Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that primarily affects medium-sized arteries. It causes inflammation in all layers of the arterial wall and perivascular inflammatory cell infiltration, leading to fibrinoid necrosis.
The incidence is 0.7 per 100,000 person-years in biopsy-confirmed cases, and the prevalence is 6.3 per 100,000, making it a rare disease. A report from a multi-ethnic population in France found a prevalence of 33 per million and an incidence of 0 to 1.6 per year 1). It typically occurs between 40 and 60 years of age, with a slight male predominance (male-to-female ratio 1.5:1) 1).
Among systemic symptoms, neurological symptoms are frequent, occurring in 79% of 348 cases in Pagnoux 2010 1). Ocular involvement occurs in 9–20% of cases, presenting various neuro-ophthalmic signs such as choroidal vasculitis, retinal vascular occlusion, ischemic optic neuropathy, and cranial nerve palsy. One characteristic of this disease is that lung involvement is generally absent.
There is an association with hepatitis B virus (HBV); currently, HBV-related PAN accounts for 7–10% of all cases. Before the widespread use of the HBV vaccine, it accounted for 36%, but this decreased after vaccination became common.
Ocular involvement occurs in 10–20% of patients. Choroidal vasculitis is the most common ocular finding, and multifocal acute ischemia of the choriocapillaris strongly suggests vasculitis. The frequency of involvement is even higher when neuro-ophthalmic findings (e.g., cranial nerve palsy, homonymous hemianopia) are included.
Constitutional symptoms often precede the initial presentation.
Ocular symptoms are as follows.
Acute visual loss can occur due to ischemic optic neuropathy (anterior ischemic optic neuropathy/posterior ischemic optic neuropathy) or central retinal artery occlusion (CRAO). In CNS vasculitis, homonymous hemianopia may also occur. Such acute visual impairment requires emergency management.
Ocular manifestations are diverse and are classified into anterior segment, posterior segment, and neuro-ophthalmic findings.
Anterior Segment Lesions
Conjunctival hyperemia and edema: Due to spread of inflammation. May be accompanied by subconjunctival hemorrhage.
Keratoconjunctivitis sicca: Dryness symptoms due to ischemia of the lacrimal gland and conjunctiva.
Peripheral ulcerative keratitis (PUK): Necrotizing ulcer at the corneoscleral junction. May lead to perforation.
Necrotizing scleritis: In severe cases, there is a risk of ocular perforation.
Iridocyclitis: Rarely observed.
Posterior segment and neuro-ophthalmic findings
Choroidal vasculitis: The most common ocular finding. Causes multifocal acute ischemia of the choriocapillaris.
Retinal vasculitis: Presents with retinal hemorrhage, edema, exudates, and vascular caliber changes.
Retinal artery occlusion: BRAO/CRAO leads to sudden vision loss.
Hypertensive retinopathy: Cotton-wool spots and arteriovenous nicking due to hypertension associated with renal impairment.
Ischemic optic neuropathy: Optic disc edema, papillitis, and optic atrophy.
Cranial nerve palsy: Oculomotor nerve palsy may be the initial symptom of PAN. Horner syndrome and nystagmus can also occur.
Homonymous hemianopia: Visual field defects corresponding to the site of CNS vasculitis.
The main prevalence rates in systemic organs are shown below.
| Organ | Main symptoms | Prevalence (%) |
|---|---|---|
| Peripheral nerves | Mononeuritis multiplex | 50–70 |
| Kidneys | Proteinuria, hypertension, renal failure | 70 |
| Skin | Purpura, ulcers, livedo reticularis, gangrene | 50 |
| Muscles | Myalgia | 50–60 |
| Gastrointestinal tract | Abdominal pain, gastrointestinal bleeding | 30–35 |
| Joints | Arthritis | 20 |
| Genitals | Testicular infarction | 20 |
The pathophysiology of PAN is not fully understood. Genetic predisposition triggered by environmental stimuli is suspected.
The basic pathology involves immune complex deposition in the walls of medium-sized arteries, leading to necrosis. Fibrinoid necrosis occurs in small and medium-sized arteries.
The main risk factors and related factors are as follows.
There is no single test to confirm PAN. Diagnosis is made by combining clinical findings, laboratory tests, imaging, and pathology.
According to the criteria of the Ministry of Health and Welfare Research Group on Intractable Vasculitis (1998), a definite case is defined as having at least 2 of the following 10 major symptoms, along with angiographic findings or pathological findings of vasculitis.
Even without angiographic or pathological findings, if 6 or more items including (1) are met, it is considered a suspected case.
Classified by meeting 3 or more of the following 10 items1).
Weight loss >4 kg, livedo reticularis, testicular pain, diffuse myalgia, mononeuritis multiplex/polyneuropathy, diastolic blood pressure >90 mmHg, renal failure, HBV positivity, angiographic abnormality (aneurysm/occlusion), neutrophil infiltration in arterial wall on biopsy.
There is no single test that confirms PAN. Nonspecific inflammatory findings such as elevated ESR and CRP are observed, while ANCA and cryoglobulins are usually negative, which can be a clue. Confirmation of HBV, HCV, and HIV serology is also essential. Definitive diagnosis requires angiography or tissue biopsy.
PAN is a life-threatening disease, and treatment should be initiated promptly in collaboration with a rheumatologist after diagnosis.
The basic treatment is a combination of steroid pulse therapy, oral steroids, and cyclophosphamide infusion.
Treatment selection by disease type is also important.
The following treatments are performed depending on the type of ocular lesion.
Attention should be paid to opportunistic infections such as CMV retinitis during immunosuppressive therapy, steroid-induced central serous chorioretinopathy, and neovascularization from retinal non-perfusion areas. Regular fundus examinations including fluorescein angiography are recommended.
The basic lesion of PAN is transmural inflammation of the walls of medium-sized arteries.
The inflammatory cascade is thought to progress as follows.
In HBV-associated PAN, immune complex deposition and complement consumption are the main mechanisms of arteritis.
Weakening of CNS arteries leads to aneurysm formation, which can rupture and cause hemorrhagic infarction. Chronic inflammation leads to stenosis and thrombosis, causing ischemic lesions. In the eye, impaired blood flow to the choroid, retina, and optic nerve produces various ocular findings.
In DADA2 (CECR1 mutation), ADA2 deficiency is thought to cause overactivation of M1 macrophages, promoting inflammation and destruction of the vessel wall.
In a report by Boistault et al. (2021), a refractory pediatric PAN case showed markedly elevated IL-6 at 106.43 pg/mL (normal 0–4.3 pg/mL)2). The high IL-6 group was predominantly male and showed significantly more joint pain and skin ulcers.
The application of tocilizumab (TCZ), an IL-6 receptor inhibitor, to refractory PAN has been reported.
Boistault et al. (2021) summarized 11 cases of refractory PAN (median age 35 years, IQR 23.5–57.5 years, 5 female) treated with TCZ2). The dose was TCZ 8 mg/kg intravenously every 2–4 weeks or TCZ 162 mg subcutaneously weekly, and remission was achieved in most cases.
In one case of childhood PAN, a 4-year-old girl refractory to high-dose steroids plus cyclophosphamide was started on TCZ 8 mg/kg every 2 weeks, resulting in clinical and biological improvement within days, and complete remission was maintained at 21 months2). The rationale for choosing TCZ was that IL-6 levels were relatively higher than TNF-α.
Four cases of PAN onset after COVID-19 mRNA vaccination have been reported.
Ohkubo et al. (2022) summarized cases of PAN onset within 7–28 days after vaccination5). Most cases occurred after the first dose, and all improved with steroids and immunosuppressants. The proposed mechanism involves an inflammatory reaction to lipid nanoparticle (LNP) injection, leading to neutrophil infiltration and inflammatory cytokine production.
A causal relationship has not been established, and the benefits of vaccination are considered to greatly outweigh the risks.
Yokota et al. (2022) reported the first case in the English literature where renal PAN developed after taking minocycline for more than 3 years, and functional and morphological remission was achieved by drug discontinuation alone 3). Repeat angiography after 7.5 years confirmed the disappearance of renal artery aneurysms, and the patient was managed without steroids or immunosuppressants.
In drug-induced PAN, discontinuation of the causative drug is the highest priority, and this finding is important as it shows the possibility of achieving remission without immunosuppressive therapy.
