Poliarteritis Nodosa

Polyarteritis nodosa
The right clinical information, right where it's needed
Last updated: Jan 05, 2018

Table of Contents
Summary 3
Basics 4
Definition 4
Epidemiology 4
Etiology 4
Pathophysiology 4
Classification 5
Prevention 8
Primary prevention 8
Screening 8
Diagnosis 9
Case history 9
Step-by-step diagnostic approach 9
Risk factors 13
History & examination factors 14
Diagnostic tests 16
Differential diagnosis 19
Diagnostic criteria 24
Treatment 27
Step-by-step treatment approach 27
Treatment details overview 29
Treatment options 30
Emerging 35
Follow up 36
Recommendations 36
Complications 36
Prognosis 38
Guidelines 40
Diagnostic guidelines 40
Treatment guidelines 40
Evidence scores 41
References 43
Images 52
Disclaimer 61
Summary
◊ Rare form of systemic vasculitis that affects only medium-sized vessels (i.e., small and medium-sized
arteries).
◊ Hepatitis B virus (HBV)-related PAN has become very rare since the introduction of effective
immunization programs against the virus.
◊ Both non HBV-related PAN and HBV-related PAN are differentiated from the other small- and
medium-vessel vasculitides by the absence of antineutrophil cytoplasmic antibodies, and by
confirmation that small vessels (i.e., arterioles, capillaries, venules) are not involved.
◊ Angiography typically demonstrates microaneurysms and focal narrowing in medium-sized blood

vessels.
◊ Pathology is characterized by focal and segmental transmural necrotizing inflammation with fibrinoid
necrosis in medium-sized vessels.
◊ Treatment for non HBV-related PAN is based on immunosuppression with corticosteroids and
cyclophosphamide.
◊ Treatment for HBV-related PAN utilizes a short course of high-dose corticosteroids, followed by a
combination of antiviral therapy and plasma exchange.
◊ Prognosis can be determined by use of the 5-factor score.

Polyarteritis nodosa Basics
Definition
The term "periarteritis nodosa" was used in the 19th century to describe any form of systemic vasculitis
without a known cause.[1] Since then, the name has changed to polyarteritis nodosa (PAN) and the definition
BASICS
has been refined to: "Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis
or vasculitis in arterioles, capillaries, or venules." This definition was proposed at the Chapel Hill Consensus
Conference (CHCC) in 1992 and published in 1994.[2]
Epidemiology
Over time, PAN has become progressively less common, largely owing to effective hepatitis B virus (HBV)
immunization programs and improved blood screening for HBV, as well as to major alterations in the
definition and classification of vasculitis. Before the Chapel Hill Consensus Conference (CHCC) definition
in 1994, microscopic polyangiitis was included in the incidence and prevalence estimates. The impact of
this is highlighted in a study comparing the incidence of PAN in 3 European regions: 4.4-9.7 per million
by the American College of Rheumatology (ACR) criteria compared with 0-0.9 per million with the CHCC
definition.[10]
The incidence of PAN is between 2 and 9 per million/year in Europe and the US by the ACR criteria.[11]
Higher incidences have been reported in some populations: 16 per million/year in Kuwait (by CHCC
definition)[12] and 77 per million/year in an Alaskan population in which HBV infection is endemic (in a study
that predates the ACR criteria and the CHCC definition).[13] The prevalence of PAN by the ACR criteria is
between 31 and 33 per million in western Europe[14] [15] [16] and, by the CHCC definition, is between 2 and
9 per million in Germany.[17] There are no recent prevalence figures for the US.
PAN can occur at any age, but the most common age at diagnosis is 40 to 60 years. There is no clear sex
difference, although most case series report a slight preponderance of males.[15] [18] [19] However, a recent
prevalence estimate in Sweden has shown the opposite, with two-thirds of the patients being female.[16] In a
multiethnic population in Paris, those with European ancestry had a higher prevalence of PAN.[15]
Etiology
In 7% to 38.5% of patients diagnosed with PAN, hepatitis B virus (HBV) infection is implicated as the
underlying cause.[15] [20] [21] The prevalence of HBV-related PAN has reduced in recent years as a result
of vaccination for HBV and improved screening of blood products.[15] [22] This is exemplified by the situation
in France, where the proportion of HBV-related PAN fell from 38.5% in the 1970s to 17.4% by the period
1997-2002.[19]
In the remainder of patients, the etiology is unknown. Genetic, infectious, and environmental agents
are thought to be important, but there is no conclusive evidence.[10] That idiopathic PAN responds to
immunosuppressive therapy suggests an immunologic mechanism.
Pathophysiology
In HBV-related PAN, the postulated mechanisms of vasculitis include direct injury to the vessel by replicating
virus or by the deposition of immune complexes. Deposition of immune complexes leads to activation of the
complement cascade, which results in an inflammatory response and subsequent damage to the vessel wall.
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jan 05, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2018. All rights reserved.
The vasculitis typically occurs within the first few months after HBV infection and can be the first presenting
feature of the infection.
In idiopathic PAN, the role of immune complexes is unclear. There is evidence of endothelial dysfunction, an
BASICS
increase in inflammatory cytokines, and an increase in expression of adhesion molecules. The inflammatory
lesions tend to occur at the bifurcation of vessels, which could be the result of increased adhesion molecules
at these sites or could simply be due to hydrostatic forces.
Whatever the inciting event, the result is focal and segmental necrotizing inflammation of small and medium-
sized arteries. This leads to intimal proliferation at these sites of inflammation, with subsequent thrombosis.
The result is ischemia or infarction of the organ or tissue supplied by the affected arteries. Aneurysms
can occur at the site of active lesions, and this morphologic appearance is what led to the term "nodosa."
Commonly involved systems include the peripheral nerves, skin, musculoskeletal system, gastrointestinal
system, renal tract, heart, and genital tract.[23] [24]
Classification
The American College of Rheumatology (ACR) 1990 criteria for the
classification of polyarteritis nodosa[3]
These criteria are used to classify which patients with known primary systemic vasculitis have PAN. These
criteria do not differentiate between PAN and microscopic polyangiitis (MPA); both are included under the
umbrella of PAN. Three of the following 10 criteria are required:
• Weight loss ≥4 kg
• Livedo reticularis
• Testicular pain or tenderness
• Myalgias, weakness, or leg tenderness
• Mononeuropathy or polyneuropathy
• Diastolic blood pressure >90 mmHg
• Elevated BUN or creatinine
• Positivity for hepatitis B virus (HBV) infection
• Arteriographic abnormality
• Biopsy of small or medium-sized artery containing polymorphonuclear leukocytes.
The sensitivity of these criteria is 82.2% and the specificity 86.6% when used in this context.[3] This was
calculated from the cohort used to develop the criteria and has not been prospectively validated.
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jan 05, 2018.
5
BASICS Polyarteritis nodosa Basics
American College of Rheumatology 1990 criteria for PAN

Adapted by the authors from Lightfoot RW Jr, Michel BA, Bloch DA, et al. The American College of
Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum. 1990;33:1088-1093
European Medicines Agency (EMA) algorithm for the classification

of the ANCA-associated vasculitides and polyarteritis nodosa for
epidemiological studies[4]
This is an algorithm to apply the disease definitions and classification criteria for the antineutrophil
cytoplasmic antibodies (ANCA)-associated vasculitides and PAN in a stepwise manner. The algorithm
is useful because MPA is absent in the ACR classification criteria (which consider it to be part of PAN),
whereas in the Chapel Hill Consensus Conference (CHCC) definition PAN and MPA are treated as separate
entities and there is evidence that they behave differently in terms of pathogenesis, organ involvement,
tendency to relapse, and prognosis.[5] In the CHCC definition, PAN is strictly a medium-vessel disease,
whereas MPA is predominantly a small-vessel disease that includes glomerulonephritis and pulmonary
capillaritis.[2]
• Entry into the algorithm is by having a clinical diagnosis of an ANCA-associated vasculitis or PAN. In
the algorithm, PAN is a diagnosis of exclusion.
• The first step is to determine whether the patient fulfills the Lanham[6] or ACR criteria[7] for Churg-
Strauss syndrome (CSS). If so, the patient is classified as having CSS.
BASICS
• If not, the next step is to determine whether the patient fulfills the ACR criteria[8] or the CHCC
definition for granulomatosis with polyangiitis (Wegener) (GPA),[2] either by direct evidence with
histology or with appropriate surrogate markers and a positive ANCA. If the patient fulfills these
criteria, he or she is classified as having GPA.
• If not, see whether the patient fulfills a definition of MPA.[2] This is either by histology showing small-
vessel vasculitis or glomerulonephritis and no surrogate markers for WG or with surrogate markers of
glomerulonephritis and a positive ANCA.
• Only when CSS, GPA, and MPA have been excluded is a diagnosis of PAN possible.
To fulfill the definition of PAN there must be histology or angiographic features consistent with the diagnosis.
Any remaining patients are determined to be unclassifiable.
French Vasculitis Study Group (FVSG) proposal for diagnostic

criteria for polyarteritis nodosa[9]
The FVSG proposed a set of predictive items to be used as a paradigm for diagnostic criteria. The items
were derived from patients with known vasculitis and not from undifferentiated patients, and this proposal is,
therefore, another form of classification criterion.
In this cohort, 8 variables were useful in distinguishing PAN from other vasculitides. There were 3 positive
and 5 negative predictive items derived from a cohort of 949 patients with known vasculitis, 262 of whom had
a diagnosis of PAN.
The positive predictive items were:
• Positivity for HBV infection

• Arteriographic abnormalities
• Mononeuropathy or polyneuropathy.
The negative predictive items were:
• Presence of antineutrophil cytoplasmic antibodies (ANCA)

• Asthma
• Ear, nose, or throat signs
• Glomerulopathy
• Cryoglobulinemia.
7
Polyarteritis nodosa Prevention
Primary prevention
The incidence of hepatitis B virus (HBV)-related PAN parallels HBV infection rates. In Alaska, an area
endemic for HBV (primarily because of vertical transmission of HBV), there is an increased annual incidence
of HBV-related PAN, at 77 per million.[13] Documented exposure to HBV (from blood products, intravenous
drug use, or sexual contact) can be found in 60% of patients with HBV-related PAN.[20] Screening of blood
products for HBV and mass vaccination against the virus has successfully reduced the incidence of HBV
PAN, as shown in French patients with the proportion of PAN due to HBV falling from 38.5% in the 1970s to
17.4% by the period 1997-2002.[19]
Screening
Hepatitis B virus (HBV) screening
There are no specific screening recommendations for PAN. Screening for HBV as a method of detecting or
preventing PAN has no evidence base, and it is not known if early recognition of HBV will have any impact.
PREVENTION
However, HBV screening to prevent hepatitis, cirrhosis, and malignancy by serologic testing is recommended
for certain high-risk groups in the US: pregnant women, children born to hepatitis B surface antigen-positive
mothers, household and sexual contacts of HBV-positive people, health care workers, men who have sex
with men, those born in areas where the prevalence of HBV is >2%, and people infected with HIV.[51]
Polyarteritis nodosa Diagnosis
Case history
Case history #1
A 55-year-old man presents with tingling of the left hand and loss of sensation in both lower limbs.
He gives a 6-week history of a 5-kg weight loss and fevers. Exam shows mononeuritis multiplex
affecting both the common peroneal nerves and the left radial nerve. Investigation reveals a normocytic,
normochromic anemia (hemoglobin 9.3 g/dL), neutrophilia (WBC count 11,500/mm^3), an elevated
creatinine (2.48 mg/dL), and elevated inflammatory markers (ESR 89 mm/hour, CRP >160 mg/L) but
normal urinary sediment. Tests are negative for antineutrophil cytoplasmic antibodies (ANCA), with no
evidence of hepatitis B infection. His blood pressure is 193/103 mmHg. Sural nerve biopsy demonstrates
a transmural vascular inflammatory infiltrate with a mixture of macrophages, lymphocytes, and neutrophils
plus evidence of focal and segmental necrotizing vasculitis with fibrinoid necrosis. Multiple aneurysms are
seen on renal angiography.
[Fig-2]
[Fig-3]
Case history #2
A 44-year-old woman presents with a 3-month history of abdominal pain, fever, and weight loss.
The abdominal pain is cramping in nature and occurs 30 minutes after eating. Abdominal exam is
unremarkable. She has widespread purpuric lesions on her lower limbs. Blood tests reveal elevated
inflammatory markers (ESR 93 mm/hour, CRP >160 mg/L) and elevated aminotransferases (ALT 300 U/
L). ANCA is negative. Hepatitis B e-antigen and hepatitis B surface antigen are positive, with elevated
hepatitis B DNA. A liver ultrasound exam is normal. A full-thickness skin biopsy of the purpuric lesions
is reported as showing segmental necrotizing vasculitis of medium vessels with fibrinoid necrosis. A
mesenteric angiogram demonstrates multiple aneurysms involving the superior and inferior mesenteric
arteries.
DIAGNOSIS
[Fig-4]
Other presentations
Testicular pain due to ischemic orchitis is a classical feature of PAN but is rare at presentation. Some
patients may present with an acute surgical abdomen resulting from infarction of bowel, liver, spleen, or
pancreas. Myocardial infarction, ischemic cardiomyopathy, optic ischemia, and ischemic complications of
the female genital tract are possible but unusual.
Step-by-step diagnostic approach

Any form of suspected systemic vasculitis should be investigated urgently, because if left untreated these
diseases cause high morbidity and mortality. Diagnosis of PAN can be challenging because individual
features are not distinguishable from those of many other diseases. The combination of constitutional
symptoms and ischemic symptoms in 1 or more organ system should raise the possibility of a systemic
vasculitis.
9
Nonspecific systemic symptoms such as fever, weight loss, weakness, and myalgia are found in 65% to 80%
of patients at time of diagnosis.[16] [19] Organ-specific manifestations may be present at disease onset,
involving just 1 organ or several systems, or the disease may follow a more indolent course, with organ
involvement being recognized only months or years later.
Renal involvement in the systemic vasculitides carries a poor prognosis. Glomerulonephritis is not a feature
of PAN, but it is common in antineutrophil cytoplasmic antibodies (ANCA) vasculitis. Making this distinction
early by way of urinalysis for protein, blood, and casts is a simple first-line test that can guide further
investigation and treatment.
Possible organ-specific manifestations

The following body systems may be involved at disease onset in non HBV-related PAN:[16] [19]
• Nervous system (in 55% of patients)

• Skin (in 44%)
• Abdominal organs (in 33%)
• Kidneys (in 11%)
• Musculoskeletal system (in 24% to 80%).
Similar rates are found for organ involvement in hepatitis B virus (HBV)-related PAN.[19]
Nervous system involvement typically presents as mononeuritis multiplex, with sensory symptoms
preceding motor deficits.[29] Central nervous system involvement is a less frequent finding and can
present as encephalopathy, seizures, or stroke.[24] [30]
Skin manifestations include purpura, nodules, livedo reticularis, ulcers, bullous or vesicular eruptions, and
segmental skin edema.[19] [21] [31] [32]
In abdominal involvement, pain is an early feature of mesenteric artery disease. Progressive involvement
may cause bowel, liver, or spleen infarction; bowel perforation; or bleeding from a ruptured arterial
aneurysm.[33] Less common presentations include appendicitis, pancreatitis, or cholecystitis resulting
DIAGNOSIS
from ischemia or infarction of these organs.[34]
Vasculitis of the renal arteries is a common finding. It can present with renal impairment or renal
infarcts or with rupture of renal arterial aneurysms. Glomerular ischemia may result in mild proteinuria
or hematuria, but red cell casts are absent because glomerular inflammation is not a feature. If there
is evidence of glomerular inflammation such as urinary casts, then an alternative diagnosis such as
microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (Wegener) (GPA), must be considered.
Hypertension is a manifestation of renal ischemia via activation of the renin-angiotensin system.[35]
Musculoskeletal involvement may manifest itself by arthritis, arthralgia, myalgia, or muscle weakness.
When muscle is involved it provides a useful site for biopsy.[19] [23]
Other manifestations may involve almost any organ system. Cardiac ischemia, cardiomyopathy, breast or
uterine involvement, and ocular symptoms from either ischemic optic neuropathy or retinopathy have been
described.[19] [24] [36] Although testicular pain from ischemic orchitis is a characteristic feature, it is an
uncommon presentation.[19] [37]
[Fig-4]
[Fig-5]
[Fig-6]
[Fig-7]
[Fig-4]
Physical exam
In patients in whom vasculitis is suspected, a thorough physical exam is necessary to identify the organ
systems potentially involved. At a minimum, the exam should include:
• General - look for elevated temperature and weight loss (current and previous)
• Skin - look for purpura, ulcers, bullous or vesicular eruptions, areas of skin infarction, and livedo
reticularis
• Ocular - test for visual impairment and look for retinal hemorrhage and optic ischemia
• Neurologic - test for peripheral neuropathies, stroke, and confusion
• Abdominal - assess for abdominal tenderness or peritonitis, and perform a rectal exam for signs of
blood loss
• Cardiovascular - check peripheral pulses and blood pressure, and look for signs of congestive
cardiac failure, pericarditis, or valvular pathology
• Musculoskeletal - assess for synovitis, arthralgia, and muscle tenderness or weakness
• Genitourinary - assess for testicular tenderness
• ENT - look for nasal crusting and signs of sinusitis, and assess for hearing loss; the presence of
these features would suggest an alternative diagnosis such as WG rather than PAN
• Respiratory - lung involvement is not seen in PAN, and abnormal respiratory findings should
suggest an alternative diagnosis
• Blood pressure - a diastolic blood pressure of >90 mmHg can be suggestive of PAN.
[Fig-4]
[Fig-5]
[Fig-8]
DIAGNOSIS
[Fig-6]
[Fig-7]
Laboratory testing
There are no specific laboratory tests to diagnose PAN, but some tests can be useful to support the
diagnosis, identify organs that may be affected, and rule out alternative diagnoses.
Test results that help to support the diagnosis include:
• Elevated CRP and/or ESR, which suggests systemic inflammation

• Elevated fibrinogen, a marker of acute inflammation; fibrinogen levels may be low in catastrophic
antiphospholipid syndrome
• Elevated serum creatinine, typically without hematuria or proteinuria on urinalysis, which may
indicate renal ischemia or infarction; however, significant proteinuria or hematuria (especially red
cell casts) would suggest glomerular disease, which is not a feature of PAN
11
• Abnormal liver function tests, which may suggest hepatitis, either from HBV or as a result of
ischemic hepatitis caused by PAN involving the hepatic arteries[19]
• Positive HBV serology, which is supportive of the diagnosis[19]
• CBC, which may show anemia as a result of chronic inflammation or from GI blood loss
• Low complement levels, caused by activation of the complement cascade by immune complexes
(especially in HBV-related PAN)
• Creatine kinase, which is either normal or mildly elevated, regardless of any muscle involvement.
Tests that should be done to exclude other causes include:
• Blood cultures, to exclude endocarditis or other infective mimics of vasculitis

• Hepatitis C virus (HCV) serology and cryoglobulins; although HCV has been associated with a
skin-limited manifestation of PAN, it is typically associated with a small-vessel vasculitis related to
cryoglobulinemia
• ANCA, which if positive would suggest another type of vasculitis, such as WG or MPA;[3] [19] a
negative ANCA is useful in supporting the diagnosis of PAN in the right context
• Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP antibodies), to rule out
rheumatoid arthritis, especially in a patient presenting predominantly with arthritic features
• Antinuclear antibody and anti-double-stranded DNA antibodies in patients with clinical features
consistent with SLE or other connective tissue diseases
• Lupus anticoagulant antiphospholipid antibodies and B2 glycoprotein, which may be present in
antiphospholipid syndrome
• HIV testing.
Imaging
Conventional angiography, MR or CT angiography, Doppler ultrasound, and chest x-ray all have their
place in the diagnosis.
Conventional angiography is the imaging modality of choice, and should be performed if there is a clinical
suspicion of PAN. The reported sensitivity is as high as 89%. The specificity is 90% when performed
DIAGNOSIS
in patients suspected of having vasculitis.[38] Classical findings are multiple small aneurysms, vessel
ectasia, and focal occlusive lesions in medium-sized vessels, most typically in the renal and mesenteric
arteries.
MR or CT angiography are less invasive alternatives to conventional angiography, but they are much less
sensitive in showing microaneurysms.[39] They do have the advantage of being able to show areas of
renal infarction and other potential pathology. In the setting of a high suspicion of PAN and a normal CT or
MR angiography, it is still necessary to proceed to conventional angiography.
Doppler ultrasound has been noted in individual case reports as successfully identifying renal and hepatic
aneurysms related to PAN.[40]
PAN does not affect the lungs, but chest x-ray may be useful in ruling out other diseases, such as other
vasculitides, which may affect the lungs and in excluding infection.
[Fig-2]
[Fig-3]
[Fig-9]
Biopsy
Biopsy should be performed if angiography is not available or does not conclusively show a medium-
vessel vasculitis. A number of organs or tissues can be sampled. The tissue chosen for sampling should
be directed by evidence of clinical involvement from the history or physical exam. Muscle, peripheral
nerves, kidney, testis, and rectum, when involved, provide the best targets. A positive skin biopsy does
not always indicate systemic involvement.[41]
A biopsy showing a medium-sized artery with evidence of focal and segmental transmural necrotizing
inflammation is supportive of a diagnosis of PAN.[24] [41] The presence of clinical or laboratory features
indicating involvement of small vessels should be pursued[42] because it suggests an alternative form of
vasculitis such as MPA.
In pathologic descriptions of PAN, the involvement of vessel bifurcations is reported to be a common

feature. Different stages of inflammation and scarring, as well as areas of normal vessel wall, often
coexist. Areas of acute inflammation typically have a pleomorphic cellular infiltrate of lymphocytes,
neutrophils, macrophages, and eosinophils. Aneurysms can occur at the site of active lesions, and this
morphologic appearance is what led to the term "nodosa." Proliferative scarring in other areas may lead to
vessel narrowing.[24] [35] [41] [42]
[Fig-10]
[Fig-11]
Risk factors
Strong
hepatitis B virus (HBV) infection
• PAN develops in 1% to 5% of patients with HBV infection,[13] [25] which equates to an approximately
1000-fold increase in risk compared with the background population.[11]
DIAGNOSIS
• HBV infection is present in 7% to 38.5% of patients with PAN, and in this setting is thought to be
directly related to the development of the disease. The prevalence of HBV-related PAN has reduced in
recent years as a result of vaccination for HBV and improved screening of blood products.[15] [22]
• Evidence for the pathogenic nature of HBV and immune complexes is supported by the effectiveness
of a treatment strategy to eradicate HBV with antiviral therapy and remove immune complexes by
plasmapheresis without the need for long-term immunosuppression.[20] [21]
age 40 to 60 years
• PAN can present at any age, but the most common age at presentation is 40 to 60 years.
Weak
hairy cell leukemia
• There are case reports describing the development of PAN in patients with preexisting hairy cell
leukemia.[26] [27] In 80% of these cases, the patient had undergone splenectomy before the
development of PAN. HBV infection was found in some of these case reports, other case reports
predating routine testing for HBV.
13
• Potential mechanisms for the association between hairy cell leukemia and PAN are cross-reactivity of
antibodies between the tumor cells and the endothelium, direct damage of the endothelium by tumor
cells, and local production of pro-inflammatory cytokines triggering vessel wall damage.[27]
blood transfusion at a time before routine screening for hepatitis B virus

(HBV)
• Before routine screening of blood products for HBV, transfusion was a major mode of transmission of
the virus.
hepatitis C virus (HCV) infection

• HCV infection has been associated with cutaneous PAN in one retrospective study of 16 patients, in
which 5 of the patients were found to have HCV infection.[21] However, cutaneous PAN (a form that
is limited to the skin and is chronic) is usually considered a separate clinical entity from systemic PAN
and is not covered here, although the pathologic findings on skin biopsy are indistinguishable between
the two.[28]
male sex
• Males seem to be over-represented in most series.[15] [18] [19] However, a recent prevalence estimate
in Sweden has shown the opposite, with two-thirds of the patients being female.[16]
History & examination factors

Key diagnostic factors
age 40 to 60 years (common)
• PAN can manifest itself at any age, but the majority of cases are diagnosed between the ages of 40 to
60 years.
fever (common)
DIAGNOSIS
• Fever is a common but nonspecific symptom.
weight loss (common)

• A history of unintended weight loss is a common but nonspecific symptom.
myalgia or arthralgia (common)

• Muscle or joint pain are common but nonspecific symptoms.
mononeuritis multiplex (common)

• Mononeuritis multiplex is a common manifestation of PAN.
paresthesia (common)
• Motor weakness and/or sensory loss in a peripheral nerve distribution is a common feature and is
suggestive of vasculitis.
muscle tenderness (common)

• A nonspecific manifestation. Areas of tenderness usually reflect areas of muscle ischemia or infarction
and provide a useful site for tissue biopsy.
abdominal pain (common)
• Abdominal pain can be caused by ischemia or infarction of bowel or other abdominal organs.
skin manifestations (common)

• Livedo reticularis, skin ulcers, bullous or vesicular eruptions, purpura, or skin infarction may occur in
PAN. However, many other diseases, including several of the vasculitides as well as infection, can
cause these skin manifestations.
• A skin biopsy showing vasculitis does not necessarily indicate systemic involvement.
diastolic blood pressure >90 mmHg (common)

• High diastolic blood pressure is associated with PAN.
blood transfusion at a time before routine screening for hepatitis B virus

(HBV) (uncommon)
• Before routine screening of blood products for HBV, transfusion was a major mode of transmission of
the virus.
previous or current intravenous drug abuse (uncommon)

• A recognized mode of transmission of hepatitis B virus.
recent hepatitis B virus (HBV) infection (uncommon)

• The majority of cases of HBV-related PAN occur in the first few months after acquiring the infection.
• The incidence of HBV-related PAN has dramatically reduced in the past 2 decades, owing to improved
screening of blood products and routine vaccination against HBV.
testicular pain (uncommon)

• Ischemic orchitis is a classically described but rare feature of PAN.
Other diagnostic factors
DIAGNOSIS
male sex (common)
• In most series males seem to be over-represented.
hairy cell leukemia (uncommon)

• There is a weak association between a preexisting diagnosis of hairy cell leukemia and the
development of PAN.
seizure (uncommon)
• An unusual manifestation of PAN, caused by CNS involvement.
upper motor neuron weakness (uncommon)

• Stroke is a rare manifestation of PAN.
GI bleeding (uncommon)
• Ischemic bowel or ruptured aneurysm can cause GI blood loss.
peritonitis (uncommon)
15
• Can be caused by ischemic bowel or infarction of any of the abdominal organs.
monocular blindness (uncommon)

• Ischemic optic neuropathy and retinopathy with retinal hemorrhages have been described but are rare
manifestations.
chest pain (uncommon)

• Ischemic pain and myocardial infarction are possible from involvement of the coronary arteries.
congestive cardiac failure (uncommon)

• Ischemic cardiomyopathy caused by PAN may present with cardiac failure.
tender breast lumps (uncommon)

• Breast involvement is a rare manifestation of PAN.
Diagnostic tests
1st test to order
Test Result
CRP elevated
• CRP is an acute phase protein that is elevated in most inflammatory
conditions. A normal CRP level would argue against a diagnosis of
PAN.
ESR elevated
• ESR is elevated in inflammatory conditions, including PAN.
CBC normocytic anemia,
mildly elevated WBC
• A normochromic, normocytic anemia is a common feature of
count, elevated platelet
DIAGNOSIS
inflammation and, therefore, a frequent finding in PAN. A neutrophilia

count
or eosinophilia may be present. An elevated platelet count
is a recognized feature. In contrast, a low platelet count may
indicate other disease processes such as SLE or catastrophic
antiphospholipid syndrome.
complement reduced
• Activation of the complement cascade by immune complexes
(especially in hepatitis B virus-related PAN) may result in low
complement levels.
serum creatinine elevated or normal
• PAN can affect the renal arteries and cause renal ischemia or
infarction with a resulting rise in serum creatinine.
midstream urine analysis mild proteinuria or normal
• Urinanalysis is useful to rule out infection and exclude
glomerulonephritis. PAN does not cause glomerulonephritis, and
the presence of red cell casts or severe proteinuria suggests an
alternative diagnosis such as granulomatosis with polyangiitis
(Wegener) (GPA), or microscopic polyangiitis (MPA).
Test Result
liver function tests elevated liver enzymes
• Mild elevation of liver enzymes is common. Acute hepatitis is possible
during initial infection with hepatitis B virus or may be a result of
ischemic hepatitis.
hepatitis B virus (HBV) serology hepatitis B surface
antigen positive and/
• HBV infection typically occurs a few months before the development
or hepatitis B e-antigen
of HBV-related PAN.
positive
hepatitis C virus (HCV) serology positive anti-hepatitis C

antibodies
• HCV infection is associated with a predominantly cutaneous form of
PAN.
cryoglobulins no cryoglobulins
• Presence of cryoglobulins would suggest an alternative diagnosis.
Cryoglobulins are strongly associated with hepatitis C virus infection
and can cause a small-vessel vasculitis.
blood culture no growth of organisms
• It is important to exclude endovascular infection, which can mimic
vasculitis, especially before embarking on immunosuppressive
therapy.
creatine kinase normal or mildly elevated
• Creatine kinase is not markedly elevated in PAN, even when there is
muscle involvement.
antineutrophil cytoplasmic antibodies (ANCA) negative
• PAN is not associated with ANCA. A positive result in the context of
suspected vasculitis would suggest an alternative type of vasculitis.
antinuclear antibody (ANA) negative
• Can be a useful test in the right context. A positive ANA may help
DIAGNOSIS
to point toward an alternative diagnosis such as SLE or another
connective tissue disorder.
anti-double-stranded DNA antibodies (anti-dsDNA) negative
• A positive result for anti-dsDNA can be useful to make a diagnosis of
SLE if manifestations fit with this diagnosis.
rheumatoid factor negative
• Useful only if rheumatoid arthritis is a possible alternative diagnosis
on the basis of the history and exam.
antibodies to cyclic citrullinated peptides (anti-CCP antibodies) negative
• Useful only if rheumatoid arthritis is a possible alternative diagnosis
based on the history and exam.
lupus anticoagulant negative
• May be present in antiphospholipid syndrome.
IgG antiphospholipid antibodies negative
B2 glycoprotein negative
17
Test Result
fibrinogen normal or elevated
• Fibrinogen may be elevated in PAN as a marker of acute
inflammation. It may be low in catastrophic antiphospholipid
syndrome.
conventional digital subtraction angiography microaneurysms, vessel
ectasia, or focal occlusive
• This is the standard method of imaging potentially affected vessels.
lesions in medium-sized
The sensitivity and specificity of the test in a selected population
vessels
suspected of vasculitis is 89% and 90%, respectively. The main
disadvantage is that it is a relatively invasive procedure.
echocardiography normal
• Useful to exclude an alternative diagnosis such as endocarditis, atrial
myxoma, or a left ventricular thrombus.
Other tests to consider
Test Result
MR angiography (MRA) aneurysms or focal
occlusive lesions of
• MRA is a noninvasive method of imaging potentially affected vessels
medium-sized vessels
but it has lower spatial resolution than conventional angiography and
is not very good at detecting microaneurysms. It has the benefit of
being able to show areas of organ infarction.
• In patients with normal MRA and suspected PAN, conventional
angiography is indicated.
CT angiography aneurysms or focal
• CT angiography is a noninvasive alternative to MRA and conventional occlusive lesions of
angiography. It has better spatial resolution than MRA, but it is not as medium-sized vessels
good as conventional angiography at detecting microaneurysms. It
has the benefit of being able to show areas of organ infarction.
• In patients with normal CT angiography and suspected PAN,
DIAGNOSIS
conventional angiography is indicated.

biopsy of affected tissue focal and segmental
transmural necrotizing
• The tissue sampled must be targeted from the history and exam.
inflammation in a
Muscle, peripheral nerves, kidney, testis, and rectum, when involved,
medium-sized vessel (i.e.,
provide the best targets. A positive skin biopsy does not always
a small or medium-sized
suggest systemic involvement.
artery)
[Fig-10]
[Fig-11]
HIV serology negative
• It is important when appropriate to rule out HIV infection, which is a
cause of vasculitis in its own right.
Differential diagnosis
Condition Differentiating signs / Differentiating tests

symptoms
Granulomatosis with • Granulomatosis with • ANCA: cANCA
polyangiitis (Wegener) polyangiitis (Wegener) (cytoplasmic pattern on
(GPA), microscopic immunofluorescence
polyangiitis (MPA), and testing) combined with
Churg-Strauss syndrome positive proteinase 3
(CSS) are forms of ANCA- antibody testing by enzyme
associated small-vessel immunoassay (EIA); pANCA
vasculitis, whereas (perinuclear pattern on
polyarteritis nodosa (PAN) immunofluorescence testing)
affects only medium-sized combined with positive
vessels (i.e., small- and myeloperoxidase antibody
medium-sized arteries). testing by EIA. ANCA is not
• Commonly presents with associated with PAN.
signs and/or symptoms • Urinalysis: may show
involving the upper or lower hematuria, proteinuria;
respiratory tract. dysmorphic red blood cells,
• Glomerulonephritis and RBC casts.
pulmonary capillaritis are • Pulmonary function testing:
features of ANCA-associated typically be normal or
vasculitis conditions but are may show evidence of
not found in PAN. extrathoracic airway
obstruction in cases of
subglottic stenosis.
• CT chest: lung nodules
(which may cavitate);
infiltrates.
• Tissue biopsy (skin, lung,
kidney): granulomatous
inflammation, necrosis
and vasculitis; minimal/
DIAGNOSIS
absent immune deposits on
immunofluorescence and
electron microscopy.
19

symptoms
Microscopic polyangiitis • Granulomatosis with • ANCA: positive pANCA
polyangiitis (Wegener) (perinuclear) more common
(GPA), microscopic than cANCA (cytoplasmic).
polyangiitis (MPA), and ANCA is not associated with
Churg-Strauss syndrome PAN.
(CSS) are forms of ANCA- • Urinalysis: may show
associated small-vessel hematuria, proteinuria;
vasculitis, whereas dysmorphic red blood cells,
polyarteritis nodosa (PAN) RBC casts.
affects only medium-sized • CT chest: alveolar
vessels (i.e., small- and hemorrhage.
medium-sized arteries). • Tissue biopsy (skin,
• MPA and GPA seem lung, kidney): absence of
to be part of a clinical granulomatous inflammation.
spectrum. However, the
upper respiratory tract is not
involved in MPA.
• Glomerulonephritis and
pulmonary capillaritis are
features of ANCA-associated
vasculitis conditions but are
not found in PAN.
Churg-Strauss syndrome • Granulomatosis with • CBC: significant (>10%

polyangiitis (Wegener) of peripheral WBC count)
(GPA), microscopic peripheral eosinophilia.
polyangiitis (MPA), and • Urinalysis: may show
Churg-Strauss syndrome hematuria, proteinuria;
(CSS) are forms of ANCA- dysmorphic red blood cells,
associated small-vessel RBC casts.
vasculitis, whereas • ANCA: usually pANCA
polyarteritis nodosa (PAN) (perinuclear). ANCA is not
affects only medium-sized associated with PAN.
DIAGNOSIS
vessels (i.e., small- and • Tissue biopsy (sural nerve,

medium-sized arteries). skin): granulomatous
• Patients typically present inflammation, may have
with a history of asthma, extravasated eosinophils.
allergic rhinitis, or sinusitis.
• Peripheral neuropathy
(typically mononeuritis
multiplex) is the most
common vasculitic
manifestation.
• Glomerulonephritis and
pulmonary capillaritis are
features of ANCA-associated
vasculitis conditions but are
not found in PAN.

symptoms
Giant cell arteritis (GCA) • GCA does not usually • MR, CT, or conventional
present with mononeuritis angiography shows affected
multiplex, orchitis, or medium-sized cranial
coronary vasculitis, nor does vessels, especially the
it involve the skin or affect temporal artery. GCA also
the renal arteries. affects extracranial large
• GCA is predominantly a vessels, such as the aorta
large and medium-sized and the carotid arteries, but
vessel vasculitis with a extra-cranial medium-sized
predilection for the cranial arteritis is more likely to be
arteries. It is associated with due to PAN.
temporal arteritis, though the
temporal artery can also be
involved in PAN, and PAN
can cause ischemic optic
neuropathy similar to that
seen in GCA.
Infection • Endovascular bacterial • Blood cultures to detect a

infection is an important bacteremia. HIV serology,
vasculitis mimic that needs HCV serology, or other viral
to be excluded before serology when clinically
immunosuppressive therapy appropriate to detect
can be started. infection. The presence of
• HIV and hepatitis C virus cryoglobulins suggests an
(HCV) are associated with HCV-related vasculitis.
causing vasculitis in their
own right.[43] HCV-related
vasculitis is usually in the
form of a cryoglobulinemia.
• Epstein-Barr virus,
cytomegalovirus, parvovirus,
and many other viruses
DIAGNOSIS
are implicated in causing
vasculitis or can cause
symptoms that mimic
vasculitis.[43]
Rheumatoid arthritis • This can present with similar • Rheumatoid factor and
symptoms to those of PAN antibodies to cyclic
or cause a secondary citrullinated peptides (anti-
vasculitis. A presentation CCP antibodies) are positive
with mainly arthritis should in rheumatoid arthritis.
lead to investigations for
rheumatoid arthritis.
Systemic lupus • SLE can present with similar • Antinuclear antibody is

erythematosus (SLE) symptoms to those of PAN positive in SLE. Anti-double-
or cause a secondary stranded DNA antibodies
vasculitis. A malar rash, (anti-dsDNA) can be useful
alopecia, oral ulcers, or to make a diagnosis of SLE if
serositis, especially in a the clinical manifestations fit
young woman, should trigger with this diagnosis.
investigation for SLE.
21

symptoms
Malignancy • Fever, weight loss, fatigue, • Investigation for malignancy
myalgia, and arthralgia should be guided by
may be due to cancer. specifics of history
In the absence of organ and exam. This may
involvement characteristic involve checking tumor
of vasculitis, a thorough markers, imaging of chest/
evaluation for malignancy abdomen/pelvis, and other
should be performed. investigations as clinically
• Vasculitis can occur as a appropriate.
paraneoplastic phenomenon,
particularly with hematologic
malignancies.[44]
Fibromuscular dysplasia • FMD can affect the renal, • Biopsy is usually difficult, so
(FMD) carotid, mesenteric, and imaging with conventional
other visceral arteries. digital subtraction
Ischemic symptoms, angiography remains the
depending on the arterial best method of diagnosis.
system involved, result from This shows a "string of
luminal narrowing. However, beads" with aneurysms and
FMD does not cause fever, stenosis.
weight loss, arthritis, skin • Angiographic findings are
lesions, or mononeuritis sometimes indistinguishable
multiplex. from those of PAN,[45] but
MR angiography may show
the appearance of a "string
of beads" with thickening of
the vessel wall.
• Inflammatory markers (CRP
or ESR) are not elevated in
FMD.
Atheroma • Atherosclerosis is the most • Conventional digital

DIAGNOSIS
common cause of organ subtraction angiography is

ischemia. Symptoms and the best test; the absence
signs depend on the arterial of microaneurysms in purely
systems involved. Atheroma atherosclerotic disease is the
formation is accelerated main discriminating factor.
in inflammatory diseases, • CRP and ESR are not
including PAN, in which a usually elevated in patients
combination of inflammation with atherosclerosis alone.
and ischemia may both be
present, making it difficult
to differentiate between
atherosclerotic disease and
vasculitis.

symptoms
Cholesterol emboli • Usually presents with distal • Biopsy of affected organ
ischemia, hypertension, shows microcrystals of
and renal impairment, but cholesterol.
can manifest itself with any
ischemic symptom, including
mononeuropathy.[46]
• Typically occurs after a
vascular interventional
procedure causing
mechanical disruption of
an atheromatous plaque.
Small cholesterol crystals
shower downstream,
or large plaques break
off and occlude larger
vessels. In the first scenario,
the crystals induce an
inflammatory reaction in
small vessels, resulting in
fibrosis and eventually tissue
ischemia.[47]
Atrial my xoma • Can cause recurrent emboli • Echocardiography reveals

to multiple organs, resulting the atrial mass.
in tissue ischemia and
infarction. Symptoms may
mimic vasculitis. In some
cases, this embolus is
purely thrombus; in others, a
combination of thrombus and
tumor material.[48]
Catastrophic • A rare disorder with • IgG anticardiolipin
DIAGNOSIS
antiphospholipid pathologic overlap to antibodies (IgG) and beta-2
syndrome antiphospholipid syndrome. glycoprotein are elevated.
It presents with multiorgan • Lupus anticoagulant may be
infarction from microthrombi present.
over a period of days to • CBC may show a low
weeks. Preceding infection is platelet count, and the partial
a risk factor.[49] thromboplastin time may be
elevated.
23

symptoms
Buerger disease • Typically occurs in men • Pathologically there is
(thromboangiitis ages 20 to 40 years who vasculitis affecting the
obliterans) are heavy smokers, but small and medium-sized
can occur in women and vessels of the hands
at older ages. Presents and feet. Angiogram of
with claudication, ischemic extremities and renal or
pain at rest, Raynaud mesenteric arteries shows
phenomenon, or gangrene of occluded vessels distal to
the extremities. the elbow or knee, with
a corkscrew appearance
of collateral vessels.
Differentiated from PAN
by the absence of visceral
vessel involvement.[50]
Diagnostic criteria
French Vasculitis Study Group (FVSG) proposal for diagnostic
criteria for polyarteritis nodosa.[9]
There are no validated diagnostic criteria for PAN. The FVSG has proposed a set of predictive items to be
used as a paradigm for diagnostic criteria. However, items were derived from patients with known vasculitis
and not from undifferentiated patients, and this methodology is typically used to identify items used in
classification rather than diagnostic criteria.
A total of 8 discriminating items were derived from a cohort of 949 patients with vasculitis, 262 of whom had
a diagnosis of PAN: 3 positive predictive items and 5 negative predictive items.
The positive predictive items were:

DIAGNOSIS
• Positivity for hepatitis B virus infection

• Arteriographic abnormalities
• Mononeuropathy or polyneuropathy.
The negative predictive items were:
• Presence of antineutrophil cytoplasmic antibodies (ANCA)

• Asthma
• Ear, nose, or throat signs
• Glomerulopathy
• Cryoglobulinemia.
These items were useful to differentiate between PAN and other vasculitides in this cohort, but have not been
evaluated in undifferentiated patients to see whether they would be useful for diagnostic purposes.
The American College of Rheumatology (ACR) 1990 criteria for the

classification of polyarteritis nodosa[3]
These criteria are used to classify which patients with known primary systemic vasculitis have PAN. These
criteria do not differentiate between PAN and microscopic polyangiitis (MPA); both are included under the
umbrella of PAN. Three of the following 10 criteria are required:
• Weight loss ≥4 kg
• Livedo reticularis
• Testicular pain or tenderness
• Myalgias, weakness, or leg tenderness
• Mononeuropathy or polyneuropathy
• Diastolic blood pressure >90 mmHg
• Elevated BUN or creatinine
• Positivity for hepatitis B virus (HBV) infection
• Arteriographic abnormality
• Biopsy of small or medium-sized artery containing polymorphonuclear leukocytes.
The sensitivity of these criteria is 82.2% and the specificity 86.6% when used in this context.[3] This was
calculated from the cohort used to develop the criteria, and has not been prospectively validated.
DIAGNOSIS
25
American College of Rheumatology 1990 criteria for PAN
European Medicines Agency (EMA) algorithm for the classification

of the ANCA-associated vasculitides and polyarteritis nodosa for
epidemiological studies[4]
This is an algorithm to apply the disease definitions and classification criteria for the antineutrophil
cytoplasmic antibodies (ANCA)-associated vasculitides and PAN in a stepwise manner. The algorithm
is useful because MPA is absent in the ACR classification criteria (which consider it to be part of PAN),
whereas in the Chapel Hill Consensus Conference (CHCC) definition PAN and MPA are treated as separate
entities, and there is evidence that they behave differently in terms of pathogenesis, organ involvement,
tendency to relapse, and prognosis.[5] In the CHCC definition, PAN is strictly a medium-vessel disease
whereas MPA is predominantly a small-vessel disease that includes glomerulonephritis and pulmonary
capillaritis.[2]
• Entry into the algorithm is by having a clinical diagnosis of an ANCA-associated vasculitis or PAN. In
the algorithm PAN is a diagnosis of exclusion.
• The first step is to determine whether the patient fulfills the Lanham[6] or ACR criteria[7] for Churg-
Strauss syndrome (CSS). If so, the patient is classified as having CSS.
• If not, the next step is to determine whether the patient fulfills the ACR criteria[8] or the CHCC
definition for granulomatosis with polyangiitis (Wegener) (GPA),[2] either by direct evidence with
histology or with appropriate surrogate markers and a positive ANCA. If the patient fulfills these
criteria, he or she is classified as having GPA.
• If not, see whether the patient fulfills a definition of MPA.[2] This is either by histology showing small-
vessel vasculitis or glomerulonephritis and no surrogate markers for GPA or with surrogate markers of
glomerulonephritis and a positive ANCA.
• Only when CSS, GPA, and MPA have been excluded is a diagnosis of PAN possible.
To fulfill the definition of PAN there must be histology or angiographic features consistent with the diagnosis.
Any remaining patients are determined to be unclassifiable.
DIAGNOSIS
Polyarteritis nodosa Treatment
Step-by-step treatment approach

PAN unrelated to hepatitis B virus (HBV) infection is treated in broadly the same way as other vasculitides,
by means of immunosuppression, with an emphasis on early and aggressive therapy, especially in severe
disease.
The treatment of HBV-related PAN is different, because although immunosuppression can lead to
control of the vasculitis it is also associated with increased viral replication. A short course of aggressive
immunosuppression is followed by plasma exchange and concomitant antiviral therapy.
The 5-factor score

This score can be used to predict survival in PAN.[18] A score of 1 or more is considered to suggest a
poor prognosis and warrants more aggressive therapy.
The 5 factors, each of which is scored 1 point if present, are:
• Proteinuria >1 g/day

• Creatinine >1.58 mg/dL
• Cardiomyopathy
• Gastrointestinal symptoms
• CNS involvement.
Non HBV-related PAN

The main goal is to control the activity of the vasculitis and thereby to prevent the progression of organ-
and life-threatening disease. Immunosuppression is the mainstay of treatment, so close attention to
prevention and detection of complications of therapy is key.
Mortality from PAN has been demonstrated to be high within the first year, with 58% to 73% of early
deaths caused by uncontrolled vasculitis.[53] [54] [55] Therefore, PAN should be treated aggressively
and without delay, especially in patients with severe disease (those with a 5-factor score ≥1). Most of the
clinical trials published have looked at a combination of patients with different types of primary vasculitis
studied together: for example, PAN and Churg-Strauss syndrome. This approach has been adopted
because of the relative rarity of these diseases.[55]
Clinical trials in non HBV-related PAN have demonstrated that the combination of cyclophosphamide and
corticosteroids reduces the rate of relapses but does not affect overall 10-year mortality.1[B]Evidence
However, in a retrospective analysis of 278 patients, those with a 5-factor score of ≥2 had a significantly
improved survival if they were treated with cyclophosphamide and corticosteroids, compared with
corticosteroids alone.2[B]Evidence
Patients with a 5-factor score of ≥1 are given an oral corticosteroid in a slowly reducing regimen, aiming
for withdrawal of corticosteroid by 15 to 18 months. Intravenous pulses of corticosteroid can be given
before cyclophosphamide infusions, which may allow for faster tapering of the oral corticosteroid.
TREATMENT
Intravenous pulses of cyclophosphamide are preferred because they have been found to be as effective
as oral regimens;3[B]Evidence they also reduce the total amount of exposure to cyclophosphamide
and reduce adverse effects.4[B]Evidence Tuberculosis screening should be considered before the use
of cyclophosphamide.[59] [60] The risk of infertility with cyclophosphamide should be discussed, with
27
options such as oocyte and sperm cryopreservation offered, although in practice this is rarely achieved
in severe disease[59] because treatment needs to be started before arrangements can be made for
harvesting.
The use of plasma exchange has not been found to reduce relapses or improve mortality compared with
corticosteroids alone5[B]Evidence or compared with corticosteroids plus cyclophosphamide.6[B]Evidence
The number of infusions of cyclophosphamide appears to be relevant in patients with poor prognostic
scores (i.e., a 5-factor score ≥1). Twelve infusions compared with 6 results in a significantly lower
probability of relapse (hazard ratio 0.44, P = 0.02).7[B]Evidence
After an initial 3- to 6-month course of cyclophosphamide, maintenance of remission with

azathioprine,[64] [65]leflunomide,[66] or methotrexate[67] has been shown to be effective in patients with
ANCA-associated vasculitis. Again, this has not been proven specifically in PAN, but the findings from one
trial3[B]Evidence in ANCA-associated vasculitides can be extrapolated to PAN, making maintenance with
alternatives to cyclophosphamide a potential treatment option.[59]
In patients who have a major relapse (defined as being life- or organ-threatening disease),
cyclophosphamide should be restarted to try and achieve remission.
Patients with a 5-factor score of 0 have a better prognosis, and such patients can be treated with
corticosteroids alone (i.e., without cyclophosphamide), but this is associated with a 12% mortality.[68]
In vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA), methotrexate, in place of
cyclophosphamide, may be effective in inducing remission in disease without severe features.[69] [70]
[71] However, there have been no such trials in PAN.
HBV-related PAN
HBV-related PAN is treated in a different way from the other primary systemic vasculitides. This is
because of the underlying pathogenesis, which, unlike classical PAN, is associated with immune
complex disease and driven by ongoing viral replication.[72] Historically, patients were treated with
immunosuppression, which could lead to control of the vasculitis[13] but that also promoted ongoing viral
replication and, therefore, led to an increase in the chronicity and intensity of HBV infection.[73] [74] [75]
Ongoing viral replication has been shown to be a poor prognostic feature in HBV infection, leading to a
high risk of cirrhosis and hepatocellular carcinoma.[76] [77] [78]
Treatment regimens now start with aggressive immunosuppression, in the form of high-dose oral
corticosteroids for 2 weeks, in order to reduce end-organ damage from uncontrolled vasculitis.
The next stage is to use plasma exchange as a means of physically removing the immune complexes.[79]
Concomitant use of antiviral therapy at this stage reduces viral load, which reduces the drive to produce
immune complexes, halts viral replication, and leads to seroconversion.[19] [80] [81] The antiviral agent
of choice is lamivudine, which has been shown to be effective in seroconverting patients with chronic
hepatitis B and can be used orally.[82] An observational trial demonstrated clinical remission in 90% of
patients by 6 months, and seroconversion from hepatitis B e-antigen positivity to hepatitis B e-antibody
in 66.7% of patients within 9 months.8[C]Evidence It has been reported that a cure can be achieved in
TREATMENT
those who seroconvert.[80] There have been no randomized controlled trials because of the rarity of the
disease.[19]
On relapse of PAN, HBV status should be checked and, if positive, needs to be eradicated before
PAN treatment. The treating physician should liaise with his or her local hepatologists for advice about
alternative antiviral therapy to treat HBV, rather than simply repeat the course of lamivudine.
Treatment details overview

Consult your local pharmaceutical database for comprehensive drug information including contraindications,
drug interactions, and alternative dosing. ( see Disclaimer )
Acute ( summary )
non HBV-related PAN
poor prognosis (5-factor 1st oral prednisone + disease-modifying

score ≥1) antirheumatic drug (DMARD)
adjunct intravenous methylprednisolone
good prognosis (5-factor 1st oral prednisone

score of 0)
adjunct disease-modifying antirheumatic drug

(DMARD)
HBV-related PAN
1st oral prednisone ± intravenous

methylprednisolone
plus plasma exchange + lamivudine
Ongoing ( summary )
relapse of disease
1st oral prednisone: increased dose

(DMARD)
HBV-related PAN plus HBV serology + alternative antiviral

therapy
TREATMENT
29
Treatment options
Acute
non HBV-related PAN
poor prognosis (5-factor 1st oral prednisone + disease-modifying

score ≥1) antirheumatic drug (DMARD)
Primary options
» prednisone: 1 mg/kg/day orally initially,

reduce dose gradually to 15 mg/day by 2
months, and cease by 15-18 months
--AND--
» cyclophosphamide: 15 mg/kg intravenously
once every 2 weeks for 3 doses, then once
every 3 weeks until remission, maximum
1200 mg/dose; or 2 mg/kg/day orally
--AND--
» azathioprine: 2 mg/kg/day orally starting
after cyclophosphamide has been ceased
-or-
» leflunomide: 20-30 mg orally once daily
starting after cyclophosphamide has been
ceased
-or-
» methotrexate: 7.5 to 15 mg orally once
weekly on the same day each week initially
starting after cyclophosphamide has been
ceased, increase by 2.5 mg/week increments
every 2-4 weeks according to response,
maximum 25 mg/week
» Oral corticosteroids are given in a reducing

regimen, eventually tapering to a dose of 15
mg/day over 2 months, followed by a slow
reduction with the aim of ceasing treatment
to 0 by 15 to 18 months. It may be possible
to taper the corticosteroid dose more rapidly
in patients 65 years old or older. One study
found similar remission rates but less toxicity in
this patient population with rapid corticosteroid
dose tapering (approximately 9 months) versus
conventional treatment with longer corticosteroid
duration.[84]
» If remission is not achieved with intravenous

cyclophosphamide in 3 to 6 months, consider
switching to oral cyclophosphamide until
remission is achieved. The maximum duration
TREATMENT
of cyclophosphamide therapy is 6 months.

When patients have achieved remission,
cyclophosphamide is withdrawn and replaced
by an alternative immunosuppressant with
continued tapering of corticosteroids.
Acute
» Maintenance of remission with
azathioprine,[64] [65] leflunomide,[66] or
methotrexate[67] has been shown to be effective
in patients with ANCA-associated vasculitis,
and it has been suggested that this could be a
potential option for PAN.3[B]Evidence [59]
Primary options
» methylprednisolone: 10 mg/kg intravenously

before cyclophosphamide infusions,
maximum 1000 mg/dose
» Intravenous pulses of methylprednisolone can

be given before each infusion of intravenous
cyclophosphamide, which may allow a faster
tapering of oral corticosteroid.
good prognosis (5-factor 1st oral prednisone
score of 0)
Primary options
» prednisone: 1 mg/kg/day orally initially,

reduce dose gradually to 15 mg/day by 2
months, and cease by 15-18 months
» Oral corticosteroids are given in a reducing

regimen, aiming at 15 mg/day by 2 months,
followed by a slow reduction to 0 by 15 to 18
months.
(DMARD)
Primary options

every 3 weeks until remission, maximum
1200 mg/dose; or 2 mg/kg/day orally
OR
» methotrexate: 7.5 to 15 mg orally once

weekly on the same day each week initially,
increase by 2.5 mg/week increments every
2-4 weeks according to response, maximum
25 mg/week
» The French Vasculitis Group have previously

recommended that patients with a 5-factor
score of 0 can be treated with corticosteroids
TREATMENT
alone, adding cyclophosphamide as second-

line therapy only if there is persistent disease
or relapse despite use of corticosteroids.[68]
However, further study by the same group
showed that 80% of patients with a 5-
factor score of 0 achieved remission with
31
Acute
corticosteroids alone, but remission was only
sustained in 40%.[85] In patients who failed to
achieve remission or relapsed on corticosteroids
alone, azathioprine or pulse intravenous
cyclophosphamide was used to induce remission
successfully.[85]
» If remission is not achieved with intravenous

cyclophosphamide in 3 to 6 months, consider
switching to oral cyclophosphamide until
remission is achieved.
» The British Society for Rheumatology

guidelines on the management of ANCA-positive
vasculitis recommends the use of methotrexate
with corticosteroids to induce disease remission
in disease with a good prognosis. Although there
is no specific evidence for this regimen in PAN,
the trial data in ANCA-positive vasculitis can be
extrapolated to include PAN, and methotrexate is
commonly used in practice.[59]
HBV-related PAN
1st oral prednisone ± intravenous

methylprednisolone
Primary options
» prednisone: 1 mg/kg/day orally for 7 days,

then taper and withdraw by 14 days
OR
» prednisone: 1 mg/kg/day orally for 7 days,

then taper and withdraw by 14 days
-and-
» methylprednisolone: 15 mg/kg/day
intravenously for 1-3 days
» Oral corticosteroids are given for 2 weeks,

with the dose tapering during the second week,
reaching 0 by the end of week 2.
» In severely ill patients, intravenous

methylprednisolone can be added for the first 1
to 3 days.
plus plasma exchange + lamivudine
Primary options
» lamivudine: 100 mg orally once daily

TREATMENT
» Plasma exchange and lamivudine are started

immediately after the 2-week corticosteroid
course.
» Three plasma exchange sessions per week

are given for 3 weeks, then 2 sessions per
Acute
week for 2 weeks, then 1 session per week
until there is seroconversion from HBeAg to
HBeAb or the patient is clinically recovered
and has been stable for 2 to 3 months. In each
plasma exchange session, 60 mL of plasma/kg
is replaced with 4% albumin.
» Lamivudine is started with plasma

exchange and continued for 6 months or until
seroconversion to HBsAb. On days when a
plasma exchange is performed, lamivudine
should be taken after the session to avoid
removal of the drug.
» Care of patients with HBV-related PAN

should always involve close consultation with
a hepatologist, as there have been cases of
fulminant hepatitis developing during acute
treatment.[19]
Ongoing
relapse of disease
1st oral prednisone: increased dose

Primary options
» prednisone: 30 mg orally once daily, then

taper gradually
» Patients who have a relapse on standard

therapy should have their oral corticosteroid
dose increased.
(DMARD)
Primary options

every 3 weeks for 3-6 doses, maximum 1200
mg/dose, followed by 2 mg/kg/day orally,
maximum 200 mg/day, to give a total of 3-6
months of treatment
» In patients who have a major relapse (defined

as being life- or organ-threatening disease),
cyclophosphamide should be started or re-
started, initially intravenously and then changing
to oral therapy.
TREATMENT

Primary options
» methylprednisolone: 10 mg/kg intravenously

before cyclophosphamide infusions,
maximum 1000 mg/dose
33
Ongoing
» Pulsed intravenous methylprednisolone
can be given before each cyclophosphamide
infusion, which may allow a faster tapering of
oral corticosteroids.
HBV-related PAN plus HBV serology + alternative antiviral
therapy
» HBV status should be checked initially on

relapse and, if positive, needs to be eradicated
before treatment for relapse of PAN.
» The treating physician should liaise with his

or her local hepatologists for advice about
alternative antiviral therapy to treat HBV, rather
than simply repeat the course of lamivudine.
TREATMENT
Emerging
Intravenous immunoglobulin (IVIG)
For patients with non HBV-related PAN who do not respond to conventional therapy, there are some case
studies using IVIG.[86] [87] [88] There are also reports that IVIG can be used as a corticosteroid-sparing
agent in less severe disease.[89] [90] There is one case report that demonstrated a good response with IVIG
in a corticosteroid-resistant patient with HBV-related PAN.[91]
Anti-tumor necrosis factor (TNF)-alpha therapy

The use of TNF-alpha antagonist therapy is now beginning to be explored as a potential treatment in patients
with resistant disease, although further trials are needed to prove its efficacy. Such trials may be limited by
the relative rarity of the disease and the fact that there is no clear rationale for TNF inhibition playing a key
role in the control of disease. Studies of infliximab (a monoclonal antibody to TNF) have shown promising
results in vasculitis,[92] 9[C]Evidence although these studies did not include any patients with PAN. However,
there are case studies in which patients with resistant PAN responded to infliximab, indicating that it is a
potential treatment option.[96] The use of etanercept is not recommended on the basis of the findings of a
study in granulomatosis with polyangiitis (Wegener),[97] although it has been used successfully in one case
to treat a child with resistant PAN.[98]
B-cell therapy
Rituximab is a chimeric monoclonal antibody specific for human CD20-positive B lymphocytes. In patients
with ANCA-associated vasculitis, the RAVE trial showed that rituximab was noninferior to oral daily
cyclophosphamide for induction of remission.[99] Subsequently, the MAINRITSAN trial has shown that
regular low dose rituximab is superior to azathioprine for the maintenance of remission in patients with
ANCA-associated vasculitis.[100] There have been no clinical trials with PAN, but there are a few case
reports of patients with classical (non-HBV related) PAN refractory to standard therapies whom have
subsequently had a good clinical response with rituximab.[101] [102] [103] Rituximab, especially when used
concomitantly with corticosteroids, can lead to the reactivation of HBV in those who have had previous HBV
infection and "clearance" (i.e., surface and core antibody positive). There are case reports of fulminant
hepatic failure in this context, and prophylactic antiviral therapy needs to be given with rituximab. Rituximab
should not be used in the context of current HBV infection.[104]
Interferon alfa
In mild or moderate HBV-related PAN that is resistant to standard therapy, the addition of interferon alfa to
the standard therapy has been described in case studies.[25] [105]
High-dose immunosuppression with corticosteroids and

cyclophosphamide in HBV-related PAN
In critically ill patients with HBV-related PAN who have uncontrolled vasculitis, one option may be to consider
a course of high-dose immunosuppression with corticosteroids and cyclophosphamide. However, this
approach carries the risk of promoting the underlying HBV infection, so the course should be as short as
possible and accompanied by lamivudine prophylaxis.[83]
TREATMENT
35
Polyarteritis nodosa Follow up
Recommendations
Monitoring
FOLLOW UP
The Birmingham Vasculitis Activity Score (BVAS)[109] has been validated for initial assessment, with
a high BVAS at baseline predictive of a worse outcome.[18] [55] The BVAS should be measured at
baseline, then monthly for the first 3 months, and then every 3 to 6 months. It can be used to assess
effectiveness of treatment over time. A flare of disease corresponds to a score above 0; remission is
indicated by a score of 0.
The Vasculitis Damage Index (VDI) should also be used initially, at 6 months, and then annually to
monitor progress.[116] Patients should be assessed monthly for the first 3 months, then every 3 to 6
months according to disease activity.[59]
Assessments should include clinical, laboratory, and investigations dependent on organ involvement.[59]
Use of cyclophosphamide, azathioprine, and other immunosuppressive agents requires specific blood
and urine monitoring as per standard protocols.[59] Repeat angiography is not routinely used in follow-up,
because improvement in clinical features has been found to parallel the resolution of aneurysms.[19] [117]
Female patients should have an annual cervical smear for 3 years after cyclophosphamide therapy.[59]
[118]
Yearly influenza vaccines are recommended.[115] Pneumococcal vaccine should be offered if antibody
levels are low.[115] Live vaccines should not be used until 3 months after cyclophosphamide has been
stopped.
Patient instructions
There are no specific known triggers to disease flares of PAN that patients can avoid. The treatment
of PAN can be intensive, as can the measures needed to prevent further morbidity from treatment, but
patients' adherence to management is key to optimizing outcomes. Support for patients from specialist
occupational therapists, physiotherapists, psychologists, rheumatology practitioners, rheumatologists, and
(in the case of HBV-related PAN) gastroenterologists is needed at the outset and throughout the disease
process. Patients are advised to contact their hospital team urgently if they suspect a relapse of their
condition. Patients are at risk of infection, especially while being treated with high doses of corticosteroids
and immunosuppressive agents, and they are advised to avoid close household contact with people who
have infectious diseases, especially varicella infections and respiratory infections.
Complications
Complications Timeframe Likelihood

complications from corticosteroids long term high
Osteoporosis secondary to prolonged corticosteroid use should be prevented with regular calcium, vitamin
D, and bisphosphonates.[55]
complications from cyclophosphamide long term medium
Cyclophosphamide increases the risk of bladder and cervical cancer. Female patients should have an
annual cervical smear for 3 years,[59] and all patients should have pretreatment with hydration and mesna
to reduce the bladder toxicity associated with cyclophosphamide.[59] [52]
Complications Timeframe Likelihood

renal failure variable high
FOLLOW UP
Renal involvement in PAN is not secondary to glomerulonephritis but rather is related to microaneurysms
and infarcts secondary to uncontrolled vasculitis.[55] Accelerated hypertension can occur as a result of
activation of the renin-angiotensin system, with up to one fifth of patients in one series developing end-
stage renal failure.[107]
Prevention should be through immunosuppression for the vasculitis, regular monitoring, and input from
renal physicians.
GI involvement variable high
Uncontrolled vasculitis can result in mesenteric ischemia, bowel infarction, and necrosis.[111] GI
involvement is an independent risk factor for poor prognosis.[18] Other abdominal organs can also be
affected, resulting in, for example, cholecystitis or pancreatitis. Hepatitis B virus (HBV)-related PAN has a
higher rate of GI involvement than non HBV-related PAN.[19]
Early diagnosis and prompt institution of appropriate medical therapy, as well as the use of appropriate
surgical therapy, can improve the prognosis of patients who present with an acute abdomen.[33]
disabling neurologic complications variable high
Mononeuritis multiplex is seen in around 80% of patients with HBV-related PAN during the course of
their disease.[19] More rarely, in less than 10% of patients, there is CNS involvement, with strokes or
encephalopathy.[19]
Treatment is as for the underlying vasculitis, but intensive occupational and physiotherapy are both
important for recovery of function.
liver failure or carcinoma variable high
The treatment of HBV-related PAN is adapted to the twin goals of control of the vasculitis and
seroconversion of the hepatitis. It has been proposed that, in roughly 50% of patients who seroconvert,
cure is attainable.[19] Those who do not seroconvert have an increased risk of chronic liver failure and
hepatocellular carcinoma.[76] [77] [78]
general complications of immunosuppression variable high
Long-term follow-up of patients with PAN demonstrates that infection is the cause of death in 12.9% of
patients.[55] Infection is the second major cause of early death (death within the first year), accounting for
26% of deaths.[53]
Treatment with cyclophosphamide should be accompanied by prophylaxis against Pneumocystis jiroveci

and fungal infections, and tuberculosis should be excluded before treatment starts.[59] Immunizations
against Pneumococcus and influenza should also be routine.[115]
cardiovascular disease variable medium
In long-term follow-up of patients with non HBV-related PAN and Churg-Strauss syndrome, cardiac
disease results in 9.4% of overall deaths.[55] Control of vasculitis is essential, but attention to other risk
factors for cardiovascular disease, such as smoking, hypercholesterolemia, and hypertension, is also
important.[59]
37
Prognosis
FOLLOW UP
The prognosis of PAN is improving because of earlier detection and better effectiveness of treatment. The
5-year survival of patients diagnosed between 1963 and 1995 was 76.5% compared with 87.9% in those
diagnosed after 1995 in one study.[106] In PAN unrelated to hepatitis B virus (HBV) infection, the 5-year
survival rate is 83.4%, compared with a 5-year survival rate of 73.4% in HBV-related PAN.[106] This is similar
to the rates in vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA).[55]
The relapse rate in HBV-related PAN is <11%, lower than that in non HBV-related PAN (19.4% to 57%).[19]
[55] [107] [106] However, the mean time to relapse is 29 months in both groups.[106] A time to diagnosis
of more than 90 days is related to an increased risk of future relapse, but is not associated with increased
mortality.[108]
When triple therapy with corticosteroids, antivirals, and plasma exchange is used in patients with HBV-related
PAN, seroconversion from hepatitis B e-antigen to hepatitis B e-antibody is achieved in 49.3% of patients;
those who seroconvert usually achieve complete remission with no relapses.[19]
Prognostic factors
The 5-factor score predicts survival in PAN.[18] The score consists of the following factors:
• Proteinuria >1 g/day

• Creatinine >1.58 mg/dL
• Cardiomyopathy
• Gastrointestinal symptoms
• CNS involvement.
Each item is scored 1 point if present. At 6 years in one prospective study, 86.1% of those with a score of 0
were alive, 69.4% with a score of 1 were alive, and 47% with a score of 2 or more were alive.[18]
Mortality can also be predicted by using the Birmingham Vasculitis Score,[109] which is a clinical index
of disease activity.[18] [55] Although included in the 5-factor prognostic score, cardiomyopathy and CNS
involvement are not independent predictors of mortality.[18]
GI involvement
GI involvement, specifically GI bleeding, perforation, infarction, and/or pancreatitis (but not cholecystitis),[18]
is an independent risk factor for higher mortality,[18] [54] [110] [111] [112] [113] especially during the acute
phase.[111]
A retrospective review of 24 patients with PAN and abdominal involvement illustrated this: 3 of 13 patients
with an acute abdomen died, compared with 1 of 11 patients with other GI symptoms.[33] This compared
favorably with a similar previous study in 1982, reporting 100% mortality in patients presenting with an
acute abdomen.[114] The lower mortality in the more recent study may be due to earlier diagnosis and
improvements in surgical and medical therapy.[33] GI involvement is more common in patients with HBV-
related PAN.[20] [19]
Renal involvement
The Chapel Hill Consensus Conference (CHCC) definition was not applied in the development of the 5-factor
score.[18] Consequently, the increased mortality in patients with elevated creatinine and proteinuria may
relate to patients with microscopic polyangiitis rather than PAN. However, a study of 10 patients with PAN (as
defined by the CHCC) found that 70% had renal involvement at diagnosis, with 2 patients developing end-
stage renal failure.[107]
Age
Older age at diagnosis is an independent predictor for death in the first year after diagnosis,[53] and age over
50 years is associated with decreased survival at 5 years.[111]
FOLLOW UP
39
Polyarteritis nodosa Guidelines
Diagnostic guidelines
International
Recommendations for the management of primary small and medium

vessel vasculitis 18413444 Mukhtyar C, Guillevin L, Cid MC, et al. EULAR
recommendations for the management of primary small and medium vessel
vasculitis. Ann Rheum Dis. 2009 Mar;68(3):310-7
Published by: European Vasculitis Study Group; European League Last published: 2009
Against Rheumatism
Treatment guidelines
International
GUIDELINES
BSR and BHPR guidelines for the management of adults with ANCA-
associated vasculitis 24729399 Ntatsaki E, Carruthers D, Chakravarty K,
et al; BSR and BHPR Standards, Guidelines and Audit Working Group.
BSR and BHPR guideline for the management of adults with ANCA-
associated vasculitis. Rheumatology (Oxford). 2014 Dec;53(12):2306-9. ht tp://
rheumatology.oxfordjournals.org/content/53/12/2306.long
Published by: British Society of Rheumatology; British Health Last published: 2014
Professionals in Rheumatology
Recommendations for the management of primary small and medium

vessel vasculitis 18413444 Mukhtyar C, Guillevin L, Cid MC, et al. EULAR
recommendations for the management of primary small and medium vessel
vasculitis. Ann Rheum Dis. 2009 Mar;68(3):310-7
Published by: European Vasculitis Study Group; European League Last published: 2009
Against Rheumatism
Polyarteritis nodosa Evidence scores
Evidence scores
1. Reduction in number of relapses: there is medium-quality evidence that the addition of
cyclophosphamide to corticosteroids is effective in reducing the number of relapses in non HBV-related
PAN, but not the 10-year mortality. This randomized controlled trial included 71 patients, some of
whom had PAN and some Churg-Strauss syndrome.[56]
Evidence level B: Randomized controlled trials (RCTs) of <200 participants, methodologically
flawed RCTs of >200 participants, methodologically flawed systematic reviews (SRs) or good quality
observational (cohort) studies.
2. Improvement in survival: there is medium-quality evidence that corticosteroids plus cyclophosphamide

improves survival in non HBV-related PAN over a mean follow-up of 88 months in those with a 5-factor
score ≥2 (p=0.041). This retrospective analysis included 278 patients, some of whom had PAN, some
microscopic polyangiitis, and some Churg-Strauss syndrome.[55]
3. Frequency of death, relapse, or treatment failure: there is medium-quality evidence that there is
no difference in efficacy between a regimen of intravenous cyclophosphamide plus corticosteroids
followed by maintenance on oral corticosteroids and a regimen of oral cyclophosphamide plus
prednisolone followed by maintenance on azathioprine. This randomized controlled trial included
54 patients, some of whom had PAN, some microscopic polyangiitis and some granulomatosis with
polyangiitis (Wegener).[57]
4. Efficacy and route of cyclophosphamide therapy: there is medium-quality evidence that oral and
intravenous regimens of cyclophosphamide are equally effective when used in conjunction with
corticosteroids in non HBV-related PAN, although the intravenous route can be preferred because of
the lower total dose and better side-effect profile. [58]
5. Reduction in relapses or mortality: there is medium-quality evidence that the addition of plasma
exchange to corticosteroid therapy does not reduce relapses or improve survival in non HBV-related
EVIDENCE SCORES
PAN. This randomized controlled trial included 78 patients, some of whom had PAN and some Churg-
Strauss syndrome.[61]
41
Polyarteritis nodosa Evidence scores
6. Reduction in relapses or mortality: there is medium-quality evidence that the addition of plasma
exchange to a combination of corticosteroids and cyclophosphamide does not reduce relapses or
improve survival in non HBV-related PAN. This randomized controlled trial involved 62 patients, some
of whom had PAN and some Churg-Strauss syndrome.[62]
7. Probability of relapse: there is medium-quality evidence that 12 infusions of cyclophosphamide

compared with 6 infusions, in combination with corticosteroids, results in a significantly lower
probability of relapse (hazard ratio 0.44, p=0.02). This randomized controlled trial involved 65 patients
with a 5-factor score ≥1, some of whom had PAN and some microscopic polyangiitis.[63]
8. Clinical recovery: there is poor-quality evidence that therapy with lamivudine and plasma exchange
following an initial 2-week course of corticosteroids is associated with clinical recovery. In a
prospective, non-blinded trial of 10 patients with HBV-related PAN, 9 patients had achieved clinical
recovery by 6 months, and 6 of these 9 patients had seroconverted from HbeAg to HbeAb. The other
patient had died from catheter-related sepsis.[83]
Evidence level C: Poor quality observational (cohort) studies or methodologically flawed randomized
controlled trials (RCTs) of <200 participants.
9. Complete or partial remission: there is poor-quality evidence that infliximab is associated with complete
or partial remission, although the studies have been conducted in non-PAN vasculitis. In a pilot study
in which infliximab was used to treat 10 patients with granulomatosis with polyangiitis (Wegener),
rheumatoid arthritis-associated vasculitis, and cryoglobulinemia with refractory disease, all patients
achieved complete or partial remission at 6 months. In a longer-term retrospective review of 15
patients with primary vasculitides treated with infliximab, over a median of 34 months, 11 entered
remission by day 45 and 5 had sustained remission at 2 years. In an open-label, prospective trial of
infliximab conducted in patients with vasculitides associated with antineutrophil cytoplasmic antibodies
(ANCA) who had persistent disease, 88% demonstrated clinical remission. However, 20% of initial
responders subsequently relapsed, and the rate of severe infections was 21%.[93] [94] [95]
Evidence level C: Poor quality observational (cohort) studies or methodologically flawed randomized
controlled trials (RCTs) of <200 participants.
EVIDENCE SCORES
Polyarteritis nodosa References
Key articles
• Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the
REFERENCES
classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum.
1990;33:1094-1100. Abstract
• Mahr A, Guillevin L, Poissonnet M, et al. Prevalences of polyarteritis nodosa, microscopic polyangiitis,

Wegener's granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in
2000: a capture-recapture estimate. Arthritis Rheum. 2004;51:92-99. Abstract
• Colmegna I, Maldonado-Cocco JA. Polyarteritis nodosa revisited. Curr Rheumatol Rep.

2005;7:288-296. Abstract
• Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small
and medium vessel vasculitis. Ann Rheum Dis. 2009 Mar;68(3):310-7 Abstract
• Ntatsaki E, Carruthers D, Chakravarty K, et al; BSR and BHPR Standards, Guidelines and Audit
Working Group. BSR and BHPR guideline for the management of adults with ANCA-associated
vasculitis. Rheumatology (Oxford). 2014 Dec;53(12):2306-9. Full text Abstract
• Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis
associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44.
Full text Abstract
• De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus

methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-
associated vasculitis. Arthritis Rheum. 2005 Aug;52(8):2461-9. Full text Abstract
References
1. Matteson EL, Kluge FJ. Think clearly, be sincere, act calmly: Adolf Kussmaul (February 22, 1822-May
28, 1902) and his relevance to medicine in the 21st century. Curr Opin Rheumatol. 2003;15:29-34.
Abstract
2. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: proposal of an
international consensus conference. Arthritis Rheum. 1994 Feb;37(2):187-92. Abstract
3. Lightfoot RW Jr, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for
the classification of polyarteritis nodosa. Arthritis Rheum. 1990;33:1088-1093. Abstract
4. Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus methodology for the
classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies.
Ann Rheum Dis. 2007;66:222-227. Abstract
5. Lhote F, Cohen P, Guillevin L. Polyarteritis nodosa, microscopic polyangiitis and Churg-Strauss

syndrome. Lupus. 1998;7:238-258. Abstract
43
6. Lanham JG, Elkon KB, Pusey CD, et al. Systemic vasculitis with asthma and eosinophilia: a clinical
approach to the Churg-Strauss syndrome. Medicine (Baltimore). 1984;63:65-81. Abstract
REFERENCES
7. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the
classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum.
1990;33:1094-1100. Abstract
8. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the
classification of Wegener's granulomatosis. Arthritis Rheum. 1990 Aug;33(8):1101-7. Abstract
9. Henegar C, Pagnoux C, Puechal X, et al. A paradigm of diagnostic criteria for polyarteritis nodosa:
analysis of a series of 949 patients with vasculitides. Arthritis Rheum. 2008;58:1528-1538. Full text
Abstract
10. Watts RA, Lane SE, Scott DG, et al. Epidemiology of vasculitis in Europe. Ann Rheum Dis. 2001
Dec;60(12):1156-7. Full text Abstract
11. Watts RA, Scott DG. Epidemiology of vasculitis. In: Bridges L, Ball G, eds. Vasculitis. Oxford, UK:
Oxford University Press; 2008:7-22.
12. el-Reshaid K, Kapoor MM, el-Reshaid W, et al. The spectrum of renal disease associated with
microscopic polyangiitis and classic polyarteritis nodosa in Kuwait. Nephrol Dial Transplant.
1997;12:1874-1882. Full text Abstract
13. McMahon BJ, Heyward WL, Templin DW, et al. Hepatitis B-associated polyarteritis nodosa in Alaskan
Eskimos: clinical and epidemiologic features and long-term follow-up. Hepatology. 1989;9:97-101.
Abstract
14. Koldingsnes W, Nossent H. Epidemiology of Wegener's granulomatosis in northern Norway. Arthritis

Rheum. 2000 Nov;43(11):2481-7. Full text Abstract
15. Mahr A, Guillevin L, Poissonnet M, et al. Prevalences of polyarteritis nodosa, microscopic polyangiitis,
Wegener's granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in
2000: a capture-recapture estimate. Arthritis Rheum. 2004;51:92-99. Abstract
16. Mohammad AJ, Jacobsson LT, Mahr AD, et al. Prevalence of Wegener's granulomatosis, microscopic
polyangiitis, polyarteritis nodosa and Churg-Strauss syndrome within a defined population in southern
Sweden. Rheumatology (Oxford). 2007 Aug;46(8):1329-37. Full text Abstract
17. Reinhold-Keller E, Zeidler A, Gutfleisch J, et al. Giant cell arteritis is more prevalent in urban than in
rural populations: results of an epidemiological study of primary systemic vasculitides in Germany.
Rheumatology (Oxford). 2000;39:1396-1402. Full text Abstract
18. Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and Churg-Strauss
syndrome: a prospective study in 342 patients. Medicine (Baltimore). 1996;75:17-28. Abstract
19. Guillevin L, Mahr A, Callard P, et al. Hepatitis B virus-associated polyarteritis nodosa: clinical
characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore).
2005;84:313-322. Abstract
20. Guillevin L, Lhote F, Cohen P, et al. Polyarteritis nodosa related to hepatitis B virus: a prospective
study with long-term observation of 41 patients. Medicine (Baltimore). 1995;74:238-253. Abstract
REFERENCES
21. Soufir N, Descamps V, Crickx B, et al. Hepatitis C virus infection in cutaneous polyarteritis nodosa: a
retrospective study of 16 cases. Arch Dermatol. 1999;135:1001-1002. Abstract
22. Pagnoux C, Cohen P, Guillevin L. Vasculitides secondary to infections. Clin Exp Rheumatol. 2006;24(2
suppl 41):S71-S81. Abstract
23. Fort JG, Griffin R, Tahmoush A, et al. Muscle involvement in polyarteritis nodosa: report of a patient
presenting clinically as polymyositis and review of the literature. J Rheumatol. 1994;21:945-948.
Abstract
24. Colmegna I, Maldonado-Cocco JA. Polyarteritis nodosa revisited. Curr Rheumatol Rep.
2005;7:288-296. Abstract
25. Erhardt A, Sagir A, Guillevin L, et al. Successful treatment of hepatitis B virus associated
polyarteritis nodosa with a combination of prednisolone, alpha-interferon and lamivudine. J Hepatol.
2000;33:677-683. Abstract
26. Wooten MD, Jasin HE. Vasculitis and lymphoproliferative diseases. Semin Arthritis Rheum.
1996;26:564-574. Abstract
27. Hasler P, Kistler H, Gerber H. Vasculitides in hairy cell leukemia. Semin Arthritis Rheum.
1995;25:134-142. Abstract
28. Nakamura T, Kanazawa N, Ikeda T, et al. Cutaneous polyarteritis nodosa: revisiting its definition and
diagnostic criteria. Arch Dermatol Res. 2009;301:117-121. Abstract
29. Trepo C, Guillevin L. Polyarteritis nodosa and extrahepatic manifestations of HBV infection: the case
against autoimmune intervention in pathogenesis. J Autoimmun. 2001;16:269-274. Abstract
30. Younger DS. Vasculitis of the nervous system. Curr Opin Neurol. 2004;17:317-336. Abstract
31. Gibson LE. Cutaneous vasculitis update. Dermatol Clin. 2001;19:603-615. Abstract
32. Gibson LE, Su WP. Cutaneous vasculitis. Rheum Dis Clin North Am. 1995;21:1097-1113. Abstract
33. Levine SM, Hellmann DB, Stone JH. Gastrointestinal involvement in polyarteritis nodosa (1986-2000):
presentation and outcomes in 24 patients. Am J Med. 2002;112:386-391. Abstract
34. Pagnoux C, Mahr A, Cohen P, et al. Presentation and outcome of gastrointestinal involvement in
systemic necrotizing vasculitides: analysis of 62 patients with polyarteritis nodosa, microscopic
polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, or rheumatoid arthritis-associated
vasculitis. Medicine (Baltimore). 2005;84:115-128. Abstract
35. Stone JH. Polyarteritis nodosa. JAMA. 2002;288:1632-1639. Abstract
45
36. Ng WF, Chow LT, Lam PW. Localized polyarteritis nodosa of breast - report of two cases and a review
of the literature. Histopathology. 1993;23:535-539. Abstract
REFERENCES
37. Teichman JM, Mattrey RF, Demby AM, et al. Polyarteritis nodosa presenting as acute orchitis: a case
report and review of the literature. J Urol. 1993;149:1139-1140. Abstract
38. Hekali P, Kajander H, Pajari R, et al. Diagnostic significance of angiographically observed visceral
aneurysms with regard to polyarteritis nodosa. Acta Radiol. 1991;32:143-148. Abstract
39. Ozaki K, Miyayama S, Ushiogi Y, et al. Renal involvement of polyarteritis nodosa: CT and MR findings.
Abdom Imaging. 2009;34:265-270. Abstract
40. Ozcakar ZB, Yalcinkaya F, Fitoz S, et al. Polyarteritis nodosa: successful diagnostic imaging utilizing
pulsed and color Doppler ultrasonography and computed tomography angiography. Eur J Pediatr.
2006;165:120-123. Abstract
41. Lie JT. Illustrated histopathologic classification criteria for selected vasculitis syndromes.
American College of Rheumatology Subcommittee on Classification of Vasculitis. Arthritis Rheum.
1990;33:1074-1087. Abstract
42. Jennette JC, Falk RJ. The role of pathology in the diagnosis of systemic vasculitis. Clin Exp
Rheumatol. 2007;25(1 suppl 44):S52-S56. Abstract
43. Luqmani RA, Pathare S, Kwok-Fai TL. How to diagnose and treat secondary forms of vasculitis. Best
Pract Res Clin Rheumatol. 2005;19:321-336. Abstract
44. Fain O, Hamidou M, Cacoub P, et al. Vasculitides associated with malignancies: analysis of sixty
patients. Arthritis Rheum. 2007;57:1473-1480. Full text Abstract
45. Siegert CE, Macfarlane JD, Hollander AM, et al. Systemic fibromuscular dysplasia masquerading as
polyarteritis nodosa. Nephrol Dial Transplant. 1996;11:1356-1358. Full text Abstract
46. Deneuville T, Tance Y, Tiev K, et al. Cholesterol crystal emboli presenting as a mononeuropathy [in
French]. Rev Med Interne. 2009;30:982-984. Abstract
47. Scolari F, Tardanico R, Zani R, et al. Cholesterol crystal embolism: a recognizable cause of renal
disease. Am J Kidney Dis. 2000;36:1089-1109. Abstract
48. Wilson YG, Thornton MJ, Prance SE, et al. Embolisation from atrial myxomas: a cause of acute on
chronic limb ischaemia. Eur J Vasc Endovasc Surg. 1997;14:502-504. Abstract
49. Ortega-Hernandez OD, Agmon-Levin N, Blank M, et al. The physiopathology of the catastrophic
antiphospholipid (Asherson's) syndrome: compelling evidence. J Autoimmun. 2009;32:1-6. Abstract
50. Malecki R, Zdrojowy K, Adamiec R. Thromboangiitis obliterans in the 21st century - a new face of
disease. Atherosclerosis. 2009;206:328-334. Abstract
51. Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health
management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57:1-20.
Full text Abstract
REFERENCES
52. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small
and medium vessel vasculitis. Ann Rheum Dis. 2009 Mar;68(3):310-7 Abstract
53. Bourgarit A, Le Toumelin P, Pagnoux C, et al. Deaths occurring during the first year after treatment
onset for polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: a retrospective
analysis of causes and factors predictive of mortality based on 595 patients. Medicine (Baltimore).
2005;84:323-330. Abstract
54. Cohen RD, Conn DL, Ilstrup DM. Clinical features, prognosis, and response to treatment in
polyarteritis. Mayo Clin Proc. 1980;55:146-155. Abstract
55. Gayraud M, Guillevin L, le Toumelin P, et al. Long-term followup of polyarteritis nodosa, microscopic
polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients.
Arthritis Rheum. 2001;44:666-675. Full text Abstract
56. Guillevin L, Jarrousse B, Lok C, et al. Longterm followup after treatment of polyarteritis nodosa and
Churg-Strauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to
steroids and plasma exchange: a prospective randomized trial of 71 patients. The Cooperative Study
Group for Polyarteritis Nodosa. J Rheumatol. 1991;18:567-574. Abstract
57. Adu D, Pall A, Luqmani RA, et al. Controlled trial of pulse versus continuous prednisolone and
cyclophosphamide in the treatment of systemic vasculitis. QJM. 1997;90:401-409. Full text Abstract
58. Gayraud M, Guillevin L, Cohen P, et al; French Cooperative Study Group for Vasculitides. Treatment of
good-prognosis polyarteritis nodosa and Churg-Strauss syndrome: comparison of steroids and oral or
pulse cyclophosphamide in 25 patients. Br J Rheumatol. 1997;36:1290-1297. Full text Abstract
59. Ntatsaki E, Carruthers D, Chakravarty K, et al; BSR and BHPR Standards, Guidelines and Audit
Working Group. BSR and BHPR guideline for the management of adults with ANCA-associated
vasculitis. Rheumatology (Oxford). 2014 Dec;53(12):2306-9. Full text Abstract
60. Ledingham J, Wilkinson C, Deighton C. British Thoracic Society (BTS) recommendations for assessing
risk and managing tuberculosis in patients due to start anti-TNF-alpha treatments. Rheumatology
(Oxford). 2005;44:1205-1206. Full text Abstract
61. Guillevin L, Fain O, Lhote F, et al. Lack of superiority of steroids plus plasma exchange to steroids
alone in the treatment of polyarteritis nodosa and Churg-Strauss syndrome: a prospective, randomized
trial in 78 patients. Arthritis Rheum. 1992;35:208-215. Abstract
62. Guillevin L, Lhote F, Cohen P, et al. Corticosteroids plus pulse cyclophosphamide and plasma
exchanges versus corticosteroids plus pulse cyclophosphamide alone in the treatment of polyarteritis
nodosa and Churg-Strauss syndrome patients with factors predicting poor prognosis: a prospective,
randomized trial in sixty-two patients. Arthritis Rheum. 1995;38:1638-1645. Abstract
47
63. Guillevin L, Cohen P, Mahr A, et al. Treatment of polyarteritis nodosa and microscopic polyangiitis
with poor prognosis factors: a prospective trial comparing glucocorticoids and six or twelve
cyclophosphamide pulses in sixty-five patients. Arthritis Rheum. 2003;49:93-100. Full text Abstract
REFERENCES
64. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis
associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44.
Full text Abstract
65. Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-
associated vasculitis. N Engl J Med. 2008;359:2790-2803. Full text Abstract
66. Metzler C, Miehle N, Manger K, et al. Elevated relapse rate under oral methotrexate versus
leflunomide for maintenance of remission in Wegener's granulomatosis. Rheumatology (Oxford).
67. Langford CA, Talar-Williams C, Barron KS, et al. Use of a cyclophosphamide-induction methotrexate-
maintenance regimen for the treatment of Wegener's granulomatosis: extended follow-up and rate of
relapse. Am J Med. 2003;114:463-469. Abstract
68. Guillevin L, Pagnoux C. When should immunosuppressants be prescribed to treat systemic

vasculitides? Intern Med. 2003;42:313-317. Full text Abstract
69. de Groot K, Muhler M, Reinhold-Keller E, et al. Induction of remission in Wegener's granulomatosis

with low dose methotrexate. J Rheumatol. 1998;25:492-495. Abstract
70. De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus
methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-
associated vasculitis. Arthritis Rheum. 2005 Aug;52(8):2461-9. Full text Abstract
71. Stone JH, Tun W, Hellman DB. Treatment of non-life threatening Wegener's granulomatosis with
methotrexate and daily prednisone as the initial therapy of choice. J Rheumatol. 1999;26:1134-1139.
Abstract
72. Prince AM, Trepo C. Role of immune complexes involving SH antigen in pathogenesis of chronic active
hepatitis and polyarteritis nodosa. Lancet. 1971;1:1309-1312. Abstract
73. Cheng AL. Steroid-free chemotherapy decreases the risk of hepatitis flare-up in hepatitis B virus
carriers with non-Hodgkin's lymphoma. Blood. 1996;87:1202. Full text Abstract
74. Hoofnagle JH, Davis GL, Pappas SC, et al. A short course of prednisolone in chronic type B hepatitis:
report of a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1986;104:12-17.
Abstract
75. Lam KC, Lai CL, Trepo C, et al. Deleterious effect of prednisolone in HBsAg-positive chronic active
hepatitis. N Engl J Med. 1981;304:380-386. Abstract
76. de Jongh FE, Janssen HL, de Man RA, et al. Survival and prognostic indicators in hepatitis B surface
antigen-positive cirrhosis of the liver. Gastroenterology. 1992;103:1630-1635. Abstract
77. Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in
patients with chronic hepatitis B. Hepatology. 2002;35:1522-1527. Full text Abstract
REFERENCES
78. Realdi G, Fattovich G, Hadziyannis S, et al. Survival and prognostic factors in 366 patients with
compensated cirrhosis type B: a multicenter study. The Investigators of the European Concerted
Action on Viral Hepatitis (EUROHEP). J Hepatol. 1994;21:656-666. Abstract
79. Chalopin JM, Rifle G, Turc JM, et al. Immunological findings during successful treatment of HBsAg-
associated polyarteritis nodosa by plasmapheresis alone. Br Med J. 1980;280:368. Full text Abstract
80. Guillevin L, Lhote F, Leon A, et al. Treatment of polyarteritis nodosa related to hepatitis B virus with
short term steroid therapy associated with antiviral agents and plasma exchanges: a prospective trial
in 33 patients. J Rheumatol. 1993;20:289-298. Abstract
81. Guillevin L, Lhote F, Sauvaget F, et al. Treatment of polyarteritis nodosa related to hepatitis B virus with
interferon-alpha and plasma exchanges. Ann Rheum Dis. 1994;53:334-337. Full text Abstract
82. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver
disease. N Engl J Med. 2004 Oct 7;351(15):1521-31. Full text Abstract
83. Guillevin L, Mahr A, Cohen P, et al. Short-term corticosteroids then lamivudine and plasma exchanges
to treat hepatitis B virus-related polyarteritis nodosa. Arthritis Rheum. 2004;51:482-487. Full text
Abstract
84. Pagnoux C, Quéméneur T, Ninet J, et al. Treatment of systemic necrotizing vasculitides in

patients aged sixty-five years or older: results of a multicenter, open-label, randomized controlled
trial of corticosteroid and cyclophosphamide-based induction therapy. Arthritis Rheumatol.
85. Ribi C, Cohen P, Pagnoux C, et al; French Vasculitis Study Group. Treatment of polyarteritis nodosa
and microscopic polyangiitis without poor-prognosis factors: a prospective randomized study of one
hundred twenty-four patients. Arthritis Rheum. 2010;62:1186-1197. Full text Abstract
86. Asano Y, Ihn H, Maekawa T, et al. High-dose intravenous immunoglobulin infusion in polyarteritis
nodosa: report on one case and review of the literature. Clin Rheumatol. 2006;25:396-398. Abstract
87. Gonzàlez-Fernàndez MA, Garcia-Consuegra J. Polyarteritis nodosa resistant to conventional

treatment in a pediatric patient. Ann Pharmacother. 2007;41:885-890. Abstract
88. Kroiss M, Hohenleutner U, Gruss C, et al. Transient and partial effect of high-dose intravenous
immunoglobulin in polyarteritis nodosa. Dermatology. 2001;203:188-189. Abstract
89. Balbir-Gurman A, Nahir AM, Braun-Moscovici Y. Intravenous immunoglobulins in polyarteritis nodosa

restricted to the limbs: case reports and review of the literature. Clin Exp Rheumatol. 2007;25(1 suppl
44):S28-S30. Abstract
90. Gedalia A, Correa H, Kaiser M, et al. Case report: steroid sparing effect of intravenous gamma
globulin in a child with necrotizing vasculitis. Am J Med Sci. 1995;309:226-228. Abstract
49
91. Boman S, Ballen JL, Seggev JS. Dramatic responses to intravenous immunoglobulin in vasculitis. J
Intern Med. 1995;238:375-377. Abstract
REFERENCES
92. de Kort SW, van Rossum MA, ten Cate R. Infliximab in a child with therapy-resistant systemic
vasculitis. Clin Rheumatol. 2006;25:769-771. Abstract
93. Bartolucci P, Ramanoelina J, Cohen P, et al. Efficacy of the anti-TNF-alpha antibody infliximab
against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology (Oxford).
94. Josselin L, Mahr A, Cohen P, et al. Infliximab efficacy and safety against refractory systemic
necrotising vasculitides: long-term follow-up of 15 patients. Ann Rheum Dis. 2008;67:1343-1346.
Abstract
95. Booth A, Harper L, Hammad T, et al. Prospective study of TNF alpha blockade with infliximab in anti-
neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol. 2004;15:717-721.
Full text Abstract
96. Wu K, Throssell D. A new treatment for polyarteritis nodosa. Nephrol Dial Transplant.
97. Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard
therapy for Wegener's granulomatosis. N Engl J Med. 2005 Jan 27;352(4):351-61. Full text Abstract
98. Feinstein J, Arroyo R. Successful treatment of childhood onset refractory polyarteritis nodosa with
tumor necrosis factor alpha blockade. J Clin Rheumatol. 2005;11:219-222. Abstract
99. Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus
cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363:221-232. Full text
Abstract
100. Guillevin L, Pagnoux C, Karras A, et al; French Vasculitis Study Group. Rituximab versus azathioprine
for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014;371:1771-1780. Full text
Abstract
101. Sonomoto K, Miyamura T, Watanabe H, et al. A case of polyarteritis nodosa successfully treated by
rituximab. Nihon Rinsho Meneki Gakkai Kaishi. 2008;31:119-123. Abstract
102. Seri Y, Shoda H, Hanata N, et al. A case of refractory polyarteritis nodosa successfully treated with
rituximab. Mod Rheumatol. 2015 Mar 12 [Epub ahead of print]. Abstract
103. Ribeiro E, Cressend T, Duffau P, et al. Rituximab efficacy during a refractory polyarteritis nodosa flare.
Case Rep Med. 2009;2009:738293. Full text Abstract
104. Pattullo V. Hepatitis B reactivation in the setting of chemotherapy and immunosuppression - prevention
is better than cure. World J Hepatol. 2015;7:954-967. Full text Abstract
105. Wicki J, Olivieri J, Pizzolato G, et al. Successful treatment of polyarteritis nodosa related to hepatitis B
virus with a combination of lamivudine and interferon alpha. Rheumatology (Oxford). 1999;38:183-185.
Full text Abstract
REFERENCES
106. Pagnoux C, Seror R, Henegar C, et al; French Vasculitis Study Group. Clinical features and outcomes
in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed
between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis
Rheum. 2010;62:616-626. Full text Abstract
107. Selga D, Mohammad A, Sturfelt G, et al. Polyarteritis nodosa when applying the Chapel Hill
nomenclature - a descriptive study on ten patients. Rheumatology (Oxford). 2006;45:1276-1281. Full
text Abstract
108. Agard C, Mouthon L, Mahr A, et al. Microscopic polyangiitis and polyarteritis nodosa: how and when
do they start? Arthritis Rheum. 2003;49:709-715. Full text Abstract
109. Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic
necrotizing vasculitis. QJM. 1994;87:671-678. Abstract
110. Edwards WH Jr, Martin RS 3rd, Edwards WH Sr, et al. Surviving gastrointestinal infarction due to
polyarteritis nodosa: a rare event. Am Surg. 1992;58:167-172. Abstract
111. Guillevin L, Le Thi Huong D, Godeau P, et al. Clinical findings and prognosis of polyarteritis nodosa
and Churg-Strauss angiitis: a study in 165 patients. Br J Rheumatol. 1988 Aug;27(4):258-64. Abstract
112. Guillevin L, Lhote F, Gallais V, et al. Gastrointestinal tract involvement in polyarteritis nodosa and
Churg-Strauss syndrome. Ann Med Interne (Paris). 1995;146:260-267. Abstract
113. Travers RL, Allison DJ, Brettle RP, et al. Polyarteritis nodosa: a clinical and angiographic analysis of 17
cases. Semin Arthritis Rheum. 1979;8:184-199. Abstract
114. Zizic TM, Classen JN, Stevens MB. Acute abdominal complications of systemic lupus erythematosus
and polyarteritis nodosa. Am J Med. 1982;73:525-531. Abstract
115. Gluck T. Vaccinate your immunocompromised patients! Rheumatology (Oxford). 2006;45:9-10. Full
text Abstract
116. Exley AR, Bacon PA, Luqmani RA, et al. Development and initial validation of the Vasculitis Damage
Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis
Rheum. 1997;40:371-380. Abstract
117. Darras-Joly C, Lortholary O, Cohen P, et al. Regressing microaneurysms in 5 cases of hepatitis B

virus related polyarteritis nodosa. J Rheumatol. 1995;22:876-880. Abstract
118. Ognenovski VM, Marder W, Somers EC, et al. Increased incidence of cervical intraepithelial
neoplasia in women with systemic lupus erythematosus treated with intravenous cyclophosphamide. J
Rheumatol. 2004;31:1763-1767. Abstract
51
Polyarteritis nodosa Images
Images
IMAGES
Figure 1: American College of Rheumatology 1990 criteria for PAN

IMAGES
Figure 2: Renal angiogram showing aneurysms, a classical feature of PAN
From the collection of Dr Raashid Luqmani
Figure 3: Renal angiogram showing aneurysms and microaneurysms
53
From the collection of Dr Loic Guillevin
Figure 4: A purpuric rash is a common feature

IMAGES
IMAGES
Figure 5: Skin ulcers in the lower limbs are a common manifestation of PAN
55
IMAGES Polyarteritis nodosa Images
Figure 6: Large skin ulcer from a patient with PAN

IMAGES
Figure 7: Vesiculo-bullous skin rash with necrosis
57
Figure 8: Digital gangrene from medium vessel vasculitis

Figure 9: Mesenteric angiogram showing small and micro aneurysms

IMAGES
Figure 10: Pathology specimen of a medium-sized muscular artery showing transmural inflammation
59
Figure 11: Biopsy specimen showing florid transmural inflammation of a small artery
Polyarteritis nodosa Disclaimer
Disclaimer
This content is meant for medical professionals. The BMJ Publishing Group Ltd (“BMJ Group”) tries to
ensure that the information provided is accurate and uptodate, but we do not warrant that it is. The BMJ
Group does not advocate or endorse the use of any drug or therapy contained within nor does it diagnose
patients. Medical professionals should use their own professional judgement in using this information and
caring for their patients and the information herein should not be considered a substitute for that.
This information is not intended to cover all possible diagnosis methods, treatments, follow up, drugs and any
contraindications or side effects. We strongly recommend that users independently verify specified diagnosis,
treatments and follow up and ensure it is appropriate for your patient. This information is provided on an “as
is” basis and to the fullest extent permitted by law the BMJ Group assumes no responsibility for any aspect of
healthcare administered with the aid of this information or any other use of this information.
View our full Website Terms and Conditions.
Contact us
+1 855-458-0579 (toll free from USA)

ussupport@bmj.com
BMJ Americas Office

2 Hudson Place,Suite 300
Hoboken,New Jersey 07030
DISCLAIMER
61
Contributors:
// Authors:
Ravi Suppiah, MBChB, PGDipSportMed, FRACP

Consultant Rheumatologist
Auckland and Counties Manukau District Health Boards, Auckland, New Zealand
DISCLOSURES: RS declares that he has no competing interests.
Joanna Robson, MBBS, PhD, MRCP

Rheumatology Registrar
Nuffield Orthopaedic Centre, Oxford, UK
DISCLOSURES: JR has attended symposia sponsored by Roche Ltd.
Loic Guillevin, MD
Professor of Medicine
Rheumatology Department, Hopital Cochin, Paris, France
DISCLOSURES: LG is an author of a number of references cited in this monograph.
Raashid Luqmani, DM, FRCP, FRCP(E)

Professor of Rheumatology
NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and
Musculoskeletal Science, University of Oxford, Oxford, UK
DISCLOSURES: RL has attended symposia sponsored by GlaxoSmithKline, the manufacturer of Epivir
(lamivudine), and has received sponsorship from Roche, Abbot Ltd, Schering Plough (the manufacturer of
Remicade [infliximab]), and Wyeth (the manufacturer of Enbrel [etanercept]) to attend conferences. RL has
received sponsorship from Sanofi Aventis (the manufacturer of Arava [leflunomide]) to support the costs of a
meeting, and is on the Roche advisory board looking at treatment of vasculitis with B cell therapy. RL is an
author of a number of references cited in this monograph.
// Peer Reviewers:
Alan Bridges, MD
Professor and Vice Chair
Department of Medicine, University of Wisconsin Hospital, Madison, WI
DISCLOSURES: AB declares that he has no competing interests.
Richard Wat ts, MA, DM, FRCP

Consultant Rheumatologist
Ipswich Hospital, Ipswich, UK
DISCLOSURES: RW has received fees for consulting from Roche Pharmaceuticals, manufacturer of
rituximab. His department has received financial support from Wyeth Pharmaceuticals, manufacturer
of etanercept, and from Schering-Plough, manufacturer of infliximab. RW is an author of a number of
references cited in this monograph.
Ellen C. Ebert, MD
Professor of Medicine
Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ
DISCLOSURES: ECE declares that she has no competing interests.

Poliarteritis Nodosa

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Poliarteritis Nodosa

Uploaded by

Copyright:

Available Formats

Polyarteritis nodosa

The right clinical information, right where it's needed

Last updated: Jan 05, 2018

◊ Angiography typically demonstrates microaneurysms and focal narrowing in medium-sized blood

◊ Prognosis can be determined by use of the 5-factor score.

American College of Rheumatology 1990 criteria for PAN

European Medicines Agency (EMA) algorithm for the classification

French Vasculitis Study Group (FVSG) proposal for diagnostic

The positive predictive items were:

• Positivity for HBV infection

• Presence of antineutrophil cytoplasmic antibodies (ANCA)

Step-by-step diagnostic approach

Possible organ-specific manifestations

• Nervous system (in 55% of patients)

from ischemia or infarction of these organs.[34]

Test results that help to support the diagnosis include:

• Elevated CRP and/or ESR, which suggests systemic inflammation

• Blood cultures, to exclude endocarditis or other infective mimics of vasculitis

In pathologic descriptions of PAN, the involvement of vessel bifurcations is reported to be a common

blood transfusion at a time before routine screening for hepatitis B virus

hepatitis C virus (HCV) infection

History & examination factors

• Fever is a common but nonspecific symptom.

weight loss (common)

myalgia or arthralgia (common)

mononeuritis multiplex (common)

muscle tenderness (common)

skin manifestations (common)

diastolic blood pressure >90 mmHg (common)

blood transfusion at a time before routine screening for hepatitis B virus

previous or current intravenous drug abuse (uncommon)

recent hepatitis B virus (HBV) infection (uncommon)

testicular pain (uncommon)

Other diagnostic factors

hairy cell leukemia (uncommon)

upper motor neuron weakness (uncommon)

monocular blindness (uncommon)

chest pain (uncommon)

congestive cardiac failure (uncommon)

tender breast lumps (uncommon)

inflammation and, therefore, a frequent finding in PAN. A neutrophilia

hepatitis C virus (HCV) serology positive anti-hepatitis C

Other tests to consider

conventional angiography is indicated.

Condition Differentiating signs / Differentiating tests

Condition Differentiating signs / Differentiating tests

Churg-Strauss syndrome • Granulomatosis with • CBC: significant (>10%

vessels (i.e., small- and • Tissue biopsy (sural nerve,

Condition Differentiating signs / Differentiating tests

Infection • Endovascular bacterial • Blood cultures to detect a

Systemic lupus • SLE can present with similar • Antinuclear antibody is

Condition Differentiating signs / Differentiating tests

Atheroma • Atherosclerosis is the most • Conventional digital

common cause of organ subtraction angiography is

Condition Differentiating signs / Differentiating tests

Atrial my xoma • Can cause recurrent emboli • Echocardiography reveals

Catastrophic • A rare disorder with • IgG anticardiolipin

Condition Differentiating signs / Differentiating tests

The positive predictive items were:

• Positivity for hepatitis B virus infection

The negative predictive items were:

• Presence of antineutrophil cytoplasmic antibodies (ANCA)

The American College of Rheumatology (ACR) 1990 criteria for the

European Medicines Agency (EMA) algorithm for the classification