Polyarteritis nodosa(PAN)

Vasculitides classification by blood vessel size

2012 International Chapel Hill Consensus Conference

PAN

1866 “periarteritis nodosa” used to describe any form of systemic vasculitis.

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).”

Epidemiology

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 endothelial damage.

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 immunosuppression.

Pathogenesis for idiopathic PAN

PAN responds to immunosuppressive therapy suggests an immunologic mechanism.

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.

Clinical presentation PAN

Clinical featureAge 40-60 years; no gender preference

Skin

Cutaneous PAN

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 with PAN

Furukawa F. Cutaneous PAN: an update. Ann Vasc Dis. 2012;5 (3) 282-8Saadon D et al. Hepatitis C ssociated PAN. Arthritis Care Res (Hoboken). 2011 Mar;63(3):427-35

Labs that support the diagnosis of PAN

TEST Support diagnosisElevated ESR/ CRP +Elevated Creatinine (w/out hematuria, proteinuria, cell casts)

+/- (suggest renal ischemia)

Abnormal liver test + (suggest HBV/ liver ischemia)Anemia + (chronic inflammation/ blood

loss)CPK + (normal/slightly elevated

despite muscle involvement )

Labs that are against PAN

TEST Against the diagnosisANCA + (GPA/ MPA)Blood Cultures + (endocarditis/ infectious vasculitis)HCV + (HCV associated cryoglobulinemia)RF, CCP + RFANA, dsDNA + SLE/CTDHIV +

ImagingAngiogram = 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

demonstrating microaneurysms.Doppler ultrasound can identify renal and hepatic aneurysms CXR –excludes other vasculitides that may affect the lungs and also to

exclude infection

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.

Coronary angiogram25-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 months later.

http://www.nejm.org/image-challenge?ci=08092012

Renal angiogram47-year-old man with abdominal pain, weight loss, and an elevated ESRRight renal arteriogram reveals multiple microaneurysms within the upper pole of the kidney on this selective right renal artery injection (upper pole branch)

ACR criteria 19903/10 criteria

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 armGemcytabine 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 (HCL)

There is a well-recognized association between HCL and PAN [Fortin, 1996].

Direct evidence linking the two conditions with histopathology showing direct invasion of the vessel wall by leukemic cells [Hasler et al. 1995].

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. 2010].

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: 616–626Ribi 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 treatment in 115 patients. Medicine (Baltimore) 84: 313–322

Prognostic

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 6 years.

Older age at diagnosis has been shown to be an important adverse predictor of survival in the first year and after 5 years of follow-up

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),Elevated creatinine

(>1.58mg/dL)Gastrointestinal

involvement CNS involvementCardiomyopathy

TreatmentUncontrolled vasculitis accounts for 58% -73% of

deaths occurring within the first yearManagement of non-HBV PAN should be

appropriate to the severity of the disease as defined by the five-factor score

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.

Non HBV PAN

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 hepatitis

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) 84:313–

322, 2005.

Outcome

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, 2001Phillip R, Luqmani R: Mortality in systemic vasculitis: a systematic review, Clin Exp Rheum 26:S51, S94–104, 2008.

Long term outcome in patients with FFS=0

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 analyzed.

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.

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