Polyarteritis Nodosa and Hepatitis B related PAN

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Polyarteritis Nodosaand Hepatitis B related PAN

• Raymond Fung
• Rheumatology Rounds
• March 16, 2004

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Case

• 41M from Sault Ste Marie
• PMH
• IV drug use, smoker, EtOH
• known hep B hep C, HIV neg
• HPI
• Dec-Jan -postprandial abdominal pain and wt loss
  25lbs
• admitted Jan 25 to SSM -SOB, CXR bilat
  infiltrates, became hypertensive
• intubated, ARDS like picture, BAL neg
• rx ceftazidime, levo, diflucan

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Case - HPI

• renal failure -on admission Cr. 194, then
  increased to Cr 343, nonoliguric, bland urine
  sediment, ? ATN
• 2D echo Gr 3LV, MR, RVSP 53 -Trop 2 ?myocarditis
• extubated but reintubated because..
• massive UGI -melena requiring gt10 PRBC
  -transferred to SMH
• acute transaminitis AST/ALT gt 1500, then
  decreased -?shock liver
• OGD -multiple large duodenal, prox jejunal ulcers

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Case -Physical Exam

• intubated, sedated
• bp 110/50, HR 75
• no evidence of vasculitic rash
• no orchitis
• heart sounds n, chest upper airway sounds
• no active joints

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Case -Lab

• Hb 83, WBC 20, Plt 49 -no fragments, toxic
  vacuolation
• CXR bilat lower lobe opacities
• Cr. 404, urine bland, heme granular casts
• AST 133, ALT 75, ALP 75, TB 36
• Ca 1.49, PO4 3.91, Alb 12
• Trop 0.26
• CK 150

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Outline

• classification and definition
• epidemiology, pathology
• clinical features
• treatment and prognosis

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History and classification

• Kussmal and Maier 1866 -systemic vasculitis
• wt loss, fever, peripheral neuropathy, renal, GI,
  skin, muscle, cardiac, hypertension
• 1990, ACR established criteria for dx of PAN
• 1994 Chapel Hill Consensus conference
  distinguished MPA from PAN

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PAN -ACR criteria

• wt loss gt 4kg
• livedo reticularis
• testicular pain/ tenderness
• myalgias, weakness, tenderness
• mono or polyneuropathy
• diastolic bp gt 90mmHg
• elevated Cr/ BUN
• hep B positive
• arteriogram -aneurysm or occlusion not due to
  atheriosclerosis
• bx PMN in small/med artery wall

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Epidemiology

• annual incidence 1-9 per 1 000 000 people
• affects men and women 1.1-1.9 1
• all ages, peak 40-60
• all racial groups
• individuals at risk for HBV-PAN
• older -infected via transfusion, accupuncture
• unvaccinated young -IVDU, tattoo, piercing

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Etiology

• studies from early 1970s found 36 of cases
  related to HBV infection
• 90s frequency of HBV - PAN 7, vaccination
• last 2yrs, fewer than 10pts / year dx in France
• HBV related PAN takes form of classic PAN
• other etiologies HIV, parvovirus B19, CMV,
  HTLV-1, HCV

Guillevin, L. Lhote, F. Polyarteritis nodosa
related to hepatitis B virus a prospective study
with long-term observation of 41 patients.
Medicine 1995 74(5) 238-253.
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Pathology -blood vessels

• medial fibrinoid necrosis
• polymorphic panarterial cellular inflammatory
  infiltrate, CD8 Tcells, macrophages, PMN
• clusters plasma cells in adventitia
• lesions result of immune complex deposition in
  vessels
• PAN -associated leukocytoclastic vasculitis of
  skin

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Sural Nerve Biopsy
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PAN in the skin
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Mechanism -Viral induced vasculitis

• viral replication -direct injury to vessel wall
• e.g equine viral arteritis
• immune mediated vascular damage
• circulating immune complex
• formation of immune complex in situ
• hepatitis B has been implicated as triggering
  antigen
• ANCA negative, therefore not considered part of
  etiology

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Clinical Features

• majority present w consitutional symptoms
  malaise, fever, wt loss
• PAN usually presents within 6 months of HBV
  infection
• HBV-PAN presents similar to other PAN except
  several manifestations more common
• GI (46)
• malignant hypertension (30)
• renal infarction and orchitis (26)

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Clinical -Neurologic

• mononeuritis multiplex most common symptoms
• motor, sensory asymmetric
• predominantly affect LE
• radial, cubital, median nerves less frequently
• motor deficit occurs abruptly
• sensory -hypo/pain in area of motor deficit
• bilateral distal sensory neuropathy
• CSF normal

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Clinical Features

• Other Neurologic
• cranial nerve palsies rare (III, IV, VI, VII)
• spinal roots, cauda equina rare
• stroke, brain hemorrhage can occur
• MSK
• myalgies 30-70 -intense
• CK usually normal
• arthralgias 40
• arthritis -asymmetric, larger joints lower
  extremity

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Clinical features

• Skin
• 25-60
• vascular purpura, papulopetechial
• livedo reticularis
• less common bullous, vesicals, SC nodules,
  distal gangrene
• Renal
• vascular nephropathy -microaneurysms, stenoses,
  infarcts
• perirenal hematoma result from rupture of
  aneurysms
• hypertension -renin dependent

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Cutaneous PAN

• Lower extremity
• tend to ulcerate
• surrounding livedo

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Cutaneous PAN
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Cutaneous PAN

• Thickened arterial wall w inflammatory infiltrate
• Tunica intima -eosinophilic ring of fibrinoid
  necrosis

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Renal Aneuryms
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Cutaneous PAN
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Cutaneous PAN
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Cutaneous PAN
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Cutaneous ulcers
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Clinical Features

• GI
• most severe manifestation -fatal
• GI bleeding, bowel perforation
• abdo pain, wt loss consequence of bowel ischemia
• vasculitis of appendix, gallbladder may be first
  presentation of PAN
• Hep B
• transaminitis usually mild-moderate
• bx -may reveal chronic inflammation

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Hepatic Aneurysms
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SMA Aneurysm
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Clinical Features

• Cardiac
• secondary to vasculitis of coronary arteries or
  to severe hypertension
• angina rare, angiography usually normal
• Orchitis
• classic symptom, more common w hep B
• Retinal vasculitis

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Back to Case

• 41M w hepatitis B
• prodrome abdo pain/ wt loss
• respiratory illness with renal failure,
  hypertension, cardiac failure
• profuse GI bleeding w multiple ulcers
• (already 4 criteria)
• Rheum requested MRA
• beading of mesenteric vessels in splenic,
  hepatic, and sup mesenteric arteries
• tapering of renal arteries

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Case -Clinical Course

• pulse solumedrol 1g X3d Feb 14-16
• Solumedrol 80mg BID
• plasma-exchange Feb 16 X5d, Feb 23, Feb 25
• IV IG Feb 20, 21
• lamivudine started Feb 16

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Treatment of PAN

• untreated 5yr mortality gt90
• corticosteroids 1950s survival 50 at 5yrs in
  late 1970s
• other therapies
• cyclophosphamide
• plasma exchanges

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Treatment of PAN -Steroids

• methylprednisolone pulses 15mg/kg 1g IV q24h
• widely used for severe systemic vasculitis
• life-threatening organ involvement, extension of
  mononeuritis multiplex
• ?need such high doses
• begin corticosteroids 1mg/kg/d until clinical
  improvement, ESR normal
• taper, usually within 1month
• more rapid taper if cyclophosphamide used
• stopped 9-12 months

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Adjunctive Therapies

• is cyclo necessary for the treatment of PAN?
• should it be used in certain subgroups? i.e. Are
  there certain prognostic factors that we can use
  to choose between steroid alone vs. steroid plus
  cyclo?
• is plasma exchange necessary?
• does adding plasma exchange to steroids make a
  difference?

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French Vasculitis Study Group

• Prognostic Factors in Polyarteritis Nodosa and
  Churg-Strauss Syndrome
• prospective study of 342 patients
• Guillevin, Loic Medicine Jan 1996
• Long Term Followup of Polyarteritis Nodosa,
  Microscopic Polyangiitis, and Churg-Strauss
  Syndrome
• Analysis of four prospective trials including 278
  patients
• Gayraud, Martine, Guillevin, Loic Arthritis
  Rheumatism March 2001

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Study Method

• pts w PAN, MPA, CCS studied prospectively for
  prognostic factors
• most were randomized into 5 treatment protocols
• age 15-75
• clinical dx histologic evidence or
  arteriographic evidence or fulfillment of ACR
  criteria

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Protocol 1 -PO cyclo

• 1980-1983
• Prednisone/ PE vs. Prednisone/ PE oral cyclo
• Pred 1mg/kg X 1mon, then tapered
• PE 3X 1st wk, 2X 2nd wk, 1X per wk X 4, 1Xper
  month X4
• oral cyclo -2mg/kg /d X1yr
• did not take into account HBV status
• stopped in 1983, began protocols 2 and 5

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Protocol 2 -PE? (1983-1988)

• pts without HBV infection included
• pred PE vs. pred alone
• cyclo PO used if failure of assigned rx
• PE 3X per wk for 2wks, 2X for 1wk, 1 session 10,
  15, 21, 30d later

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Protocol 3 ?PE in severe PAN (89-93)

• (no HBV) at least one of
• age gt50
• GI tract involvement
• cardiomyopathy
• renal insufficiency Crgt 140 or GN
• CNS involvement
• WCB gt 12
• Pred / IV cyclo / PE vs. Pred/ IV cyclo
• IV cyclo 0.6mg/m2 monthly pulse

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Protocol 4 PO vs IV cyclo

• PAN (no HBV), no factors of poor prognosis
• pred po cyclo vs pred IV cyclo

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Protocol 5 Hep B -PAN

• corticosteroids X 2wks
• PE and vidarabine
• interferon alpha 2b
• more to follow

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Results
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Results - Univariate Analysis
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Results -Multivariate Analysis
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Results -5 yr Mortality
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Limitations

• heterogenous group with different diseases
• in the past treated the same way
• even HBV related PAN included
• did not take into account differences in
  treatment
• different efficacy
• different side effects
• they later show prognosis quite similar for these
  diseases

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Follow-up Report

• 278 pts
• mean age at dx 53.8 /- 15yrs
• 54.3 M, 45.7 F
• mean follow up 7yrs /- 52 months
• CCS 64
• MPA 58
• PAN 93
• HBV PAN 63

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Survival - FFS
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Survival - Type of Vasculitis
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Relapses

• 20 experienced
• not correlated w FFS or use of cytotoxic agents
  (23 vs. 24)
• type of vasculitis HBV - PAN (7.9), PAN
  (19.4), CCS (20.3), MPA (34.5)
• time to relapse similar for all types (24-37
  months)

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Deaths
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Deaths

• 41 (of 85) pts died as consequence of vasculitis
  or treatment
• 22 died uncontrolled vasculitis
• 11 died s/e sepsis
• 6 sudden death
• 2 sequelae of cardiomyopathy
• 18 of 22 pts who died of uncontrolled vasculitis
  had poor prognostic factors

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CS vs. CS Cyclo
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FFSgt2 CS vs. CS Cyclo
P 0.044
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Side Effects

• 93 of 278 (35)
• 85 had received Cyclo
• infectious disease (31 of 37 had cyclo)
• osteoporotic fractures 8.6 (14 of 24 had cyclo)
• all 11 pts who died of sepsis had taken Cyclo
• oral cyclo 59, IV cyclo 62 had s/e
• none had major s/e in hepB PAN protocol

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ConclusionsCS vs. CS Cyclo

• no difference in survival overall
• Cyclo prolonged survival in FFS scores gt2
  (p0.044)
• of 22 who died of uncontrolled vasculitis, 15
  took CS alone
• Cyclo did not prevent relapse
• side effects were more frequent in cyclo group,
  especially infectious complications
• only one case of bladder ca attributed to cyclo

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Conclusions oral vs. IV Cyclo

• protocol 4, 25 patients, good prognosis (no FFS)
• no significant difference
• IV pulse cyclo increasingly used, small trials
• less hemorrhagic cystitis, bladder hematologic
  malignancies, lower cumulative dose
• case reports of oral cyclo being effective after
  IV pulse has failed to control activity

Gayraud M, Luillevin L et al. Treatment of
goo-prognosis polyarteritis nodosa and
Churg-Strauss syndomre comparison of steroids
and oral or pulse cyclophosphamide in 25
patients. Br J Rheumatol 1997 36
1290-7. Genereau T et al. Treatment of systemic
vasculitis with cyclophosphamide and steroids
daily oral low-dose cyclophosphamide
administration after failure of a pulse
intravenous high-dose regimen in four patients.
Br J Rheumatol 1994 33959-62. Adu D et al.
Controlled trial of pulse vs. continuous
prednisolone and cyclophosphamide in the
treatment of systemic vasculitis. QJM 1997 90
401-9.
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Conclusions Plasma Exchanges (no Hep B)

• 62 pts with severe PAN (FFS) (protocol 3)
• no difference in 5 yr survival (75 PE, 88
  without)
• 78pts with non-selected PAN, only used cyclo for
  failed initial rx
• no difference 7 yr survival (83 PE, 79 without)
• PE as 2nd line rx with PAN refractory to therapy

Guillevin L et al. Lack of superiority of
steroids puls plasma exchanges to steroids alone
int eh treatment of polyarteritis nodosa and
Churg-Strauss syndrome a prospective, randomized
trial in 78 patients. Arthritis Rheum 1992
35208-15. Guillevin L et al. Corticosteroids
plus pulse cyclophosphamide and plasma exchanges
vs. corticosteroids plus pulse cyclophosphamide
alone in the treatment of polyarteritis nodosa
and Chur-Strauss syndrome patients with factors
predicting poor prognosis a prospective,
randomized trial in sixty-two patients. Arthritis
Rheum 1995 38 1638-45.
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Limitations

• though studies prospective, randomized, very
  small
• not enough power to exclude differences
• probably does not apply to MPA/ WG who have
  necrotizing glomerulonephritis
• cyclophosphamide still treatment of choice (MTX
  also been used)

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Treatment of hep B related PAN

• corticosteroids and immunosuppressive agents
  perpetuate chronic hepatitis B infection and
  facilitate progression to cirrhosis
• survival rates at one year significantly lower in
  pts with HBs antigenemia than without (70 vs.
  85)
• heightened mortality related to GI complications,
  including GI bleeding and perforations, more
  frequently found in HBV associated polyarteritis

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Protocol 5, HBV

• study effectiveness of antiviral agents used in
  association with short-term immunosuppression
• included HBsAg and HBeAg , active replication
  shown by HBV DNA
• initial CS to control vasculitis activity, then
  anti-viral agents to treat hepatitis B while
  using PE to suppress disease activity without
  immunosuppresion

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Protocol 5, HBV

• Pred 1mg/kg/d X1wk, tapered X1wk - stop
• if clinical remission/ failure, continue pred
  X1wk, then try to taper
• Vidarabine X 3wks after stopping pred IV infusion
• repeat if HBeAg did not seroconvert within 4mon
• PE 3X/wk for 2wks, 4X during vidarabine wk1, 5X
  during 2nd and 3rd
• 3X /wk for 3wks, 2X/wk for 2wks, then 1-2X/wk
  then stopped depending on clinical

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Protocol 5, HBV

• 1987 -interferon-alpha 2b used as second line
  agent if failure of HBeAg seroconversion
• early 1990s -interferon-alpha 2b used as first
  line agent instead of vidarabine
• 3million units, 3X/wk for max of 1yr

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Results

• 41 pts followed 35 vidarabine, 6 IFN alph2b
• 10 yr survival rate 83
• HBeAg/ HBeAb servoconversion in 21 or 41
• total viral clearance HBsAg/HBsAb seroconversion
  in 10 (24)
• vidarabine only used X3 wks because of
  neurotoxicity

Guillevin L, Lhote F et al. Polyarteritis nodosa
related to hepatitis B virus a prospective study
with long-term observation of 41 patients.
Medicine (Baltimore) 1995 74238-53.
68
Interferon alpha 2b

• more effective antiviral against Hep B
• case reports of successful therapy for PAN
• replaced vidarabine

Avsar E, et al. Successful treatment of
polyarteritis nodosa related to hepatitis B virus
with interferon alpha as first-line therapy. J
Hepatology 1998 28 525-526. Simsek H, et al.
Successful treatment of hepatitis B
virus-associated polyarteritis nodosa by
interferon alpha alone. J Clin Gastroenterol
1995 20 263-265.
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Lamivudine

• nucleoside analogue, selectively inhibits reverse
  transcriptase
• first discovered in HIV/ HBV pts
• reduction of 3-4 log HBV DNA in 1st 3 mons
• associated w HBeAg loss, improved AST/ALT
• well tolerated, therefore replacing IFN alpha

Ganem D. Hepatitis B virus infection - Natural
history and clinical consequences. NEJM 2004
3501118
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Lamivudine

• elevated ALT pretreatment predicts good response
  (adequate host immune response)
• reduces viral load, allowing host immune system
  to deal more effectively with remaining infected
  hepatocytes
• limitation drug resistance mediated by mutations
  at catalytic center of viral RT
• 1 yr 15-20 resistance, 40 at 2yrs, 67 at 4
  yrs

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Lamivudine in HepB PAN

• now being used as first line anti-viral agents
  for hep B-PAN, along w steroids /- PE or
  cyclophosphamide
• several case reports published, including NEJM
  CPC
• some case reports used anti-viral agents alone
  but severity of vasculitis usually mandates
  treatment w steroids
• lamivudine used 6-12mons until HBeAg conversion,
  HBV DNA titres down, HBsAg conversion

Coblyn J, McCluskey RT. Case 3-2003 a
36-year-old man with renal failure, hypertension,
and neurologic abnormalities. NEJM 2003
348333 Maclachlan D, Battegay M. Successful
treatment of hepatitis B-associated polyarteritis
nodosa with a combination of lamivudine and
conventional immunosuppressive therapy a case
report. Rheumatology 2000 39106-8.
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Conclusion

• treatment of PAN
• corticosteroids to control vasculitis activity
• cyclophosphamide for serious organ involvement or
  failure to control activity with steroids alone
• no evidence to support plasmaphoresis
• treatment of hep B- PAN
• corticosteroids to control vasculitis activity
• cyclophosphamide may also be needed if CS alone
  fails
• lamivudine /other anti hep B rx
• role of PE?

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Back to Case

• Neuro
• flaccid quadriplegia EMG -myopathy vs.
  neuropathy
• quadriceps bx -severe atrophy, muscle fibre
  necrosis
• sural nerve bx -healed vasculitis (2.5wks after
  steroidsPE)
• vasculitis critical illness myopathy
• Resp
• increasing infiltrates in lungs -ARDS
• BAL -blood clots seen
• negative except HSV
• ID -nonspecific

Guo X, Gopalan R, et al. Hepatitis related PAN
complicated by pulmonary hemorrhage. Chest 2001
1191608-1610
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Case Contd

• CVS
• hemodynamically stable mostly
• on levophed 1-2days
• GI
• bleeding stopped after 1wk of steroids PE
• ascites, abdominal hemorrhage, thickened bowel on
  CT scan
• ascitic fluid -coag neg staph, enterococcus,
  neisseria
• bacteremic with above organisms
• therefore bowel perforation
• too unstable for surgery

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Case Contd

• Hepatic
• continued rise in bilirubin to gt350
• HBV DNA titre 5.6 X 109
• Renal
• high phosphate, low Ca necessitated initiation of
  dialysis
• HD 3X/wk
• Hematologic
• thrombocytopenia 20-50 range
• transient leukopenia responded to IVIG
• remains on solumedrol 40mg BID and lamivudine