RheumatologyTier 2Disease (DEADMAN)

Vasculitis - polyarteritis nodosa

Description

Necrotising vasculitis of MEDIUM-sized muscular arteries
- *No glomerulonephritis, no pulmonary capillaritis, ANCA-negative* - the three facts that separate it from AAV
Segmental, at branch points -> aneurysm formation alternating with stenosis
Lesions of different ages coexist in the same patient - the histological hallmark

Subtypes

Idiopathic (classic) PAN
Hepatitis B-associated - now uncommon where vaccination is widespread
Cutaneous PAN - limited to skin and subcutis; benign course, rarely systemic
Monogenic: DADA2 (adenosine deaminase 2 deficiency) - childhood-onset PAN-like disease with early strokes; test in young or familial cases

PAN vs ANCA-associated vasculitis

	PAN	AAV
Vessel	Medium muscular arteries	Small vessels (capillaries, venules)
Kidney	Renal infarcts, microaneurysms, renovascular hypertension	Glomerulonephritis
Lung	Spared	Capillaritis, haemorrhage, nodules
ANCA	Negative	Positive in 70-90%
Urine	Haematuria without red cell casts	Dysmorphic RBC and red cell casts

Rare - ~2-9/million/yr and falling (hepatitis B vaccination)
Peak age 40-60; M slightly > F
Hepatitis B accounts for ~1/3 of cases historically, now <10% in vaccinated populations

Immune complex deposition in the vessel wall (best demonstrated in HBV-associated disease) -> complement activation -> fibrinoid necrosis of the media and intima
-> aneurysm where the wall is destroyed, stenosis and thrombosis where intimal proliferation dominates
-> downstream infarction - the clinical picture is ischaemic, not inflammatory-exudative
No granulomas, no eosinophils, no immune deposits in glomeruli (there is no glomerulonephritis)

Associations and triggers

Hepatitis B (~1/3 historically) - typically within 6 months of acute infection
Hepatitis C, HIV, parvovirus B19
Hairy cell leukaemia
DADA2 - loss-of-function ADA2 mutations

Clinical features

Constitutional ~80% - fever, malaise, weight loss, myalgia
Neurological: mononeuritis multiplex in ~70% - often the presenting feature; asymmetric, painful, motor and sensory (foot drop, wrist drop)
Renal - the most commonly affected organ
- Renal infarcts, renal artery microaneurysms
- Hypertension from renin-angiotensin activation (may be severe/malignant)
- Haematuria and proteinuria WITHOUT red cell casts - there is no glomerulonephritis
Gastrointestinal - mesenteric arteritis
- Postprandial abdominal pain ("abdominal angina"), bowel infarction, perforation, haemorrhage
- A major cause of death
Skin: palpable purpura, livedo reticularis, subcutaneous nodules along arteries, digital gangrene, ulceration
Musculoskeletal: arthralgia, myalgia, non-erosive arthritis
Orchitis ~10% - testicular pain is a distinctive and highly suggestive symptom
Cardiac: coronary arteritis, MI, cardiomyopathy
*Lungs are spared* - pulmonary involvement should make you rethink the diagnosis

Investigations

inc ESR/CRP, normocytic anaemia, leucocytosis, thrombocytosis
ANCA NEGATIVE; complement normal; RF and ANA usually negative
Hepatitis B (HBsAg, HBV DNA), hepatitis C, HIV - mandatory, because it changes treatment entirely
Creatinine, urinalysis (haematuria/proteinuria without casts)
CK, nerve conduction studies (asymmetric axonal sensorimotor neuropathy)
Genetic testing for DADA2 in young or familial cases

Confirming the diagnosis - two routes

A. Biopsy of an involved vessel
- Skin (deep wedge including subcutis - a punch biopsy misses medium vessels), sural nerve, muscle, testis
- Histology: transmural necrotising inflammation, fibrinoid necrosis, luminal narrowing, aneurysm, thrombosis, lesions of different ages
- Do not biopsy the kidney - the risk of bleeding into an aneurysm is high and there is no glomerular lesion to find
B. Angiography (conventional, CT or MR) - often diagnostic
- Multiple saccular microaneurysms with irregular constrictions of larger vessels, occlusion of small penetrating arteries
- Renal, mesenteric and hepatic arteries
- Wedge-shaped areas of ischaemia/infarction

Differential for microaneurysms

PAN, fibromuscular dysplasia, segmental arterial mediolysis, infective (mycotic) aneurysm, Ehlers-Danlos type IV, amphetamine/cocaine vasculopathy

Axis: first determine whether there is a virus. Then stratify by severity using the Five Factor Score.

A. Hepatitis B-associated PAN - a different disease to treat

Antiviral therapy is the cornerstone - entecavir or tenofovir
Short course of corticosteroid only (to control the acute vasculitis), then rapid withdrawal
Plasma exchange to clear immune complexes
*Prolonged immunosuppression is harmful - it promotes viral replication*

B. Idiopathic PAN - stratify by Five Factor Score (FFS)

FFS items: age >65, cardiac insufficiency, renal insufficiency (creatinine >150 micromol/L), GI involvement, absence of ENT symptoms

FFS = 0 (mild): glucocorticoid alone, with an immunosuppressant added if relapse or failure to control
FFS >=1 (severe): glucocorticoid + cyclophosphamide for induction
- Pulse methylprednisolone for organ- or life-threatening disease

C. Maintenance

Switch to azathioprine or methotrexate after 3-6 months of cyclophosphamide
Total treatment duration typically ~18 months
PAN, unlike AAV, is usually monophasic - long-term maintenance is generally not required and relapse rates are low

D. Refractory disease

Rituximab, TNF inhibitors, IVIG - limited evidence
DADA2: TNF inhibitors are the treatment of choice (prevent stroke; steroids and other immunosuppressants do not)

E. Supportive

Aggressive blood pressure control - ACE inhibitors/ARBs for renin-driven hypertension
Surgical review for GI ischaemia, perforation or bleeding - a surgical emergency, and a common cause of death
Bone protection, PJP prophylaxis, fertility preservation before cyclophosphamide, bladder protection (mesna)
Neuropathic pain management and rehabilitation for mononeuritis multiplex

Hepatitis B (~1/3 of cases historically)
Hepatitis C, HIV, parvovirus B19, cytomegalovirus
Hairy cell leukaemia - a recognised paraneoplastic association
DADA2 (ADA2 deficiency) - childhood PAN with lacunar strokes, livedo, immunodeficiency, cytopenias
Minocycline-induced PAN-like vasculitis
Familial Mediterranean fever (PAN-like vasculitis)
Renovascular hypertension; mesenteric ischaemia

Untreated 5-yr survival ~13%; with treatment ~80%
Usually monophasic - relapse in only ~10-20% (far lower than ANCA-associated vasculitis)
- Relapse is more common in HBV-negative idiopathic disease
Cutaneous PAN has an excellent prognosis and rarely becomes systemic

Poor prognostic factors (the Five Factor Score)

Causes of death

Complications

Permanent neurological deficit from mononeuritis multiplex - often the most disabling long-term sequela
Chronic kidney disease and refractory hypertension
Bowel resection and short bowel
Digital gangrene and amputation
Cyclophosphamide toxicity: infertility, haemorrhagic cystitis, bladder cancer, MDS

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