Rheumatology & Internal Medicine & Infectious Diseases
Periarteritis nodosa (PAN)
Periarteritis nodosa (PAN) - the historic term coined by Kussmaul and Maier in 1866, when this entity was first described - is a focal, segmental systemic necrotizing vasculitis affecting medium-caliber and small muscular arteries, with no involvement of capillaries, venules or arterioles (which fundamentally distinguishes it from ANCA-associated small-vessel vasculitides such as microscopic polyangiitis or granulomatosis with polyangiitis). Histologically, it is characterized by necrotizing transmural inflammation (fibrinoid necrosis) of the arterial wall, with infiltration of neutrophils and then mononuclear cells, leading to destruction of the elastic laminae, luminal thrombosis and ischemia of the organs irrigated by the affected arteries - mainly the kidneys, peripheral nerves, muscles, skin, digestive tract, heart and testes, but sparing the lungs (absence of parenchymal lung involvement = major differential criterion with ANCA vasculitides). Angiography reveals multiple arterial aneurysms (string-like microaneurysms along the renal and mesenteric branches) pathognomonic of the disease, reflecting areas of parietal fragility and dilatation secondary to media necrosis. PAN is a rare disease - incidence estimated at 2 to 9 cases per million inhabitants per year - with a peak between the ages of 40 and 60 and a preponderance of males (ratio 2:1). Its association with chronic hepatitis B, well-documented in early studies (30-50 % of PANs in the 1970s-1980s), has declined considerably since the widespread introduction of hepatitis B vaccination and now accounts for less than 10 % of cases in Western countries - but remains an important cause in regions where hepatitis B prevalence is high, and radically modifies the therapeutic approach (antivirals as first-line treatment rather than corticosteroids alone). ANCA is always negative in genuine PAN - if it is positive, the diagnosis should be reconsidered in favor of ANCA vasculitis (PAM or GPA).
Pathophysiology and association with hepatitis B
- Idiopathic PAN (not associated with hepatitis B — 90% % currently): Immune mechanism not fully elucidated + circulating immune complex deposits in the medium-sized arterial wall → complement activation → neutrophil recruitment → necrotizing transmural inflammation + no specific autoantibodies identified (ANCA negative ++) + possible genetic susceptibility (HLA-DR4 + HLA-DQ8) + in some cases: triggered by an infection (streptococcus + CMV + parvovirus B19 + HIV) or a drug
- Hepatitis B virus-associated pancreatitis (HBV-PAN): Mechanism: Circulating immune complex deposits containing HBs antigen + anti-HBs antibodies + complement in the vascular wall → necrotizing inflammation + mediated by active HBV replication (high HBV DNA + HBeAg positive + high transaminases) → viral load is a determinant of severity + specific treatment: antivirals active against HBV (tenofovir disoproxil + entecavir) + short course of initial corticosteroids (to control inflammation) + plasma exchange (to remove immune complexes) + DO NOT maintain corticosteroids long-term (risk of worsening viral replication)
- Other causal associations: HCV (rare - HCV-related cryoglobulinemic vasculitis type II can mimic PAN but involves small vessels and cryoglobulins) + HIV + CMV + parvovirus B19 + medications (minocycline + propylthiouracil + levamisole + cocaine cut with levamisole)
Clinical manifestations
| Organ or system | Clinical manifestations | Frequency and mechanism |
|---|---|---|
| General signs (prodrome) | Prolonged fever + significant weight loss (5–10 kg) + profound asthenia + diffuse myalgia + arthralgia + night sweats + the prodrome can precede organ damage by several weeks to months | 80–100 % of PAN + intense biological inflammatory syndrome (very high ESR + CRP) + hyperleukocytosis + reactive thrombocytosis + inflammatory anemia |
| Peripheral nervous system | Mononeuritis multiplex (asymmetrical involvement of several peripheral nerves in different areas) → foot drop (peroneal nerve) + sensory deficit in a stocking or glove distribution + neuropathic pain + mononeuritis multiplex is the most characteristic clinical sign of PAN + occurs stepwise (one nerve after another) | 50–75% % of PAN + most suggestive sign + EMG: asymmetric axonal neuropathy + sural nerve or muscle biopsy may show vasculitis of the vasa nervorum |
| Rein | Renovascular hypertension (refractory hypertension due to renal ischemia from vasculitis of medium-sized renal arteries) + renal infarction (flank pain + hematuria + elevated creatinine) + renal artery branch microaneurysms on arteriography + NO glomerulonephritis (no glomerular capillary involvement - unlike HSP) | 50-70% % of PAN + often severe HTN + renal failure due to ischemia (not glomerulonephritis) + urinary sediment usually slightly abnormal (no red blood cell casts) + fundamental distinction from MPA (RPGN + red blood cell casts) |
| Digestive tract | Mesenteric angina (postprandial abdominal pain due to mesenteric ischemia) + intestinal infarction (surgical emergency) + gastrointestinal bleeding + intestinal perforation + ischemic cholecystitis + ischemic pancreatitis | 30–50 % des PAN + l'ischémie mésentérique peut conduire à une perforation ou une nécrose intestinale nécessitant une intervention chirurgicale urgente + complication la plus mortelle à court terme |
| Cutaneous | Livedo reticularis (bluish, net-like pattern on the skin of the lower limbs) + painful subcutaneous nodules along the course of the arteries (hence the name «nodular») + skin ulcers + distal gangrene of the fingers or toes + necrotic purpura | 20–40 % of the PAN + palpable arterial subcutaneous nodules give the disease its name + skin biopsy of the nodules → necrotizing vasculitis of medium-sized arteries |
| Testicle | Ischemic orchitis (acute testicular pain + swelling) + simulating testicular torsion or epididymitis + highly characteristic of PAN + to be considered in cases of unexplained bilateral or recurrent orchitis in middle-aged adults | 10–20 % of PAN + often revealing + very specific sign of PAN among systemic vasculitides + scrotal Doppler ultrasound: focal ischemia |
| Heart | Myocardial ischemia (myocardial infarction due to vasculitis of medium-sized coronary arteries) + congestive heart failure + pericarditis + ischemic cardiomyopathy | 10-30 % of PAN + can be revealing + normal coronary angiogram (no atherosclerosis) + coronary angiography → coronary aneurysms |
Diagnosis
- ANCA — negative in authentic PAN: ANCA positivity (anti-MPO or anti-PR3) should prompt reconsideration of the diagnosis towards microscopic polyangiitis (MPA) or GPA. Additionally, ANCA negativity is a classification criterion for PAN according to the 2022 ACR/EULAR guidelines.
- Non-specific inflammatory biology Extremely high VS + CRP + leukocytosis + reactive thrombocytosis + normocytic inflammatory anemia + possible microscopic hematuria (kidney infarction) but no red blood cell casts (no glomerulonephritis) + normal or slightly reduced complement (unlike immune complex vasculitis - SLE + Hep B PAN where C3 and C4 can be low)
- Tissue biopsy — histological confirmation: biopsy of clinically affected area = gold standard diagnostic method + neuromuscular biopsy (sural nerve + peroneus brevis muscle) if peripheral neuropathy + skin biopsy of nodules + testicular biopsy if orchitis + histology: segmental and focal necrotizing vasculitis of medium-sized arteries + fibrinoid necrosis of the media + transmural inflammatory infiltrate + aneurysms + thromboses
- Visceral arteriography or CT angiography - alternative if biopsy is impossible: Conventional angiography or CT angiography + MR angiography + visualizes multiple microaneurysms and beaded stenoses of the renal + mesenteric + hepatic artery branches → beaded appearance of microaneurysms = nearly pathognomonic appearance of PAN + indicated if biopsy is non-contributory or impossible.
- HBV serology - mandatory in any P.A.N. workup: HBsAg + Anti-HBs + Anti-HBc (IgM + IgG) + Quantitative HBV DNA (viral load) + transaminases + if HBV positive → radically different therapeutic strategy (antivirals first)
ℹ️
PAN is one of the few systemic vasculitides that does NOT affect the lungs (no pulmonary capillaritis + no alveolar hemorrhage + no pulmonary granulomas) and is NOT associated with ANCA. These two characteristics allow it to be distinguished clinically and biologically from microscopic polyangiitis (MPA — ANCA positive + RPGN + possible pulmonary capillaritis) and granulomatosis with polyangiitis (GPA — anti-PR3 ANCA positive + destructive ENT involvement + granulomas).
Treatment
- Idiopathic Psoriatic Arthritis (Hepatitis B negative) — immunosuppressive treatment: prednisone 1 mg/kg/day orally × 4–6 weeks then gradual tapering over 12–18 months + methylprednisolone IV 500 mg–1 g/day × 3 days if severe involvement (visceral + severe neurological) + cyclophosphamide IV (monthly infusions) if severe visceral involvement (renal + mesenteric + cardiac infarction) + severe neuropathy + or corticosteroid resistance → remission rate 80–90 % + relapse risk 10–20 % at 5 years
- Hepatitis B virus-associated pancreatitis (HBV-PAN) — antiviral treatment: radically different strategy + tenofovir disoproxil (Viread® 300 mg/day) or entecavir (Baraclude® 0.5 mg/day) → potent antivirals against HBV + short initial course of corticosteroids (prednisone 1 mg/kg × 2–4 weeks then rapid tapering) to control acute inflammation + plasma exchange (3 sessions/week × 3 weeks) to eliminate immune complexes + DO NOT maintain corticosteroids long-term (promote HBV replication → worsening of hepatitis) + the goal is HBe seroconversion (disappearance of HBeAg → appearance of anti-HBe Ab) under antiviral treatment → durable remission of vasculitis + excellent results (90% survival % at 5 years) compared to immunosuppressive treatments alone
- Five Factor Score (FFS) — guides therapeutic decision-making: proteinuria > 1 g/24 h + creatinine > 140 µmol/L + cardiomyopathy + severe gastrointestinal involvement + CNS involvement → each factor = 1 point + FSS = 0: corticosteroids alone + FSS ≥ 1: corticosteroids + cyclophosphamide
- Pure cutaneous PAN (limited form): Limited to skin and peripheral nerves without severe visceral involvement → favorable prognosis + less intensive treatment: colchicine + NSAIDs + dapsone + or moderate-dose prednisone + generally without cyclophosphamide + close monitoring to detect visceral extension
Urgent rheumatological and medical consultation
Consult a rheumatologist or internal medicine specialist urgently for unexplained prolonged fever + weight loss + mononeuritis multiplex (foot drop + asymmetrical sensory deficit) + postprandial abdominal pain + rapidly developing refractory hypertension + or ischemic orchitis in a middle-aged man. This presentation strongly suggests polyarteritis nodosa, requiring urgent workup (HBV serology + ANCA + angio-CT scan + neuromuscular biopsy) and rapid initiation of treatment to prevent irreversible visceral ischemic complications (renal infarct + mesenteric infarct + intestinal necrosis).
For the initial assessment of suspected vasculitis (ANCA+, HBV serology, inflammatory markers, angio-CT scan) and urgent rheumatological referral, Clinique Omicron offers medical consultations at its service points in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron's physician associates and nurse practitioners (NPs) prescribe the initial workup for suspected systemic vasculitis (ANCA+, viral serologies, inflammatory markers, renal function tests, and EMG), refer urgently to rheumatology or internal medicine for confirmed or highly suspected systemic vasculitis, and manage patients in remission on immunosuppressive therapy—monitoring for adverse effects, infection prevention, blood pressure control, and renal follow-up. Consultations are available at several service locations in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content of this page is provided for informational purposes only and does not substitute for medical or rheumatological advice. Polyarteritis nodosa (PAN) is a rare and serious disease requiring urgent specialized care. The treatment of PAN associated with hepatitis B is radically different from idiopathic PAN and requires the expertise of an infectious disease specialist or hepatologist in addition to a rheumatologist.
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