Vasculitides classification by blood
1866 “periarteritis nodosa” used to describe any form of systemic
Vasculitis predominantly affecting medium arteries defined as the
main visceral arteries and their branches.
Polyarteritis nodosa (PAN) = “Necrotizing arteritis of medium or
small arteries without glomerulonephritis or vasculitis in
arterioles, capillaries, or venules, and not associated with
antineutrophil cytoplasmic antibodies (ANCAs).”
Incidence: 2 - 9 per million in Europe and the US (ACR criteria)
16 per million (by CHCC definition) in Kuwait
77 per million described in an Alaskan population endemic for HBV (based on only
13 actual cases of HBV PAN – study before ACR criteria or CHCC definitions)
Changed since vaccination for HBV: incidence of HBV-related PAN follows HBV
infection rates: 7% to 38.5% of patients dg with PAN
PAN develops in 1% to 5% of patients with HBV infection, confers an approximately
1000-fold increase in risk compared with the background population
Watts RA et al. Epidemiology of vasculitis. In Bridges L, Ball G, editors: Vasculitis, Oxford, UK, 2008, Oxford University Press, pp 7–22.; el-Reshaid
K et al: The spectrum of renal disease associated with microscopic polyangiitis and classic polyarteri- tis nodosa in Kuwait, Nephrol Dial Transplant
12:1874–1882, 1997. McMahon BJ et al. Hepatitis B-associated polyarteritis nodosa in Alaskan Eskimos: clinical and epidemiologic features and
long-term follow-up, Hepatology 9:97–101, 1989.
Pathogenesis in HBV- PAN
Direct vessel injury by replicating virus or deposition of immune
complexes leads to activation of the complement cascade,
resulting in an inflammatory response and subsequent
The vasculitis typically occurs within the first few months
following HBV infection and may be the first presenting feature
Mechanism supported by treatment strategy to eradicate HBV
with antiviral therapy and removal of immune complexes by
plasmapheresis without the need for long-term
Pathogenesis for idiopathic PAN
PAN responds to immunosuppressive therapy suggests an immunologic
Evidence of endothelial dysfunction, an increase in inflammatory
cytokines, and an increase in expression of adhesion molecules.
Propensity for the inflammatory lesions to occur at the sites of
bifurcation in vessels, where there is most likely to be turbulent flow.
Following the inciting event, there is focal and segmental necrotizing
inflammation of medium- and small-sized arteries. This leads to
intimal proliferation with subsequent thrombosis, resulting in
ischemia or infarction of the organ or tissue supplied by these arteries.
Implies a separate entity from PAN limited to the skin, but there is
some uncertainty as to whether these are actually just early cases of
PAN and whether progression to PAN will occur.
Pathologically the findings on skin biopsy are indistinguishable
In a retrospective review of cutaneous PAN patients from a Japanese
group, 22 patients with histologically proven cutaneous vasculitis were
followed: 32% had a peripheral neuropathy, and 27% had myalgia,
suggesting a need to revise the current criteria to differentiate
between the two entities of cutaneous PAN and PAN
HCV infection has been associated with cutaneous PAN-31/161 (19%) dg
Furukawa F. Cutaneous PAN: an update. Ann Vasc Dis. 2012;5 (3) 282-8
Saadon D et al. Hepatitis C ssociated PAN. Arthritis Care Res (Hoboken). 2011 Mar;63(3):427-35
Labs that support the diagnosis of
TEST Support diagnosis
Elevated ESR/ CRP +
Elevated Creatinine (w/out
hematuria, proteinuria, cell casts)
+/- (suggest renal ischemia)
Abnormal liver test + (suggest HBV/ liver ischemia)
Anemia + (chronic inflammation/ blood
CPK + (normal/slightly elevated despite
muscle involvement )
Labs that are against PAN
TEST Against the diagnosis
ANCA + (GPA/ MPA)
Blood Cultures + (endocarditis/ infectious vasculitis)
HCV + (HCV associated cryoglobulinemia)
RF, CCP + RF
ANA, dsDNA + SLE/CTD
Angiogram = imaging of choice shows multiple small aneurysms, vessel
ectasia, and focal occlusive lesions in medium-sized vessels, typically
in the renal and mesenteric arteries.
Sensitivity -89% and specificity 90%
MR/ CT angiography are less invasive but are much less sensitive in
Doppler ultrasound can identify renal and hepatic aneurysms
CXR –excludes other vasculitides that may affect the lungs and also to
Hekali P, et al: Diagnostic significance of angiographically observed visceral aneurysms with regard to polyarteritis nodosa, Acta Radiol
32:143–148, 1991. Ozaki K, et al: Renal involvement of polyarteritis nodosa: CT and MR findings, Abdom Imaging 34:265–270, 2009.
Ozcakar ZB, et al: Polyarteritis nodosa: successful diagnostic imaging utilizing pulsed and color Doppler ultrasonography and computed
tomography angiography, Eur J Pediatr 165:120–123, 2006.
25-year-old F dg with PAN 3 years
earlier and was receiving
prednisolone maintenance therapy
when she presented with cardiac
arrest. Although severe cardiac
involvement in polyarteritis
nodosa is unusual, it can result in
myocardial infarction and confers
a poorer prognosis. Despite
treatment, the patient died a few
47-year-old man with abdominal
pain, weight loss, and an elevated
Right renal arteriogram reveals
multiple microaneurysms within the
upper pole of the kidney on this
selective right renal artery injection
(upper pole branch)
ACR criteria 1990
Sensitivity 82%; Specificity 86%
Did not differentiate PAN from MPA or GPA
PAN and drugs
Minocycline (many case reports)
Levamisole (antihelmintic, immunomodulator –withdrawn
from US market in 2003 ) –SE agranulocytosis and
erythematous painful papules on the skin; Thiabendazole
Abatacept-cutaneous PAN to one arm
Hep B vaccination (child)
Interferon tx for HepC
PAN & drugs - references
Minocycline-induced polyarteritis nodosa-like vasculitis presenting as brainstem stroke. Klaas JP, Matzke T, Makol A, Fulgham JR. J
Clin Neurosci. 2015 May;22(5):904-7. doi: 10.1016/j.jocn.2014.12.003. Epub 2015 Mar 14.
Minocycline-induced polyarteritis nodosa-like vasculitis. Agur T, Levy Y, Plotkin E, Benchetrit S.Isr Med Assoc J. 2014 May;16(5):322-
3. No abstract available.
Eur J Dermatol. 2013 Sep-Oct;23(5):738-9. doi: 10.1684/ejd.2013.2160.Cutaneous polyarteritis nodosa localized to the arm
receiving an infusion of abatacept Shibata S1, Asano Y, Sato S.
Levamisole-induced vasculitis with ecchymosis and necrosis syndrome from contaminated cocaine. Desai N, Patel M, Desai S, Cerceo
E. BMJ Case Rep. 2012 Nov 21;2012. pii: bcr2012007319. doi: 10.1136/bcr-2012-007319. No abstract available.
Thiabendazole-induced acute liver failure requiring transplantation and subsequent diagnosis of polyarteritis nodosa. Groh M,
Blanche P, Calmus Y, Guillevin L. Clin Exp Rheumatol. 2012 Jan-Feb;30(1 Suppl 70):S107-9. Epub 2012 May 11.
Eur J Dermatol. 2009 Jul-Aug;19(4):400-1. doi: 10.1684/ejd.2009.0695. Epub 2009 May 25. Cutaneous polyarteritis nodosa in a child
following hepatitis B vaccination. Ventura F, Antunes H, Brito C, Pardal F, Pereira T, Vieira AP.
PAN and Hairy cell leukemia
There is a well-recognized association between HCL and PAN [Fortin,
Direct evidence linking the two conditions with histopathology
showing direct invasion of the vessel wall by leukemic cells [Hasler et
In a literature review of 42 cases of vasculitis associated with HCL, 21
cases were consistent with PAN ( 4 cases showed vessel wall
infiltration by the leukemic cells).
PAN often occurred after the diagnosis of HCL and splenectomy.
Fortin P.R. (1996) Vasculitides associated with malignancy. Curr Opin Rheumatol 8: 30–33
Gabriel S.E., Conn D.L., Phyliky R.L., Pittelkow M.R., Scott R.E. (1986) Vasculitis in hairy cell leukemia: Review of literature and
consideration of possible pathogenic mechanisms. J Rheumatol 13: 1167–1172
Hasler P., Kistler H., Gerber H. (1995) Vasculitides in hairy cell leukemia. Semin Arthritis Rheum 25: 134–142
PAN and the risk of cancers
In a series of 115 patients with HBV-PAN, 3 patients (2.6%) died from
cancer over a mean follow-up of 69 months ( 2 lung, 1 prostate cancer)
[Guillevin et al. 2005].
In a prospective, randomized, open-label treatment study that included
58 patients with non-HBV PAN, three PAN patients (5.2%) developed
cancer over follow-up [Ribi et al. 2010] (to CS vs azathioprine alone) -- 1
Hodgkin's lymphoma and 2 colon cancer ( The cancers occurred 19 mo, 10
mo and 4 years after inclusion in the study)
348 patients with PAN with mean follow up of 68.3 months, there were 5
cancer-related deaths (1.4%): 1 lung, 1 liver, 2 prostate cancers, and 1
myelodysplasia occurring 4—19 years after PAN diagnosis [Pagnoux et al.
Pagnoux C.et al. (2010) 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 62:
Ribi C., et al. (2010) Treatment of polyarteritis nodosa and microscopic polyangiitis without poor-prognosis factors: A prospective
randomized study of one hundred twenty-four patients. Arthritis Rheum 62: 1186–1197
Guillevin L. et al. (2005) Hepatitis B virus-associated polyarteritis nodosa: Clinical characteristics, outcome, and impact of
prognostic tool designed for use to
distinguish patients with higher or lower
risk of poor outcome.
Allocating 1 point per item, there is a
reduced survival for patients with higher
scores (86% survival for 0 points, 69%
survival for 1 point, 47% survival for 2 or
more points) at onset when followed up for
Older age at diagnosis has been shown to
be an important adverse predictor of
survival in the first year and after 5 years
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) 84:323–330, 2005. Guillevin L, Lhote F, Gayraud M, et al: Prognostic factors in polyar- teritis nodosa and Churg-Strauss syndrome: a
prospective study in 342 patients, Medicine (Baltimore) 75:17–28, 1996.
Five Factor Score
Proteinuria (<1 g/day),
Uncontrolled vasculitis accounts for 58% -73% of deaths
occurring within the first year
Management of non-HBV PAN should be appropriate to
the severity of the disease as defined by the five-factor
Five factor score > 1 aggressive immunosuppression
with corticosteroids and cyclophosphamide
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 44:666–675, 2001.
HBV related PAN
High-dose corticosteroids followed by combination
plasma exchange and antiviral agents
Reduce early mortality from vasculitis and late
mortality from the consequences of chronic
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)
Earlier diagnosis and initiation of treatment has improved outcomes.
Non-HBV PAN the 7-year survival rate is 79%, compared with a 5-year
survival rate of 72.5% in HBV-related PAN ( similar to ANCA –vasculitis)
The relapse rate in HBV-related PAN is low (<10%) compared with non–
HBV-related PAN (19.4% to 57% relapse rates).
Delayed diagnosis (>3 months) increases the risk of relapse but does
not affect mortality risk.
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 44:666–675, 2001
Phillip R, Luqmani R: Mortality in systemic vasculitis: a systematic review, Clin Exp Rheum 26:S51, S94–104, 2008.
Long term outcome in patients with
PAN or MPA without Five-Factor Score (FFS =0) (2005-2012) and data were recorded prospectively –
mean follow up 98.2±41.9months.
Long-term survival, disease-free survival (DFS), relapses, therapeutic responses and sequelae were
After having initially received glucocorticoids (GC) alone, according to the study protocol, 82%
(97/118) patients achieved remission but 18% (21/118) required ≥1 immunosuppressant(s) (IS) before
19/21 achieved remission. Two patients died before entering remission. After remission, 53% (61/116)
patients relapsed 25.6±27.9months after starting treatment.
The 5- and 8-year overall survival rates were 93% and 86%, respectively, with no difference between
PAN and MPA, and between relapsers and nonrelapsers. DFS was shorter for MPA than PAN patients
(P=0.02). Throughout follow-up, 47% of patients required ≥1 IS. At the last follow-up visit, 44% were
still taking GC and 15% IS. The mean vasculitis damage index score was 1.9±1.9; the most frequent
sequelae were peripheral neuropathy, hypertension and osteoporosis.
PAN or MPA without poor-prognosis factors at diagnosis and treated initially with GC alone, long-term
survival was excellent. However, relapses remained frequent, requiring IS introduction for nearly half
of the patients.Autoimmun Rev. 2014 Feb;13(2):197-205. doi: 10.1016/j.autrev.2013.10.001. Epub 2013 Oct 23. Samson M et al. French
Vasculitis Study Group (FVSG) Long-term follow-up of a randomized trial on 118 patients with polyarteritis nodosa or microscopic
polyangiitis without poor-prognosis factors.