PAN is partly a diagnosis of exclusion among vasculitides.

The diagnostic workup for PAN follows a logical sequence: suspect → screen → confirm → classify severity → identify etiology.

3. Investigation Modalities — Detailed

Let's go through each investigation systematically, explaining why it is done, what you expect to find, and how to interpret the results.

3.1 Baseline Blood Tests

Investigations: CBC D/C, ↑↑ESR/CRP, ANCA, RFT & urinalysis ^[2]

Finding	Expected in PAN	Interpretation
Normocytic normochromic anaemia	Common	Anaemia of chronic disease — cytokine-mediated suppression of erythropoiesis (IL-6 → ↑hepcidin → ↓iron availability) ^[14]^[15]
Leukocytosis (neutrophilia)	Common	Reflects active inflammation; also exclude infection
Thrombocytosis (reactive)	Common	Acute phase response — IL-6 stimulates thrombopoietin production by liver
Eosinophilia	Absent	If present, reconsider EGPA (Churg-Strauss). Eosinophilia essentially excludes classic PAN

High Yield

If you see marked eosinophilia in a patient with suspected medium-vessel vasculitis → rethink the diagnosis. This is much more consistent with EGPA than PAN. The 2022 ACR/EULAR criteria explicitly give points for absence of eosinophilia.

Marker	Expected	Interpretation
ESR	↑↑ (often markedly elevated, > 50–100 mm/hr) ^[3]	Non-specific marker of systemic inflammation. ESR rises because acute phase proteins (fibrinogen, Ig) increase plasma viscosity → faster RBC sedimentation
CRP	↑↑ ^[2]^[3]	Direct measure of hepatic acute phase protein production (IL-6 driven). More rapidly responsive than ESR

These markers are useful for monitoring disease activity during treatment — declining ESR/CRP suggests response to immunosuppression.

Renal: HT, ↑urea/Cr ^[2]

Finding	Expected	Interpretation
↑ Urea and creatinine	In renal involvement	Renal insufficiency from arterial occlusion/infarction — NOT from GN. The pattern is usually a slowly rising creatinine (vs the rapid decline in RPGN of MPA)
eGFR decline	Variable	Depends on extent of renal arterial vasculitis

Finding	Expected	Interpretation
↑ AST/ALT	If HBV-associated PAN	Chronic hepatitis B causing hepatocellular damage
↑ ALP	Less common	Cholestatic pattern less typical
Hypoalbuminaemia	Possible	Chronic inflammation → negative acute phase response + renal protein loss

Finding	Expected in PAN	Interpretation
Proteinuria (subnephrotic, < 3.5 g/day)	Common	From renal infarction and ischaemic nephropathy — NOT from glomerular inflammation
Haematuria (microscopic, non-glomerular)	Common	From renal parenchymal infarction
RBC casts	Absent	RBC casts indicate glomerulonephritis — their presence would suggest MPA, NOT PAN
Dysmorphic RBCs	Absent or minimal	Dysmorphic RBCs indicate glomerular origin — again, would point to GN/MPA

Renal (most common): variable renal insufficiency, hypertension, renal infarctions, subnephrotic proteinuria/haematuria (no glomerular inflammation) ^[3]

Critical Distinction

In PAN, urinalysis shows subnephrotic proteinuria and haematuria from renal infarction but NO active sediment (no RBC casts, no dysmorphic RBCs). If you see active nephritic sediment (RBC casts, dysmorphic RBCs), the diagnosis shifts to MPA or another GN-causing vasculitis, NOT PAN ^[3]^[4].

Serum complement level: important in helping narrow the differential diagnosis ^[14]^[15]

Finding	Interpretation
Normal C3/C4	Expected in PAN — PAN is NOT immune complex–mediated in the classical sense (even HBV-PAN does not typically consume systemic complement to a measurable degree)
↓C3/C4	Suggests IC-mediated GN: MPGN, PSGN, lupus, cryoglobulinaemia, IE, shunt nephritis — NOT PAN

This is a simple but powerful screening test to narrow the differential. In the context of renal impairment with multi-system disease:

Normal complement + no GN + ANCA negative → think PAN
Low complement → think immune complex disease (lupus, cryoglobulinaemia, MPGN)

3.4 Autoantibody and Serological Panel

ANCA: anti-neutrophil cytoplasmic antibodies — p-ANCA (perinuclear) = anti-myeloperoxidase (anti-MPO); c-ANCA (cytoplasmic) = anti-proteinase-3 (anti-PR3) ^[2]

Finding	Interpretation
ANCA negative	Expected in PAN — PAN is defined as ANCA-negative ^[1]
Low-titre p-ANCA (anti-MPO) in < 20%	Can occur in PAN but is not diagnostically significant ^[3]^[4]^[6]
High-titre c-ANCA (anti-PR3)	Strongly suggests GPA (Wegener's), NOT PAN
High-titre p-ANCA (anti-MPO)	Strongly suggests MPA or EGPA, NOT PAN

PAN: Anti-PR3 5%, Anti-MPO 15% ^[6]

Why check ANCA? Not to confirm PAN (which is ANCA-negative), but to exclude MPA/GPA/EGPA. The ANCA result is the single most important serological test in separating PAN from the ANCA-associated vasculitides.

HBV-infection: Yes (50%) in PAN ^[4]

Test	Interpretation
HBsAg	If positive → HBV-associated PAN (changes management: antivirals become part of treatment)
Anti-HBs	May be positive (indicates current or past infection)
Anti-HBc (IgM)	If positive → acute HBV infection
HBV DNA (viral load)	Quantifies viral replication; guides antiviral therapy
HBeAg	Marker of active viral replication

HBsAg is included in the ACR criteria ^[2] — always check it.

Test	Interpretation
Anti-HCV	If positive, consider HCV-associated PAN or cryoglobulinaemic vasculitis (these overlap)
HCV RNA	Confirms active infection

Test	Purpose	Expected in PAN
ANA, anti-dsDNA	Exclude SLE/lupus nephritis ^[14]^[15]	Negative
Anti-GBM antibodies	Exclude Goodpasture/anti-GBM disease ^[14]^[15]	Negative
Cryoglobulins (cryocrit)	Exclude cryoglobulinaemic vasculitis ^[14]^[15]	Negative
ASLO (anti-streptolysin O)	Confirm recent strep infection (if post-strep mechanism suspected) ^[14]^[15]	May be positive in strep-associated PAN
Blood cultures	Exclude infective endocarditis ^[14]^[15]	Negative (unless concurrent infection)
RF (Rheumatoid Factor)	Exclude RA vasculitis, cryoglobulinaemia	Usually negative

3.5 Tissue Biopsy — The Gold Standard

Diagnosis: clinical + compatible underlying cause + Bx showing necrotizing medium-sized vasculitis ^[3]

Skin biopsy: histology & direct IF (for deposition of Ig around blood vessels). Biopsy of involved organs: kidney, vessels ^[2]

Biopsy is the gold standard for confirming PAN. The choice of biopsy site depends on which organ is clinically involved and accessible.

Feature	Details
When to biopsy	When subcutaneous nodules, livedo reticularis, or ulcers are present
Technique	Deep excisional or incisional biopsy reaching the subcutaneous fat (punch biopsy may be too superficial to capture medium-artery vasculitis)
Key finding	Necrotizing vasculitis in deep dermis or between fat lobules ^[3] — transmural fibrinoid necrosis of medium-sized arteries with neutrophilic infiltration
Direct IF	Deposition of Ig around blood vessels ^[2] — immune complex deposition (especially in HBV-PAN). In idiopathic PAN, IF may be pauci-immune or show minimal deposits

Biopsy Depth Matters

A superficial punch biopsy will miss PAN because the affected vessels are medium arteries at the dermal-subcutaneous junction and within the subcutaneous fat (septal vessels). You need a deep biopsy that includes subcutaneous fat to see the necrotizing arteritis. If the biopsy is too superficial, you'll get a false-negative result.

PAN: Primary vasculitis of septal vessels of subcutaneous fat ^[3]

Feature	Details
When to biopsy	Mononeuritis multiplex — sural nerve biopsy (combined nerve + adjacent gastrocnemius muscle biopsy)
Key finding	Necrotizing vasculitis of epineurial arteries (vasa nervorum); axonal degeneration from nerve infarction
Sensitivity	~50–60% for PAN; increased to ~80% when combined with adjacent muscle biopsy

Feature	Details
When to biopsy	When renal impairment is present and the diagnosis is unclear
Key finding	Necrotizing arteritis of arcuate and interlobar arteries. No glomerulonephritis (this is the critical distinction from MPA). May show ischaemic glomerular changes secondary to arterial occlusion
Caution	Risk of haemorrhage from microaneurysms — renal angiography should be performed first to identify aneurysms; blind percutaneous biopsy carries bleeding risk if aneurysms are present

Feature	Details
When to biopsy	When orchitis is present — the testis is an accessible biopsy site
Key finding	Necrotizing vasculitis of testicular artery branches

Stage	Light Microscopy Findings
Acute	Transmural neutrophilic infiltration of medium artery wall; fibrinoid necrosis of the media; destruction of internal elastic lamina
Subacute	Mixed inflammatory infiltrate (lymphocytes, macrophages, fibroblasts); early fibrosis; microaneurysm formation
Chronic	Fibrosis and intimal proliferation → luminal narrowing/occlusion; loss of normal vessel architecture

Characteristic feature: Lesions at different stages of evolution coexist in the same specimen (acute + subacute + chronic) — this reflects the ongoing, segmental, relapsing nature of the disease.

3.6 Angiography — The Imaging Gold Standard

Abnormal angiogram with microaneurysms: Yes (in PAN), No (in MPA) ^[4]

When tissue biopsy is not feasible or non-diagnostic, conventional catheter angiography (or CT angiography) of the mesenteric and renal arteries is the key confirmatory investigation.

Feature	Details
When to perform	When PAN is suspected but biopsy is not accessible; when GI or renal symptoms dominate
Key findings	Microaneurysms (small saccular aneurysms, typically 1–5 mm, at arterial branch points) + segmental stenoses + occlusions of medium-sized visceral arteries
Distribution	Most commonly seen in renal, mesenteric (celiac, SMA), and hepatic arteries
Specificity	Microaneurysms on visceral angiography are highly suggestive of PAN when combined with the appropriate clinical context. However, they can also be seen in other conditions (see below)

Feature	Details
Role	Non-invasive alternative to conventional angiography; increasingly used as first-line imaging
Findings	Same as conventional angiography — microaneurysms, stenoses, occlusions — but may miss very small aneurysms ( < 2 mm)
Additional value	Can identify organ infarction (renal, splenic, hepatic), bowel wall thickening (mesenteric ischaemia), perinephric haemorrhage (ruptured renal microaneurysm)

Feature	Details
Role	Alternative when CT contrast is contraindicated (e.g. severe renal impairment)
Limitations	Lower spatial resolution than CTA for detecting small microaneurysms

While microaneurysms are characteristic of PAN, they are not absolutely pathognomonic. Other causes include:

Condition	How to Distinguish
Mycotic aneurysms (infective endocarditis)	Blood cultures positive; echocardiographic vegetations
Fibromuscular dysplasia (FMD)	"String of beads" pattern; young women; no inflammation
SLE vasculitis	ANA/anti-dsDNA positive; low complement
Ehlers-Danlos syndrome	Connective tissue fragility; no inflammation; family history
Segmental arterial mediolysis	Older patients; non-inflammatory; dissections more prominent

Feature	Details
When to perform	When mononeuritis multiplex is suspected clinically
Key findings	Asymmetric axonal neuropathy — reduced compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) in named nerve distributions; normal or minimally reduced conduction velocities (axonal, not demyelinating pattern)
Role	Confirms the pattern and extent of neuropathy; helps select the best nerve for biopsy (choose a moderately affected nerve, not a completely destroyed one)

CXR, CT thorax, DLCO for pulmonary involvement if cough ± haemoptysis ^[14]^[15]

Finding	Interpretation
Normal CXR / CT chest	Expected in PAN — PAN characteristically spares the lungs
Pulmonary infiltrates, nodules, cavities	Suggests GPA, not PAN
Ground-glass opacification / DAH pattern	Suggests MPA or Goodpasture, not PAN

CXR/CT is performed in PAN primarily to exclude pulmonary involvement (which would redirect the diagnosis to an ANCA-associated vasculitis).

Echocardiogram for IE if persistent fever + murmur ^[14]^[15]

Indication	Purpose
Rule out infective endocarditis	Persistent fever + new murmur → vegetations on echo would suggest IE, not PAN
Assess cardiac function	Coronary vasculitis → ischaemic cardiomyopathy → LV dysfunction; pericarditis
Coronary involvement	Rare; may show wall motion abnormalities from MI

Finding	Interpretation
ST/T wave changes	Myocardial ischaemia from coronary arteritis
Q waves	Prior MI from coronary occlusion
LVH pattern	Secondary to renovascular hypertension
Arrhythmias	Ischaemic substrate

Investigation	Indication	Expected Finding
Testicular USS	Orchitis — distinguish from torsion/tumour	Increased vascularity (orchitis) vs absent flow (torsion) vs solid mass (tumour)
MRI Brain	CNS involvement (5–10%)	Infarcts in medium artery territories; may see microhaemorrhages
Ophthalmological slit-lamp exam	Suspected PUK, scleritis, retinal vasculitis	Peripheral corneal thinning/ulceration; scleral inflammation ^[9]
Fundoscopy	Hypertensive retinopathy; retinal vasculitis	Flame haemorrhages, cotton-wool spots (from severe HTN or retinal vasculitis)

Investigation Category	Expected Findings in PAN
CBC	NcNc anaemia, leukocytosis, thrombocytosis; NO eosinophilia
ESR/CRP	↑↑ ^[2]^[3]
RFT	↑ Urea, ↑ Cr ^[2]
Urinalysis	Subnephrotic proteinuria, haematuria; NO RBC casts, NO dysmorphic RBCs
Complement (C3/C4)	Normal ^[14]^[15]
ANCA	Negative (< 20% low-titre p-ANCA) ^[3]^[4]^[6]
HBsAg	Positive in ~50% ^[4]
ANA, anti-dsDNA, anti-GBM	Negative
Cryoglobulins	Negative
Angiography	Microaneurysms + segmental stenoses/occlusions of visceral arteries ^[4]
Biopsy	Necrotizing arteritis of medium artery with fibrinoid necrosis, PMN infiltration ^[2]^[3]
CXR	Normal (lungs spared)
NCS/EMG	Asymmetric axonal neuropathy (mononeuritis multiplex pattern)

To tie it all together, here's how you would work through a case systematically:

Step 1 — Suspect PAN clinically: Multi-system disease with constitutional symptoms + any combination of skin lesions (livedo, nodules), mononeuritis multiplex, renal impairment with hypertension, GI ischaemia, orchitis.

Step 2 — Baseline screening: CBC, ESR/CRP, RFT, LFT, urinalysis. Look for inflammatory markers ↑↑, renal impairment, and absence of active nephritic sediment.

Step 3 — Serological panel to narrow DDx:

ANCA → negative = consistent with PAN; positive = redirect to MPA/GPA/EGPA
HBsAg → positive = HBV-associated PAN
Complement → normal = consistent with PAN
ANA, anti-dsDNA, anti-GBM, cryoglobulins → negative = excludes SLE, Goodpasture, cryoglobulinaemia

Step 4 — Confirm vasculitis:

Tissue biopsy of affected organ (skin, nerve, muscle, testis, kidney) → necrotizing medium-vessel arteritis
AND/OR visceral angiography → microaneurysms + stenoses + occlusions of renal/mesenteric/hepatic arteries

Step 5 — Assess severity (Five-Factor Score): Proteinuria > 1g, Cr > 140, cardiomyopathy, GI involvement, CNS involvement → guides treatment intensity.

Step 6 — Identify etiology: HBV/HCV status (determines whether antivirals are needed); streptococcal/IBD history.

High Yield Summary — Diagnosis of PAN

ACR 1990 criteria: ≥ 3 of 10 criteria (weight loss, livedo, testicular pain, myalgias, neuropathy, diastolic HTN, ↑BUN/Cr, HBV, angiographic abnormality, biopsy showing PMN in artery wall)
CHCC 2012 definition: Necrotizing arteritis of medium/small arteries, NO GN, NO capillary/venular vasculitis, NOT ANCA-associated
Key investigations:
- ANCA negative (to exclude MPA/GPA/EGPA) ^[4]^[6]
- HBsAg positive in ~50% ^[4]
- Normal complement ^[14]^[15]
- Angiography: microaneurysms of visceral arteries ^[4]
- Biopsy: necrotizing medium-vessel arteritis with fibrinoid necrosis ^[2]^[3]
- Urinalysis: subnephrotic proteinuria, NO RBC casts (no GN) ^[3]
- CXR normal (lungs spared) ^[4]
Diagnosis = clinical suspicion + exclusion of other vasculitides + histology or angiography confirmation

Active Recall - Diagnosis and Investigations of PAN

References

Management of Polyarteritis Nodosa (PAN)

Before diving into specifics, let's understand the overarching management logic for PAN. There are three pillars to think about:

Immunosuppression — to halt the necrotizing arteritis that is destroying vessel walls and causing organ ischaemia/infarction
Treat the underlying cause — particularly antivirals for HBV-associated PAN (this fundamentally changes the approach)
Supportive and organ-specific management — addressing hypertension, pain, organ damage, and complications

The intensity of immunosuppression is guided by disease severity, which is assessed using the Five-Factor Score (FFS) — essentially a prognostic scoring system that identifies features predicting mortality and therefore requiring more aggressive treatment.

Management: Induction: steroids + steroid-sparing agents: CYC (severe) vs MTX/AZA (non-severe). Maintenance: non-GC non-CYC immunosuppressant × 18 months, taper GC ^[2]

The FFS (Guillevin et al., revised 2011) is the key tool that guides treatment intensity. Each factor present scores +1 point.

Factor	Points	Why This Predicts Mortality
Proteinuria > 1 g/day	+1	Reflects significant renal arterial damage → progressive renal failure
Renal insufficiency (Cr > 140 μmol/L)	+1	Indicates substantial renal infarction → reduced renal reserve
Cardiomyopathy	+1	Coronary vasculitis → ischaemic myocardium → HF and arrhythmias
GI involvement (bowel perforation, GI bleeding, pancreatitis)	+1	Mesenteric infarction → surgical emergency with high mortality
CNS involvement	+1	Cerebral artery vasculitis → stroke → high morbidity/mortality

FFS Score	5-Year Mortality	Treatment Implication
FFS = 0	~12%	Glucocorticoids ± AZA/MTX (steroid-sparing agent)
FFS = 1	~26%	Glucocorticoids + Cyclophosphamide
FFS ≥ 2	~46%	Glucocorticoids + Cyclophosphamide ± IV pulse steroids ± plasma exchange

4. Detailed Treatment Modalities

4.1 Glucocorticoids (GC) — The Backbone

Glucocorticoids are the first-line agent in virtually all PAN cases. They work by broadly suppressing the immune-inflammatory cascade at multiple levels.

Glucocorticoids bind to intracellular glucocorticoid receptors → translocate to the nucleus → suppress NF-κB and AP-1 transcription factors → ↓ production of pro-inflammatory cytokines (IL-1, IL-6, TNF-α), ↓ adhesion molecule expression on endothelium (so fewer neutrophils migrate into vessel walls), ↓ prostaglandin and leukotriene synthesis, and ↑ production of anti-inflammatory proteins (lipocortin-1, IL-10). In PAN specifically, this halts the neutrophilic infiltration and fibrinoid necrosis that drive vessel wall destruction.

Regimen	Indication	Details
Oral prednisolone 1 mg/kg/day ^[3]	All PAN (induction)	Starting dose, typically up to 60 mg/day; maintained for 2–4 weeks until clinical response, then gradual taper
IV pulse methylprednisolone (500–1000 mg/day × 3 days) ^[3]	Severe/refractory disease ^[3]	Used for rapidly progressive organ damage (e.g. impending bowel infarction, acute renal failure, CNS vasculitis). The "pulse" delivers a massive anti-inflammatory bolus that cannot be achieved with oral dosing
Tapering schedule	After remission achieved	Typically taper by 5–10 mg every 2–4 weeks, guided by clinical response and ESR/CRP. Target: ≤ 7.5 mg/day prednisolone by 6–12 months, then aim to discontinue

Induction: steroids + steroid-sparing agents: CYC (severe) vs MTX/AZA (non-severe) ^[2]

Side Effect	Mechanism	Preventive Measure
Osteoporosis	GC ↓ osteoblast activity + ↑ osteoclast activity + ↓ GI Ca²⁺ absorption	Calcium + Vitamin D supplementation; consider bisphosphonate if prolonged course
Cushingoid features (moon face, buffalo hump, truncal obesity)	Redistribution of fat from limbs to trunk	Minimise dose and duration
Hyperglycaemia / steroid-induced DM	GC ↑ hepatic gluconeogenesis + ↑ insulin resistance	Monitor BSL; oral hypoglycaemics or insulin if needed
Peptic ulcer disease	GC ↓ prostaglandin synthesis → ↓ gastric mucosal protection	PPI co-prescription (especially if combined with NSAIDs)
Immunosuppression → infections	Suppressed cell-mediated immunity (T-cells, macrophages)	Infection surveillance; consider TMP-SMX for PJP prophylaxis if high-dose prolonged GC
Hypertension	Mineralocorticoid effect → Na⁺ and water retention	Monitor BP; ACEI/ARB if needed
Adrenal suppression	Negative feedback on HPA axis → adrenal atrophy	Never stop abruptly — always taper; stress-dose steroids during illness/surgery
Proximal myopathy	Catabolic effect on skeletal muscle	Exercise; minimise dose
Cataracts / glaucoma	Posterior subcapsular cataract from altered lens metabolism; ↑IOP from ↓ aqueous outflow	Annual ophthalmological review
Avascular necrosis (AVN)	Disrupted blood supply to bone (esp. femoral head)	Clinical vigilance; MRI if hip pain

Steroid Complications — Know Them Cold

Every exam paper loves asking about steroid side effects. The mnemonic "Cushing's MOPED" covers the major ones:

Cushing's appearance
Myopathy (proximal)
Osteoporosis
Peptic ulcer, Psychiatric disturbance
Electrolytes (↑Na, ↓K), hyperglycaemia (Endocrine)
Diabetes, (a)Drenal suppression

4.2 Cyclophosphamide (CYC) — For Severe Disease

Oral steroid + cyclophosphamide for moderate/severe disease ^[3]

"Cyclo-" = cyclic; "phosph-" = phosphorus-containing; "-amide" = nitrogen mustard derivative. It's an alkylating agent — it cross-links DNA strands, preventing cell division. Originally developed as a cancer drug, it's one of the most potent immunosuppressants available.

CYC is a prodrug that is activated in the liver by cytochrome P450 enzymes into its active metabolite (phosphoramide mustard). This alkylates DNA in rapidly dividing cells (especially lymphocytes) → prevents B-cell and T-cell proliferation → suppresses both humoral and cell-mediated immunity. In PAN, this halts the immune-mediated destruction of arterial walls.

Route	Protocol	Notes
IV pulse CYC (preferred)	15 mg/kg (max 1.2 g) every 2–3 weeks × 6–9 pulses	Pulsed IV administration has lower cumulative toxicity than daily oral dosing while maintaining comparable efficacy
Oral CYC	2 mg/kg/day × 3–6 months	Higher cumulative dose → more toxicity; now less commonly used

FFS ≥ 1 (any of: renal insufficiency, proteinuria > 1g, GI involvement, cardiomyopathy, CNS involvement) ^[3]
Life-threatening or rapidly progressive disease
Failure to respond to glucocorticoids alone

Side Effect	Mechanism	Management
Haemorrhagic cystitis	Acrolein (toxic metabolite) excreted in urine → direct bladder epithelial damage	Adequate hydration; co-administer MESNA (2-mercaptoethane sulfonate sodium) — MESNA binds acrolein in the urine, neutralising it
Bone marrow suppression (leukopenia, thrombocytopenia, anaemia)	DNA alkylation of haematopoietic precursors	Monitor CBC every 2 weeks; dose-adjust based on nadir WCC; target WCC > 3.0 × 10⁹/L
Gonadal toxicity (infertility)	Damage to rapidly dividing germ cells	Sperm banking pre-treatment in males; GnRH agonist co-administration in females to suppress ovarian function during CYC
Malignancy risk (bladder cancer, lymphoma, leukaemia)	Cumulative DNA mutagenesis	Limit cumulative dose (avoid > 36 g lifetime); use IV pulse rather than daily oral
Infections (opportunistic)	Severe immunosuppression, especially lymphopenia	PJP prophylaxis (TMP-SMX) during CYC course; monitor for infections
Nausea and vomiting	GI mucosal irritation	Anti-emetics (ondansetron)
Teratogenicity	Alkylation of fetal DNA	Absolute contraindication in pregnancy — Category D/X

CYC Key Monitoring

When prescribing cyclophosphamide, you MUST:

Check CBC every 2 weeks (nadir WCC at ~10–14 days post-dose)
Adequate hydration + MESNA to prevent haemorrhagic cystitis
Regular urinalysis for haematuria (early cystitis detection)
Contraception counselling (teratogenic)
PJP prophylaxis with TMP-SMX
Limit cumulative dose to minimise long-term malignancy risk

4.3 Steroid-Sparing Agents — For Mild Disease and Maintenance

Oral steroid (prednisolone 1 mg/kg/d) ± azathioprine/methotrexate for mild disease ^[3]

Name breakdown: "Aza-" = nitrogen; "-thio-" = sulfur; "-prine" = purine analogue. AZA is a purine antimetabolite — it mimics purine bases and gets incorporated into DNA, blocking further replication.

Mechanism: AZA is a prodrug → converted to 6-mercaptopurine (6-MP) → further metabolised to thioguanine nucleotides (TGN) → incorporated into DNA → halts DNA synthesis and triggers apoptosis in rapidly dividing lymphocytes → selective immunosuppression.

Aspect	Details
Indication in PAN	(1) Mild disease (FFS = 0): as initial steroid-sparing agent alongside prednisolone; (2) Maintenance therapy: after CYC-induced remission in severe disease
Dose	2–3 mg/kg/day orally
Duration	× 18 months (maintenance) ^[2], though some centres extend to 24 months
Key side effects	Bone marrow suppression (dose-dependent); hepatotoxicity; GI intolerance (nausea, diarrhoea); pancreatitis (rare, idiosyncratic); ↑ infection risk
Pre-treatment check	TPMT genotype/phenotype — thiopurine methyltransferase is the key enzyme that metabolises AZA. ~1 in 300 people are TPMT-deficient (homozygous) → dramatically ↑ risk of severe myelosuppression at standard doses. These patients need significantly reduced doses or an alternative agent
Monitoring	CBC every 2–4 weeks initially, then every 1–3 months; LFT every 3 months

Name breakdown: "Metho-" = methyl group; "-trex-" = from "tetrahydrofolate"; "-ate" = suffix. MTX is a dihydrofolate reductase inhibitor — it blocks the enzyme needed to convert dihydrofolate to tetrahydrofolate, which is essential for purine and thymidine synthesis → DNA synthesis is blocked.

Mechanism: At immunosuppressive doses, MTX also increases extracellular adenosine (an anti-inflammatory mediator) → suppresses T-cell activation and cytokine production. This dual mechanism (anti-proliferative + anti-inflammatory) makes it useful in autoimmune conditions.

Aspect	Details
Indication in PAN	Alternative to AZA for mild disease (FFS = 0) or maintenance; particularly useful when AZA is not tolerated
Dose	15–25 mg/week orally or SC (always given weekly, not daily — daily dosing is lethal!)
Key side effects	Bone marrow suppression; hepatotoxicity (↑ALT, fibrosis, cirrhosis); pneumonitis (hypersensitivity lung toxicity); stomatitis/oral ulcers; teratogenicity
Co-administration	Folic acid 5 mg weekly (taken 24–48h after MTX) — to replenish folate stores and reduce mucositis and marrow suppression without reducing efficacy
Monitoring	CBC, LFT, RFT every 2–4 weeks initially, then monthly; CXR at baseline

MTX Dosing Error — A Common Fatal Mistake

MTX for immunosuppression is given ONCE WEEKLY — not daily. Prescribing MTX daily (a common medication error) leads to fatal pancytopenia. Always write the specific day of the week on the prescription (e.g. "MTX 15 mg every Monday").

MMF is occasionally used as a maintenance agent in PAN, though evidence is more established in ANCA-associated vasculitis and lupus nephritis.

Mechanism: MMF is converted to mycophenolic acid (MPA) → inhibits inosine monophosphate dehydrogenase (IMPDH) → blocks de novo purine synthesis. Lymphocytes are uniquely dependent on the de novo pathway (unlike most other cells which can use the salvage pathway), so MMF is selectively lymphotoxic.

Aspect	Details
Indication	Second-line maintenance if AZA/MTX intolerant
Dose	1–2 g/day in divided doses
Key side effects	GI (diarrhoea, nausea — most common); bone marrow suppression; ↑ infection risk; teratogenicity

4.4 Management of HBV-Associated PAN — A Fundamentally Different Approach

This is one of the most important conceptual distinctions in PAN management. In HBV-associated PAN, the vasculitis is driven by immune complex deposition from HBsAg–anti-HBs complexes. Therefore, the logical treatment is to eliminate the antigen source (HBV replication) rather than simply suppressing the immune system (which would paradoxically increase viral replication and worsen the disease long-term).

Antivirals only if mild PAN + HBV/HCV infection ^[3]

Updated approach (current practice, 2025 guidelines): Antivirals are now used in all HBV-associated PAN, not just mild disease.

This is a critical concept to understand from first principles:

In HBV-PAN, the disease is driven by HBsAg–anti-HBs immune complexes
If you give prolonged immunosuppression (GC, CYC, AZA), you suppress the anti-HBs antibody response → this temporarily reduces immune complex formation and improves symptoms
BUT simultaneously, you allow uncontrolled HBV replication (because the immune system is no longer keeping the virus in check) → viral load rises dramatically
When you eventually taper immunosuppression → the immune system "rebounds" against the massively increased viral load → explosive immune complex formation → severe vasculitis flare + hepatitis flare (potentially fulminant hepatic failure)
This is why the correct strategy is: short GC burst (only if life-threatening) + antivirals (to eliminate the antigen source) + rapid GC taper + plasma exchange if severe (to remove existing immune complexes)

High Yield — HBV-PAN vs Idiopathic PAN Management

Feature	Idiopathic PAN	HBV-Associated PAN
Mainstay	Immunosuppression (GC ± CYC/AZA/MTX)	Antivirals (Entecavir/Tenofovir)
GC use	Prolonged course with gradual taper	Short course only, rapid taper
CYC	Used for severe disease	Generally AVOIDED (worsens HBV replication)
Plasma exchange	Not typically used	Used for severe HBV-PAN to remove immune complexes
Goal	Sustained immunological remission	HBsAg seroconversion (eliminate antigen source)

Drug	Class	Mechanism	Key Points
Entecavir	Nucleoside analogue	Inhibits HBV polymerase (reverse transcriptase) → blocks HBV DNA replication	High barrier to resistance; preferred first-line
Tenofovir disoproxil	Nucleotide analogue	Same mechanism — inhibits HBV polymerase	Also high barrier to resistance; monitor renal function (nephrotoxic in rare cases)

Note: Older agents like lamivudine and interferon-α are no longer recommended first-line due to high resistance rates (lamivudine) and risk of immune flare (interferon).

Aspect	Details
Indication	Severe HBV-associated PAN with life-threatening organ involvement; occasionally in refractory idiopathic PAN
Mechanism	Physically removes circulating immune complexes (HBsAg–anti-HBs) and inflammatory mediators from the plasma. The patient's plasma is separated, discarded, and replaced with albumin or fresh frozen plasma
Rationale in HBV-PAN	Rapidly reduces the pathogenic immune complex load while antivirals work to reduce HBsAg production — buys time for antiviral therapy to take effect
Not routinely used in idiopathic PAN	Because idiopathic PAN is not primarily immune complex–driven (mechanism is more cell-mediated/unclear), plasma exchange has less theoretical benefit

ACEI/ARB if HTN ^[3]

Clinical Problem	Management	Rationale
Hypertension	ACEI or ARB ^[3]	PAN causes renovascular hypertension (renal artery vasculitis → RAAS activation). ACEI/ARBs block the RAAS — they inhibit angiotensin-converting enzyme (ACEI) or block AT₁ receptors (ARB) → ↓ angiotensin II effects → vasodilation + ↓ aldosterone → ↓ BP. Caution: avoid in bilateral renal artery stenosis (can precipitate AKI — the kidneys depend on angiotensin II to maintain GFR via efferent arteriolar constriction when perfusion pressure is already low)
Pain management	Paracetamol; opioids for severe ischaemic pain; neuropathic agents (gabapentin, pregabalin) for mononeuritis multiplex	Avoid NSAIDs if possible — ↑ renal impairment risk + GI bleeding risk (especially with concurrent steroids)
GI prophylaxis	PPI (omeprazole, pantoprazole)	GC + mesenteric ischaemia → very high peptic ulcer risk. PPI inhibits H⁺/K⁺ ATPase → ↓ gastric acid production → mucosal protection
Bone protection	Calcium 1000 mg + Vitamin D 800 IU daily; bisphosphonate (alendronate) if prolonged GC	GC-induced osteoporosis prevention. Bisphosphonates inhibit osteoclasts → ↓ bone resorption
Infection prophylaxis	TMP-SMX (co-trimoxazole) for PJP prophylaxis if on high-dose GC + CYC	Trimethoprim-sulfamethoxazole blocks two sequential steps in folate synthesis in Pneumocystis jirovecii → bactericidal. PJP is a life-threatening opportunistic infection in immunosuppressed patients
Vaccination	Influenza vaccine annually; pneumococcal vaccine; HBV vaccination if not immune	Immunosuppressed patients are at ↑ risk; give inactivated vaccines only (live vaccines are contraindicated in immunosuppressed patients)
DVT prophylaxis	Consider LMWH if immobilised; compression stockings	Active vasculitis + GC → hypercoagulable state + immobility
Surgical emergency	Laparotomy for bowel perforation/infarction; aneurysm rupture	GI complications (mesenteric infarction, bowel perforation) are surgical emergencies requiring urgent intervention alongside medical immunosuppression
Cardiac	Standard ACS management if coronary vasculitis → MI; heart failure management (ACEI, beta-blocker, diuretics) if ischaemic cardiomyopathy
Renal replacement therapy	Dialysis if ESRD develops	Bridge to recovery or long-term if irreversible renal damage

The management of PAN follows the same induction → remission → maintenance → taper paradigm used across autoimmune rheumatic diseases.

Maintenance: non-GC non-CYC immunosuppressant × 18 months, taper GC ^[2]

Phase	Goal	Duration	Agents
Induction	Achieve remission (clinical quiescence, normalisation of inflammatory markers)	3–6 months	GC ± CYC (severe) or GC ± AZA/MTX (mild)
Maintenance	Prevent relapse while minimising drug toxicity	18–24 months ^[2]	Non-GC, non-CYC immunosuppressant ^[2]: AZA (preferred) or MTX; taper GC to lowest effective dose, aim to stop
Taper/Withdrawal	Gradually withdraw immunosuppression if sustained remission	Variable	Slow taper of maintenance agent; monitor for relapse with ESR/CRP, RFT, urinalysis every 1–3 months

Why switch from CYC to AZA/MTX for maintenance? Because CYC has cumulative toxicity (bladder cancer, myelodysplasia, infertility) — it's too toxic for long-term use. Once remission is achieved (typically after 3–6 months or 6–9 IV pulses), CYC is switched to a safer maintenance agent ^[2]^[3].

Parameter	Frequency	Purpose
ESR/CRP	Every 1–3 months	Monitor disease activity; guide GC taper
CBC with differential	Every 2–4 weeks (on CYC); every 1–3 months (on AZA/MTX)	Detect bone marrow suppression early
RFT	Every 1–3 months	Monitor renal function (disease progression + drug nephrotoxicity)
LFT	Every 1–3 months	MTX/AZA hepatotoxicity; HBV hepatitis monitoring
Urinalysis	Every visit	Detect haematuria (haemorrhagic cystitis from CYC; renal disease progression)
HBV viral load (if HBV-PAN)	Every 3–6 months	Monitor antiviral response; aim for undetectable HBV DNA
Blood pressure	Every visit	Renovascular hypertension control
Blood glucose	Regularly during GC therapy	Steroid-induced hyperglycaemia
DEXA scan	At baseline if prolonged GC anticipated; repeat every 1–2 years	GC-induced osteoporosis monitoring

Prognosis: poor (13% 5-year survival) if untreated, fair (80% 5-year survival) if treated ^[3]

Outcome	Details
Untreated	13% 5-year survival — death from renal failure, mesenteric infarction, cardiac infarction, cerebral infarction
Treated	80% 5-year survival with immunosuppression
Relapse	Not uncommon (9.2% at 1 year, 24% at 5 years) but lower than other ANCA-vasculitis ^[3]
Major sources of mortality	Renal failure, mesenteric/cardiac/cerebral infarction ^[3]
Late mortality	Increasingly from treatment complications (infections from immunosuppression, cardiovascular disease from GC) rather than active vasculitis

8. Special Scenarios

Cutaneous PAN (limited to skin without systemic involvement) has a much better prognosis and can often be managed with:

Low-dose prednisolone alone (0.5 mg/kg/day with taper)
Colchicine or dapsone for mild cases
NSAIDs for pain
Rarely needs CYC/AZA

If PAN does not respond to first-line therapy:

Rituximab (anti-CD20 monoclonal antibody) — depletes B-cells; evidence extrapolated from ANCA-associated vasculitis; increasingly used in refractory PAN
TNF-α inhibitors (infliximab) — case reports of efficacy in refractory PAN
Tocilizumab (anti-IL-6 receptor) — emerging evidence; theoretical benefit given IL-6's role in systemic inflammation

MTX and CYC are absolutely contraindicated (teratogenic — Category X)
AZA is relatively safe in pregnancy (Category D but widely used in autoimmune disease with careful monitoring)
Glucocorticoids are generally safe but cross the placenta (prednisolone is preferred over dexamethasone/betamethasone as it is more extensively metabolised by placental 11β-HSD2)

Scenario	Induction	Maintenance	Special Considerations
Mild idiopathic PAN (FFS = 0)	Prednisolone 1 mg/kg/day ± AZA or MTX ^[3]	AZA or MTX × 18–24 months; taper GC ^[2]	Bone protection, PPI, infection monitoring
Moderate-severe idiopathic PAN (FFS ≥ 1)	Prednisolone + CYC (IV pulses preferred) ^[3]	Switch CYC → AZA or MTX × 18–24 months ^[2]	MESNA + hydration with CYC; PJP prophylaxis; fertility counselling
Fulminant/refractory	IV pulse methylprednisolone (500–1000 mg × 3 days) + CYC ^[3]	As above	Consider plasma exchange; rituximab for refractory cases
HBV-associated PAN	Short GC burst + antivirals (Entecavir or Tenofovir) ^[3]	Antivirals continued until HBsAg seroconversion; STOP GC rapidly	Avoid prolonged IS; plasma exchange if severe
Cutaneous PAN	Low-dose prednisolone ± colchicine/dapsone	Taper and stop	Excellent prognosis; rarely needs systemic IS

High Yield Summary — Management of PAN

Severity guides treatment: FFS = 0 → GC ± AZA/MTX; FFS ≥ 1 → GC + CYC
Induction: steroids + steroid-sparing agents: CYC (severe) vs MTX/AZA (non-severe) ^[2]
Maintenance: non-GC non-CYC immunosuppressant × 18 months, taper GC ^[2]
IV pulse steroid for severe/refractory disease ^[3]
HBV-PAN is fundamentally different: antivirals (entecavir/tenofovir) are the mainstay; GC used only briefly; CYC generally AVOIDED; plasma exchange for severe disease
ACEI/ARB for HTN ^[3] (renovascular hypertension)
Prognosis: 13% 5-year survival untreated → 80% treated ^[3]
Major mortality: renal failure, mesenteric/cardiac/cerebral infarction ^[3]
Relapse: 9.2% at 1 year, 24% at 5 years — lower than ANCA-vasculitis ^[3]
Always co-prescribe: PPI, bone protection, infection prophylaxis, and monitor CBC/RFT/LFT regularly

Active Recall - Management of PAN

References

Complications of Polyarteritis Nodosa (PAN)

To understand the complications of PAN from first principles, remember that this is a necrotizing vasculitis of medium-sized arteries. Every complication stems from two fundamental pathological processes ^[1]:

Vasculitis is defined by the presence of inflammatory leukocytes in vessel wall with reactive damage to mural structures. Loss of vessel integrity leads to bleeding. Compromise of the lumen leads to downstream tissue ischaemia and necrosis. ^[1]

So all PAN complications fall into two categories:

Vessel wall weakening → aneurysm formation → rupture → haemorrhage
Luminal narrowing/thrombosis → downstream ischaemia → organ infarction → organ failure

Plus a third category: 3. Treatment-related complications — from the immunosuppressive drugs used to manage PAN

The clinical significance of complications is enormous — they account for the bulk of morbidity and are the primary drivers of mortality.

Major source of mortality: renal failure, mesenteric/cardiac/cerebral infarction ^[3]

Complication	Pathophysiology	Clinical Consequence
Renal infarction	Vasculitis of arcuate and interlobar arteries → luminal thrombosis → segmental renal parenchymal necrosis	Flank pain, haematuria, rising creatinine; repeated infarctions lead to progressive renal insufficiency
Renovascular hypertension (often severe/malignant)	Renal artery branch vasculitis → renal ischaemia → juxtaglomerular apparatus senses ↓ perfusion pressure → ↑ renin secretion → angiotensinogen → angiotensin I → (ACE) → angiotensin II → vasoconstriction + aldosterone release → Na⁺/H₂O retention → ↑↑ BP	Malignant hypertension (DBP > 120 with end-organ damage) → hypertensive retinopathy, hypertensive encephalopathy, LVH, heart failure
Renal microaneurysm rupture	Necrotizing vasculitis weakens the arterial wall → saccular microaneurysm forms → may rupture spontaneously or during biopsy	Retroperitoneal/perinephric haemorrhage — can be life-threatening. This is why renal angiography should precede percutaneous biopsy to identify aneurysms and avoid catastrophic bleeding
Chronic kidney disease / End-stage renal disease	Cumulative bilateral renal infarction → progressive nephron loss → irreversible renal failure	Need for long-term dialysis or renal transplantation; renal failure is a major source of mortality ^[3]

Why PAN Causes Hypertension but NOT Glomerulonephritis

This is worth re-emphasizing: PAN causes renovascular hypertension via RAAS activation from medium-artery vasculitis, but does NOT cause GN (no capillary/venular involvement). The renal damage is from infarction, not from glomerular inflammation. If you see GN (RBC casts, dysmorphic RBCs) → reconsider MPA ^[3]^[4].

GI complications are among the most serious and are a major source of mortality ^[3].

Complication	Pathophysiology	Clinical Consequence
Mesenteric ischaemia / Bowel infarction	Vasculitis of mesenteric arteries (celiac, SMA, IMA branches) → luminal narrowing/thrombosis → bowel wall ischaemia → transmural necrosis → gangrene	Acute abdomen — severe abdominal pain, peritonism, absent bowel sounds. Requires emergency laparotomy for resection of gangrenous bowel. Mortality is very high (30–50%)
Bowel perforation	Full-thickness bowel wall necrosis from ischaemia → perforation → peritonitis	Pneumoperitoneum on erect CXR; faecal peritonitis → septic shock. Surgical emergency
GI haemorrhage	Mucosal ischaemia → ulceration → erosion into submucosal vessels → haematemesis/melaena	May be massive and life-threatening; requires endoscopic or angiographic intervention ± surgery
Mesenteric microaneurysm rupture	Weakened arterial wall → aneurysm rupture → intra-abdominal haemorrhage	Haemoperitoneum → haemodynamic instability. May require emergency angiographic embolisation or surgery
Intestinal stricture (chronic)	Healed ischaemic segments → fibrotic stricture formation	Chronic partial bowel obstruction, recurrent postprandial pain
Pancreatitis	Vasculitis of pancreatic arterial branches → pancreatic ischaemia/necrosis	Epigastric pain radiating to back, ↑ amylase/lipase. Included in the Five-Factor Score as a GI complication
Acalculous cholecystitis	Vasculitis of cystic artery → gallbladder wall ischaemia → inflammation without gallstones	RUQ pain, fever, positive Murphy's sign

GI: mesenteric arteritis leading to postprandial angina, weight loss, N/V, GIB, diarrhoea, bowel infarction ^[3]

GI Complications — Surgical Emergency

Bowel infarction and perforation are the most feared GI complications and a leading cause of death in PAN. Any patient with PAN who develops acute severe abdominal pain with peritoneal signs needs immediate surgical consultation. Delay → peritonitis → sepsis → multi-organ failure → death.

Complication	Pathophysiology	Clinical Consequence
Myocardial ischaemia / Myocardial infarction (MI) ^[2]	Coronary artery vasculitis → luminal thrombosis or aneurysm formation → myocardial necrosis	Chest pain, troponin rise, ECG changes (ST elevation/depression, Q waves). PAN is a recognised cause of non-atherosclerotic coronary artery disease — MI in a young patient without traditional risk factors should raise suspicion
Ischaemic cardiomyopathy	Recurrent/chronic coronary vasculitis → diffuse myocardial ischaemia → progressive LV systolic dysfunction	Progressive dyspnoea, orthopnoea, peripheral oedema. Included in the Five-Factor Score
Heart failure	Consequence of ischaemic cardiomyopathy + renovascular hypertension → combined pressure + volume overload	Congestive heart failure (raised JVP, bibasal crackles, S3, hepatomegaly, pedal oedema)
Pericarditis	Direct vascular inflammation → pericardial irritation/effusion	Pleuritic chest pain, pericardial rub, ECG showing diffuse ST elevation with PR depression
Coronary artery aneurysm	Necrotizing vasculitis weakens coronary artery wall → aneurysmal dilatation	Risk of rupture or thrombotic occlusion → MI; may resemble Kawasaki disease aneurysms on echo/angiography

CVS: MI ^[2] Cardiac: myocardial ischaemia, ischaemic cardiomyopathy, heart failure ^[3]

Complication	Pathophysiology	Clinical Consequence
Mononeuritis multiplex (most common neuro complication, up to 70%)	Vasculitis of vasa nervorum (medium-sized arteries supplying peripheral nerves) → nerve infarction → acute axonal neuropathy in named nerve distributions	Foot drop (common peroneal nerve), wrist drop (radial nerve), sensory loss, burning pain in affected territories. Typically asymmetric and sequential. May progress to confluent polyneuropathy if many nerves are involved ^[3]^[7]
Polyneuropathy	Confluent mononeuritis multiplex → symmetrical sensorimotor neuropathy	Glove-and-stocking sensory loss + distal weakness; may be mistaken for diabetic neuropathy or GBS if the sequential mononeuropathy pattern is not elicited in the history
Permanent neurological deficit	If nerve infarction is severe → irreversible axonal loss	Chronic foot drop requiring orthotic (AFO), chronic neuropathic pain, muscle wasting from denervation
CNS vasculitis (rare, 5–10% ^[3])	Vasculitis of cerebral medium arteries → focal cerebral ischaemia/infarction	Stroke (hemiparesis, aphasia, visual field defects); seizures; cranial nerve palsies; cognitive decline
Subarachnoid haemorrhage (rare)	Rupture of cerebral microaneurysm	Thunderclap headache, meningism, reduced consciousness

Neurological: mononeuritis multiplex (up to 70%), CNS involvement (5–10%) ^[3]

Complication	Pathophysiology	Clinical Consequence
Digital gangrene	Vasculitis of digital arteries → complete occlusion → critical ischaemia → necrotic tissue	Black, insensate, dry gangrene of fingers/toes; may require amputation
Non-healing ulcers	Chronic dermal ischaemia from vasculitis → impaired wound healing	Particularly on lower extremities; risk of secondary infection
Secondary skin infection / cellulitis	Ulcerated skin breaches the barrier → bacterial entry; compounded by immunosuppressive therapy	Requires antibiotics; may progress to sepsis in immunosuppressed patients
Scarring and disfigurement	Healed ulcers and nodules leave atrophic scars; lipoatrophy at sites of resolved panniculitis	Cosmetic and psychosocial impact

Skin: livedo reticularis, digital ulcers / gangrene, subcutaneous nodules ^[2]

Complication	Pathophysiology	Clinical Consequence
Peripheral ulcerative keratitis (PUK)	Immune complex deposition in peripheral cornea → complement activation → MMP production by stromal keratocytes → corneal breakdown ^[9]	Pain, redness, tearing, photophobia, ↓ vision. Crescent-shaped corneal ulcer ('Mooren's ulcer' if isolated). Corneal thinning ± perforation, melting ^[9]
Scleritis	Vasculitis of scleral vessels → deep scleral inflammation	Deep boring eye pain, violaceous hue, scleral thinning. Risk of globe perforation (necrotising scleritis)
Retinal vasculitis	Vasculitis of retinal arteries → ischaemia → cotton-wool spots, haemorrhages	Visual field defects, ↓ visual acuity
Hypertensive retinopathy	Severe renovascular hypertension → retinal arteriolar damage	Flame haemorrhages, cotton-wool spots, papilloedema (in malignant HTN)

Systemic association of PUK: polyarteritis nodosa ^[9]

PUK — Sight-Threatening Complication

PUK associated with PAN can progress to corneal perforation if not treated aggressively. Management requires both systemic immunosuppression (to control the underlying vasculitis) and local ophthalmological management (lubricants, avoid topical steroids if corneal melting, surgical repair if perforation) ^[9].

Complication	Pathophysiology	Clinical Consequence
Testicular infarction	Vasculitis of testicular artery → complete occlusion → testicular necrosis	Severe testicular pain, swelling; may require orchidectomy if irreversible necrosis
Infertility (from disease or treatment)	Testicular vasculitis → impaired spermatogenesis; CYC → gonadal toxicity	Long-term reproductive consequences; counsel pre-treatment

GU: orchitis (testicular pain) ^[2]

Complication	Pathophysiology	Clinical Consequence
Muscle infarction	Vasculitis of muscle-supplying arteries → segmental muscle necrosis	Severe localised myalgia, muscle swelling, elevated CK
Chronic muscle wasting	Repeated ischaemic episodes + disuse from pain + GC-induced myopathy	Proximal muscle weakness, reduced functional capacity

These are increasingly important because with effective immunosuppression, patients survive longer but accumulate treatment toxicity. In fact, in the modern era, treatment complications are a major cause of late mortality — sometimes exceeding disease-related mortality.

Complication	Mechanism	Details
Opportunistic infections	GC suppress cell-mediated immunity (T-cells, macrophages) → ↑ susceptibility to intracellular organisms	Pneumocystis jirovecii pneumonia (PJP), herpes zoster reactivation, TB reactivation, invasive fungal infections. This is why PJP prophylaxis (TMP-SMX) is critical
GC-induced osteoporosis → fragility fractures	↓ Osteoblast function + ↑ osteoclast activity + ↓ GI Ca²⁺ absorption + ↓ renal Ca²⁺ reabsorption	Vertebral compression fractures, hip fractures. Prevented by calcium + vitamin D + bisphosphonate
Avascular necrosis (AVN) of femoral head	GC disrupt blood supply to subchondral bone (multifactorial: fat embolism to small vessels, ↑ marrow adiposity, endothelial dysfunction)	Hip/groin pain; if severe → requires total hip replacement
Steroid-induced diabetes mellitus	↑ Hepatic gluconeogenesis + ↑ peripheral insulin resistance	Hyperglycaemia → may require insulin; ↑ cardiovascular risk
Peptic ulcer disease / GI bleeding	↓ Prostaglandin synthesis → ↓ gastric mucosal protection; exacerbated by concurrent mesenteric ischaemia in PAN	Upper GI bleeding; prevented by PPI co-prescription
Cushing syndrome	Prolonged supraphysiological GC → exogenous Cushing's	Moon face, buffalo hump, central obesity, striae, thin skin, easy bruising
Adrenal suppression	Chronic exogenous GC → negative feedback on HPA axis → adrenal cortex atrophies	Addisonian crisis if GC abruptly stopped during physiological stress; always taper
Psychiatric disturbances	GC affect CNS neurotransmitter systems (serotonin, dopamine)	Insomnia, mood lability, psychosis, depression
Accelerated atherosclerosis	GC → dyslipidaemia + hyperglycaemia + hypertension → accelerated atherogenesis	Increased long-term cardiovascular risk; ischaemic heart disease, stroke
Cataracts / glaucoma	Posterior subcapsular cataract from altered lens protein metabolism; ↑ IOP from ↓ aqueous humour outflow	Visual impairment; annual ophthalmological screening
GC-induced myopathy	Catabolic effect on type II (fast-twitch) muscle fibres	Proximal limb weakness (difficulty rising from chair, climbing stairs); compounds disease-related myalgia

Complication	Mechanism	Details
Haemorrhagic cystitis	Acrolein (CYC metabolite) excreted in urine → direct bladder urothelial toxicity	Dysuria, haematuria (may be severe). Prevented by adequate hydration + MESNA
Bladder cancer (long-term)	Chronic acrolein exposure → urothelial DNA damage → malignant transformation	Transitional cell carcinoma; risk increases with cumulative CYC dose. Lifetime urine surveillance in heavily exposed patients
Bone marrow suppression	Alkylation of haematopoietic stem cell DNA → impaired proliferation	Leukopenia (nadir ~10–14 days post-dose) → opportunistic infections; thrombocytopenia → bleeding; anaemia
Gonadal failure / Infertility	Alkylation of germ cell DNA → destruction of oocytes/spermatogonia	Premature ovarian failure (amenorrhoea), azoospermia. Risk is cumulative and age-dependent. Fertility preservation counselling is essential pre-treatment
Secondary malignancy	Cumulative DNA mutagenesis	Myelodysplastic syndrome, acute leukaemia, lymphoma — risk increases with total dose
Teratogenicity	DNA alkylation of embryonic/fetal cells	Absolutely contraindicated in pregnancy (Category X)

Drug	Key Complications	Notes
Azathioprine	Bone marrow suppression (especially if TPMT-deficient); hepatotoxicity; pancreatitis (rare, idiosyncratic); ↑ infection risk	Check TPMT genotype before starting; monitor CBC and LFT
Methotrexate	Bone marrow suppression; hepatotoxicity (fibrosis, cirrhosis); MTX pneumonitis (hypersensitivity lung disease); stomatitis; teratogenicity	Co-prescribe folic acid 5 mg weekly; never prescribe daily; monitor CBC, LFT, RFT

Drug	Key Complications	Notes
Entecavir	Lactic acidosis (rare); headache, nausea	Generally well-tolerated
Tenofovir disoproxil	Nephrotoxicity (Fanconi syndrome — proximal tubular dysfunction); bone mineral density loss	Monitor RFT, serum phosphate; consider tenofovir alafenamide (TAF) if renal concerns

Relapse: not uncommon (9.2% at 1 year, 24% at 5 years) but lower than other ANCA-vasculitis ^[3]

Aspect	Details
Frequency	9.2% at 1 year, 24% at 5 years ^[3] — lower than MPA/GPA but still clinically significant
Triggers	Premature withdrawal of immunosuppression, intercurrent infection, non-compliance
Presentation	Recurrence of constitutional symptoms (fever, weight loss) + new organ ischaemia; may present with new mononeuritis multiplex, worsening renal function, or new skin lesions
Management	Re-induction with GC ± CYC (as for initial severe disease); consider rituximab for multiply-relapsing disease
Monitoring	Regular ESR/CRP, RFT, urinalysis every 1–3 months for at least 5 years after remission

Even after successful treatment and remission, PAN survivors face significant long-term morbidity:

Sequela	Mechanism	Impact
Chronic kidney disease	Cumulative renal infarction → irreversible nephron loss	May require lifelong dialysis or transplantation
Chronic neuropathic pain	Incomplete nerve recovery after infarction	Requires long-term neuropathic pain management (gabapentin, pregabalin, duloxetine)
Permanent motor deficits	Severe axonal loss → irreversible denervation	Foot drop → requires ankle-foot orthosis (AFO); chronic hand weakness
Cardiovascular disease	Accelerated atherosclerosis from GC use + residual coronary vasculitis	Increased long-term MI/stroke risk; aggressive cardiovascular risk factor management needed
Chronic pain and disability	Multi-organ damage + neuropathy + myopathy + steroid-related complications	Reduced quality of life; may require multidisciplinary rehabilitation
Psychological morbidity	Chronic disease burden + GC psychiatric effects + body image changes + chronic pain	Depression, anxiety; consider psychological support/referral

Organ System	Key Complications	Included in FFS?	Mortality Contribution
Renal	Infarction, renovascular HTN, CKD/ESRD, microaneurysm rupture	Yes (Cr > 140, proteinuria > 1 g)	Major ^[3]
GI	Mesenteric ischaemia, bowel infarction/perforation, GI bleed, pancreatitis	Yes	Major ^[3]
Cardiac	MI, ischaemic cardiomyopathy, HF, coronary aneurysm	Yes (cardiomyopathy)	Major ^[3]
Neurological	Mononeuritis multiplex, stroke, seizures	Yes (CNS involvement)	Major (cerebral infarction) ^[3]
Skin	Digital gangrene, non-healing ulcers, secondary infection	No	Morbidity mainly
Ophthalmic	PUK, scleritis, retinal vasculitis	No	Sight-threatening
Genitourinary	Testicular infarction, infertility	No	Morbidity mainly
Treatment-related	Infections, osteoporosis/AVN, bladder cancer, infertility, DM, CVD	N/A	Increasingly important cause of late mortality

High Yield Summary — Complications of PAN

Disease-related complications arise from two fundamental processes:

Vessel wall weakening → microaneurysm → rupture → haemorrhage (renal, mesenteric, cerebral)
Luminal thrombosis → downstream ischaemia → organ infarction (kidney, bowel, heart, brain, nerves, testes)

Major sources of mortality: renal failure, mesenteric/cardiac/cerebral infarction ^[3]

Five-Factor Score complications (the ones that predict death): proteinuria > 1 g, renal insufficiency, cardiomyopathy, GI involvement, CNS involvement.

Key organ complications:

Renal: infarction, renovascular HTN (RAAS), CKD/ESRD, aneurysm rupture
GI: bowel infarction/perforation (surgical emergency), GI bleed, pancreatitis
Cardiac: MI ^[2], ischaemic cardiomyopathy, HF
Neuro: mononeuritis multiplex (up to 70%), stroke (5–10%)
Eye: PUK → corneal perforation ^[9], scleritis
Skin: digital gangrene, non-healing ulcers

Treatment complications (GC + CYC): opportunistic infections (PJP), osteoporosis, AVN, haemorrhagic cystitis, bladder cancer, gonadal failure, steroid-induced DM, accelerated atherosclerosis.

Relapse rate: 9.2% at 1 year, 24% at 5 years ^[3] — lower than ANCA-vasculitis but requires long-term monitoring.

Prognosis: 13% 5-year survival untreated → 80% treated ^[3]

Active Recall - Complications of PAN

References

High Yield Summary

Definition: Necrotizing vasculitis of medium/small arteries; NO GN, NO capillary/venular involvement, ANCA-negative.

Epidemiology: Rare (incidence 4.4–9.7/million/year); peak 6th decade; M > F (1.5:1); declining due to HBV vaccination.

Key Etiology: Idiopathic (majority) or HBV-associated (~50% historically); also HCV, streptococcal, IBD, hairy cell leukaemia.

Pathophysiology: Immune complex deposition (in HBV-PAN) or cell-mediated → transmural fibrinoid necrosis → microaneurysms + luminal thrombosis → organ ischaemia/infarction.

Anatomy: Targets medium muscular arteries (arcuate, interlobar, mesenteric, coronary, vasa nervorum, testicular, dermal).

Clinical Features (Think: SKIN-GUT-KIDNEY-NERVE-TESTIS):

Systemic: Fever, weight loss, malaise
Skin: Tender subcutaneous nodules, livedo reticularis, digital ulcers/gangrene
Neuro: Mononeuritis multiplex (up to 70%); CNS (5–10%)
Renal: Hypertension (renovascular), renal insufficiency, infarction — NOT GN
GI: Mesenteric ischaemia, bowel infarction, GI bleeding
Cardiac: MI, cardiomyopathy, HF
Testis: Orchitis (relatively specific)
Lungs: Spared (no pulmonary haemorrhage)

PAN vs MPA: PAN = no GN, no lung, ANCA-negative, microaneurysms on angio, HBV; MPA = GN, lung haemorrhage, pANCA+, no microaneurysms.

High Yield Summary — Differential Diagnosis of PAN

GPA is distinguished by ENT involvement + c-ANCA + granulomas.

EGPA is distinguished by asthma + eosinophilia + p-ANCA.

HSP is distinguished by IgA deposition + pediatric age + self-limiting tetrad.

Non-vasculitic mimics include atheroembolism, APS, FMD, and diabetic vasculopathy.

Complement levels help narrow the differential: PAN has normal C3/C4.

Biopsy IF pattern: PAN does NOT cause GN → no IF pattern on renal biopsy. If RPGN with crescents → reclassify as MPA/GPA/anti-GBM/IC-mediated.

High Yield Summary — Diagnosis of PAN

ACR 1990 criteria: ≥ 3 of 10 criteria (weight loss, livedo, testicular pain, myalgias, neuropathy, diastolic HTN, ↑BUN/Cr, HBV, angiographic abnormality, biopsy showing PMN in artery wall)
CHCC 2012 definition: Necrotizing arteritis of medium/small arteries, NO GN, NO capillary/venular vasculitis, NOT ANCA-associated
Key investigations:
- ANCA negative (to exclude MPA/GPA/EGPA) ^[4]^[6]
- HBsAg positive in ~50% ^[4]
- Normal complement ^[14]^[15]
- Angiography: microaneurysms of visceral arteries ^[4]
- Biopsy: necrotizing medium-vessel arteritis with fibrinoid necrosis ^[2]^[3]
- Urinalysis: subnephrotic proteinuria, NO RBC casts (no GN) ^[3]
- CXR normal (lungs spared) ^[4]
Diagnosis = clinical suspicion + exclusion of other vasculitides + histology or angiography confirmation

High Yield Summary — Management of PAN

Severity guides treatment: FFS = 0 → GC ± AZA/MTX; FFS ≥ 1 → GC + CYC
Induction: steroids + steroid-sparing agents: CYC (severe) vs MTX/AZA (non-severe) ^[2]
Maintenance: non-GC non-CYC immunosuppressant × 18 months, taper GC ^[2]
IV pulse steroid for severe/refractory disease ^[3]
HBV-PAN is fundamentally different: antivirals (entecavir/tenofovir) are the mainstay; GC used only briefly; CYC generally AVOIDED; plasma exchange for severe disease
ACEI/ARB for HTN ^[3] (renovascular hypertension)
Prognosis: 13% 5-year survival untreated → 80% treated ^[3]
Major mortality: renal failure, mesenteric/cardiac/cerebral infarction ^[3]
Relapse: 9.2% at 1 year, 24% at 5 years — lower than ANCA-vasculitis ^[3]
Always co-prescribe: PPI, bone protection, infection prophylaxis, and monitor CBC/RFT/LFT regularly

High Yield Summary — Complications of PAN

Disease-related complications arise from two fundamental processes:

Vessel wall weakening → microaneurysm → rupture → haemorrhage (renal, mesenteric, cerebral)
Luminal thrombosis → downstream ischaemia → organ infarction (kidney, bowel, heart, brain, nerves, testes)

Major sources of mortality: renal failure, mesenteric/cardiac/cerebral infarction ^[3]

Five-Factor Score complications (the ones that predict death): proteinuria > 1 g, renal insufficiency, cardiomyopathy, GI involvement, CNS involvement.

Key organ complications:

Renal: infarction, renovascular HTN (RAAS), CKD/ESRD, aneurysm rupture
GI: bowel infarction/perforation (surgical emergency), GI bleed, pancreatitis
Cardiac: MI ^[2], ischaemic cardiomyopathy, HF
Neuro: mononeuritis multiplex (up to 70%), stroke (5–10%)
Eye: PUK → corneal perforation ^[9], scleritis
Skin: digital gangrene, non-healing ulcers

Treatment complications (GC + CYC): opportunistic infections (PJP), osteoporosis, AVN, haemorrhagic cystitis, bladder cancer, gonadal failure, steroid-induced DM, accelerated atherosclerosis.

Relapse rate: 9.2% at 1 year, 24% at 5 years ^[3] — lower than ANCA-vasculitis but requires long-term monitoring.

Prognosis: 13% 5-year survival untreated → 80% treated ^[3]

Polyarteritis Nodosa (PAN)

1. Definition

2. Epidemiology

Incidence and Prevalence

Age and Sex

Geographic/Ethnic Considerations (Hong Kong Relevance)

3. Risk Factors

4. Anatomy and Function of Affected Vessels

Which Vessels Are Affected?

Why Does This Matter Clinically?

Commonly Affected Vascular Beds

5. Etiology

5.1 Idiopathic PAN (Majority)

5.2 Secondary PAN

5.3 Drug-Associated

6. Pathophysiology

6.1 Overview of the Pathogenetic Cascade

HBV-Associated PAN (Immune Complex–Mediated)

Idiopathic PAN

6.2 Histopathological Stages

6.3 Connecting Pathophysiology to Clinical Features

7. Classification

7.1 Chapel Hill Consensus Conference (CHCC) 2012 Classification

7.2 Clinical Subclassification

7.3 Severity Classification (for Treatment Decisions)

7.4 PAN vs. MPA — The Critical Distinction

7.5 ANCA Positivity Across Vasculitides

8. Clinical Features

8.1 Symptoms

A. Constitutional / Systemic Symptoms

B. Skin Symptoms (~50% of patients)

C. Neurological Symptoms (~60–70%)

D. Renal Symptoms (Most Common Organ Involvement)

E. Gastrointestinal Symptoms (~50%)

F. Cardiac Symptoms

G. Genitourinary Symptoms

H. Musculoskeletal Symptoms

8.2 Signs

A. General Examination

B. Skin Signs

C. Neurological Signs

D. Abdominal Signs

E. Cardiovascular Signs

F. Testicular Signs

G. Ophthalmological Signs

H. Renal Signs

8.3 Summary Table: Organ Involvement and Frequency

8.4 Distinguishing Features Table (From Senior Notes)

8.5 Red Flag Features (Suggesting Severe/Life-Threatening Disease)

9. Pulmonary Eosinophilia Connection

10. PAN as a Cause of Systemic Disease in Other Contexts

Active Recall - Polyarteritis Nodosa (PAN)

References

1. Approach to Differential Diagnosis — The Thinking Framework

2. Differential Diagnosis by Category

2.1 Other Systemic Vasculitides (Primary Differentials)

A. Microscopic Polyangiitis (MPA) — The Most Important Differential

B. Granulomatosis with Polyangiitis (GPA, formerly Wegener's)

C. Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss)

D. IgA Vasculitis (Henoch-Schönlein Purpura, HSP)

E. Kawasaki Disease (KD)

F. Large-Vessel Vasculitis (Giant Cell Arteritis / Takayasu Arteritis)

G. Behçet's Syndrome

H. Cryoglobulinaemic Vasculitis

2.2 Non-Vasculitic Mimics (Organized by Dominant Presentation)

A. When PAN Presents as Mononeuritis Multiplex

B. When PAN Presents as Livedo Reticularis ± Skin Nodules

C. When PAN Presents as Renal Impairment + Hypertension

D. When PAN Presents as Mesenteric Ischaemia / Acute Abdomen

E. When PAN Presents as Testicular Pain

F. When PAN Presents as CNS Symptoms

3. Diagnostic Algorithm for Narrowing the Differential

4. Key Distinguishing Features Summary Table

5. Narrowing DDx by Biopsy Immunofluorescence Pattern (Renal Context)

6. Special Considerations by Presentation Context

6.1 PAN in the Context of Purpura

6.2 PAN in the Context of Panniculitis

Active Recall - Differential Diagnosis of PAN

1. Diagnostic Criteria

1.1 The 1990 ACR Classification Criteria for PAN