case microscopic polyangiitis

Interesting case conference

A woman with hemoptysis and renal failure

ประจำ��วั�นที่�� 27 ตุ�ล�คม 2553น��เสนอโดย: นพ.ปร�ชญ�

ภั�สสร�นนที่�

History

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1st admission 28 ก.ย . 2553

CC: ไอเป*นเล+อด 10 วั�นก'อนม�รพ .

Underlying disease

วั�ณโรคปอดเม+�ออ�ย� 6 ขวับ เคย tracheostomy closed 2 years PTA

acute symmetrical polyarthritis 3 weeks, involve MCP, PIP, DIP, wrist, elbow, shoulder, knee, ankle, no morning stiffness

RF+ 86, ANA+ 1:160 fine-speckled pattern, anti-Sm -ve , anti-Ro 3+

ช�ฝ่!�ม+อขวั� 3½ น#/วั, ช�เที่ �สองข �งถึ1งข อเที่ � FBS 88 Iron def. anemia : ferritin 23 Coomb -ve FeSO4 น�/�หน�กลด 50 40kg Rx : pred 30mg/d 1 wk, Chloroquine 250mg/d 6 mo

loss to F/U Hct 23 MCV 60 RDW 22 Hct 31.2 MCV 93 RDW 12

(27ตุ.ค.52)

Present illness

2 weeks PTA โที่รบอกญ�ตุ#วั'�ไปร�บหล�นไม'ไหวั9 days PTA ไอเป*นเล+อดแดงสดคร�/งละ ½ แก วั

หอบเหน+�อย ไม'ม�ไข เป*น 2 วั�น จำ1งไปรพ.เอกชนแห'งหน1�ง

7 days PTA BT 37.3°c BP 100/60 HR 110 RR 26

fine crepitation RLL5 days PTA ไม'ม�ไข ย�งเหน+�อย ไอปนเล+อด1 day PTA ช�ก GTC 5 น�ที่� ET-tube refer

4.7 7300 N 81% 15 100,000 L 16%

126 5.7 53 97 18 4.3

Past history

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ล��บ�ก

Physical examination

A middle-aged female, fully conscious, cooperative

BT 36.3°c HR 100 BP 140/90 RR 24 On PSV PS 8 PEEP 5 FiO2 0.4 O2sat =

98%HEENT : mildly pale, no jaundice

nose and nasal septum - normal no cervical lymphadenopathy

Lung : coarse crepitation both lower lungHeart : no heave, no thrill, normal S1S2, no murmur

Physical examination

Abdomen: soft, not tender, no hepatosplenomegaly

no chronic liver stigmataExtremities: no rash, no pitting edema

Neuro : E4M6VT

cranial nerve – intactmotor – gr.V all

Problem list

underlying rheumatoid arthritis?

Hemoptysis with anemia Renal failure Generalized tonic clonic seizure

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CBC

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Hct 22.6 31.2 15 29.1 23.5 26.9 26.1MCV 61 93 83 75.8 75.3 77.3 81.9RDW 22.4 12.3 26.1 26.4 25.9 26.6

WBC

7830

4100

7300

10310

8230

9760

10800

N% 85% 70% 81 84% 91% 91% 93%L% 7% 19% 16 10% 5% 6% 4%

Platelet

225,000

136,000

100,000

30,000

64,000

100,000

103,000

PT 12

PTT 28

BUN/Cr

5.8 / 0.5

53 / 4.3

86 / 4.0

89 / 4.2

89 / 4.3

99 / 4.5

Lab – referer hospital

UA sp.gr 1.025 alb 2+ WBC 5-10 RBC 10-20

UPCI = 2.2 CRP 24 ESR 106 ANA -ve ANCA –ve

Coomb –ve anti-HIV –ve H/C – no growth sputum AFB –ve USG KUB – WNL Rx : PRC 5u, Ceftriaxone, oseltamivir

methylprednisolone 1g iv x 3 day

Lab

E’lyte Na+ 132 K+ 4.4 Cl- 107 HCO3-

23 LFT TB/DB 0.5/0.1 AST / ALT 26 / 22

ALP 62 alb / glb 2.6 / 3.0 Ca 7.7 PO4 4.2Mg 2.1 LDH 649 ABG pH 7.41 pCO2 28 pO2 73 HCO3 18

UA sp.gr 1.010 alb 2+ WBC 2-3 RBC 30-50 glomerular RBC 40%

broad cast 2-3 UPCI = 4.4

Lab

ANA +ve Anti-dsDNA – pending Anticardiolipin – pending Anti-beta-2-GP1 – pending ANCA – pending Anti-GBM – pending H/C – no growth sputum – no bacteria, AFB-ve

What to do next?

Bronchoscope?CT scan?

Dexamethasone?

hemodialysis?

Plasma exchange?

Continue antibiotic?

Kidney biopsy?

Doppler ultrasound?Doppler ultrasound?

Consult nephro?Consult nephro?V/Q scan?

CPR?

Factor VIIa ?

Echo?Cyclophosphamide?

Sputum PCR-TB

28 29 30 1 2 3 4

Pip/Taz

FOB

Bronchoscope (30/9/53)

Finding : mucosal petichiae hemorrhage, no endobronchial lesion

BAL at antr basal RLL

persistent bloody BAL fluid RBC numerous WBC 565 (N 24, L 8, M 1, Eo 2,

macrophage 65) Hemosiderin score =0

What to do next?

Bronchoscope?CT scan?

Dexamethasone?

hemodialysis?

Plasma exchange?

Continue antibiotic?

Kidney biopsy?

Doppler ultrasound?Doppler ultrasound?

Consult nephro?Consult nephro?V/Q scan?

CPR?

Factor VIIa ?

Echo?Cyclophosphamide?

Sputum PCR-TB

Management

Plasma exchange วั�นที่�� 5, 6, 7, 11, 13, 15, 17 ตุ.ค.

Antibiotic VCV ventilator

28 2511 184

Pip/Tazdexa 5q8

meropenemcolistin// colistin

Methyl P x3

GTCPRES

P.Ex x7

WBC, schistocytePT,PTT , haptoglobin <10Sputum – A.baum

tracheostomy

levofloxacin

dexa 5q6vancoampho

dexa 5q12

Sputum – MRSA yeast

Hct

WBC

Plt

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26/10/53 ไข้� Sputum – A.baum, S.maltophilia

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26/10/53 ยั�งมีเสมีหะปนเลื�อด ,Hct 25 Cr 3.9

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26/10/53 รู้��ตั�วด ไมี�มีไข้� Sputum - MRSA

Microscopic polyangiitis

MPA

ANCA-associated vasculitis (AAV) involve small vessels, primarily affects kidneys and lungs.

History

1866 Kussmaul and Maier described a case with “p eculiar mostly nodular thickening of countless arteries of and below the caliber of the liver arte

ry…” which they dubbed periarteritis nodosa1950 Davson recognized microscopic polyarteritis

as a distinct entity of polyarteritis nodosa1954 Godman and Churg noted that the

“microscopic form of periarteritis” was closely related to WG and CSS.

1982 Davies and colleagues discovered ANCA1988 Jennette and Falk reported that serum from

patients with WG, renal-limited vasculitis, and MPA was associated with p-ANCA

Rheum Dis Clin North Am -2010 36 3 54558. Aug; ( ):Rheum Dis Clin North Am -2010 36 3 54558. Aug; ( ):

1990 ACR classification criteria

at least 2 of the 4 criteria Nasal or oral

inflammation (oral ulcers or bloody nasal drainage)

Abnormal chest radiograph (nodules, fixed infiltrates, cavities)

Urinary sediment (>5 RBC/hpf or RBC casts)

Granulomatous inflammation on biopsy (in wall of artery or arteriole, perivascular, or extravascular)

at least 3 of the 10 criteria Weight loss > 4 kg Livedo reticularis Testicular pain or

tenderness Myalgias, weakness, leg

tenderness Mononeuropathy or

polyneuropathy Diastolic BP > 90 Elevated BUN/creatinine Hepatitis B virus Arteriographic

abnormality Biopsy of small or medium

artery containing PMN

Wegener’s granulomatosis

Polyarteritis nodosa

Polyarteritis nodosa vs. microscopic polyangiitis

Small/medium muscular artery

Renal vascular nephropathy

No lung involvement

ANCA negative

Small/medium arteries, arterioles, venules, capillaries

Glomerulonephritis Lungs involved in

up to one third ANCA positive


Polyarteritis nodosa

1994 Chapel Hill nomenclature

Arthritis Rheum - 1994 37 2 18792. Feb; ( ): .


Clincical Dx primary vasculitis

WG surrogate marker

Upper airway- bloody nasal discharge/crusting > 1 mo.- sinusitis, otitis media, mastoiditis > 3 mo.- retro-orbital mass or inflammation- subglottic stenosis- Saddle nose, destructive sinonasal disease

Lower airway- fixed pulm. infiltrates, nodules, cavity > 1 mo.- bronchial stenosis

Ann Rheum Dis 2007. February; 66 2( ): 222–227

classificaton algorithm

What is ANCA ?

Anti-neutrophil cytoplasmic antibody is positive in 50-75% of MPA patients

indirect immunofluorescence assay p-ANCA

ELISA anti-myeloperoxidase (a serine proteases)

20091361101 1111CHEST ; : –

Indirect immunofluorescence assay

cANCA

Granulocyte antigen of ANCA

MPA, SLE, RA, UC, CD, PSC, AIH

-2 0 0 0 : 1 8 : 6 2 9 6 3 5 .

Problem with pANCA detection

Perinuclear staining by ANAgranulocyte-specific ANA?

Epitope conformation

does ANCA has role in pathogenesis ?

A report of pulmonary hemorrhage and glomerulonephritis in neonate which mother had MPA

Remission is often accompanied by decrease in ANCA levels

In a prospective 100 pt with WG, increase in ANCA titer predicts a clinical relapse with sensitivity 79% and specificity 68%, though time period varies from 0–20 mo.

In another study of 106 pt with WG, serial changes in ANCA titers correlated with altered disease status in 64% of patients.

A 156prospective cohort of pat ients wwww wwwwww Ww wwwwwwww wwww wwwwwwwww ww wR -3 ANCA wwwwww were not associated with relapse

Nat Rev Rheumatol - 2010 6 11 65364. Nov; ( ): .

I have no MPO

Anti-MPO

Pauciimmune NCGNSystemic vasculitis

lipopolysaccharide

Now I have MPO

Anti-PR3

and pauciimmune glomerulonephritis !

Normal mice

does ANCA has role in pathogenesis ?

reduced leukocyte

rolling

augmented adhesion

and transmigration

across the

endothelium


Kelly’s textbook of Rheumatology, 8th ed.

What does ANCA do with body ?



RITUXIVASRITUXIVAS

N Engl J Med - 2010 15363 3 21120. Jul ; ( ):N Engl J Med - 2010 15363 3 22132. Jul ; ( ): .

RAVERAVE

SteroidRituximab x 4 weeks

IVCY x 2 pulses

SteroidIVCY x 3-6 mo.

Azathioprine

New Dx AAV and renal involvementNon-blind RCT

severe new or relapse 148 WG, 24 MPAdouble-dummy, noninferiority db-RCT

Stone JH. M MMMMMMMMMMMM M MMMMMM M MMMMMMM . USAJones RB. MMMMMMMMMMMMM M MMMMMMM. UK

Ritu (33)

Cy (11)

remission

76% 82%

Severe AE

42% 36%

mortality

18% 18%

Pulse + pred 5 mo.Rituximab x 4 weeks

placebo CY

Pulse + pred 5 mo.oral CY x 3-6 mo.

placebo Rituximab

Ritu (99)

Cy (98)

Remission

without pred

64% 53%

relapse pt.

67% 42%*

DAH pt.

57% 41%*

MPA 67% 62%

Placebo Aza Azathioprine

Ritu (99)

Cy (98)

Pulmonary

52% 54%

DAH 27% 24%

Renal 66% 66%

noninferi

or

I

M

Where ANCA come frome ?


Epidemiology

Rheum Dis Clin North Am -2010 36 3 54558. Aug; ( ):Rheum Dis Clin North Am -2010 36 3 54558. Aug; ( ):

MPA is more prevalent than WG in Asian population.

Clinical presentation

Average age of onset 50-60 years Onset may be hyperacute, with

rapidly progressive glomerulonephri tis and pulmonary hemorrhage

Or can be insidious with several years of intermittent constitutional s

ymptoms, purpura, mild renal disea se, and even periodic bouts of hemo

ptysisMurray and Nadel’s Textbook of Respiratory Medicine, 5th ed.

Autoimmun Rev - 2010 9 12 8129. Oct; ( ):

Clinical presentation

pulmonary

25–55% of patients . 10–30% with diffuse alveolar hemorrhage . Fibrosis, focal infiltrates, effusions, pulmonary arterial hypertension

renal Segmental necrotizing glomerulonephritis and RPGN is almost universal .

Upper airway

5–30% of patients, with sinus disease most common

musculoskeletal

Arthralgias and myalgias in at least 50% of patients

eyes 0–30% of patients . Scleritis, episcleritis, uveitis .

Cardiac 10–15% of patients . CHF and pericarditis have been described .

GI 35–55% of patients . Pain, bleeding, ischemia . Rare visceral aneurysms .

skin 35–60% of patients. Commonly purpura

Neuro 10–50% of patients . Mononeuritis multiplex reported cerebral infarction

Murray and Nadel’s Textbook of Respiratory Medicine, 5th ed.

Pathology

Neutrophilic capillaritis without granuloma, fibrinoid necrosis and arterial wall disruption, intra alveolarRBC - and hemosiderin laden macrophages

Focal segmental necrotizing glomerulonephritis


Imaging of pulmonary vasculitis

CXR findings is alveolar infiltrations , most often bilateral diffuse pattern.

Lung fibrosis in relapsing alveolar inflammation

J Comput Assist Tomogr - - 2004 28 5 7106. Sep Oct; ( ):

CT finding in 51 MPO-ANCA patients

Radiology -2010 255 2 32241. May; ( ):

Radiographics - -2002 22 4 73964. Jul Aug; ( ):

consolidation with interlobular septal thickeningGround-glass opacity

fine reticular pattern superimposed on a background of groundglass - attenuation that is the crazy paving pattern

J Comput Assist Tomogr - - 2004 28 5 7106. Sep Oct; ( ):

F 74y MPO. F/U HRCT show new honeycombing at 5 months

3 mo.

M 60Y MPO resemble IPFCT show GGO and reticulation in subpleural regionVAT Bx shows irregular interstitial fibrotic thickening, hemosiderin ladenmacrophages

Radiology -2010 255 2 32241. May; ( ):

Prognosis of MPAPrognosis of MPA

prognostic five-factor score proteinuria (>1 g/24 hours) serum creatinine greater than 1.58 mg/dL Gastrointestinal involvement Cardiac involvement central nervous system involvement

The 5-year survival with a score of 0 is 88%, while a score 2 is associated with 54% survival

Relapses after successful induction therapy are common (25-33% ) but usually less severe and responsive to therapy Murray and Nadel’s Textbook of Respiratory Medicine, 5th ed.

Arthritis Rheum - 1999 42 3 42130. Mar; ( ):

Prognosis of MPA with DAHPrognosis of MPA with DAH

alveolar hemorrhage tends to be severe and is often life-threatening

Early mortality rate 25%. 5-year survival 65%


Treatment – systemic vasculitisTreatment – systemic vasculitis

Chest - 2006 129 2 45265. Feb; ( ): .

Remission induction phase and maintenance phase

Titrate immunosuppression to control disease while minimizing the potential for adverse side effect

Treatment - MPATreatment - MPA

prednisone 1 mg/kg/d (often preceded by pulse of m ethylprednisolone 1 g/d x 3 days ) pl us

cycl ophosphami de ar e t he usual appr oach t oinduce remission.

Cyclophosphamide may be administered orally ( 2mg/kg/d ) or intravenously ( 15mg/kg iv q 2-3 weeks )

Activity of disease = Birmingham Vasculitis Activity Score (BVAS)

After remission, patients may be switched to either azathioprine ( up to 2 mg/kg per day ) or methotrexate ( up to 25 mg/week).

optimal duration of maintenance is not clear. 1 year is reasonable.

Refractory case : IVIG, infliximab, mycophenolate mofetil, rituximab, deoxyspergualin, Antithymocyte globulin

Induction Maintenance

WG

MPA

oral cyclophophamide+bactrimsteroid oral CY

Induction Maintenance

WG

MPA

oral cyclophophamide+bactrimsteroid

pulse IVCY less SE

Azathioprine = oral CY

Methotrexate = Aza

MTX = oral CY non-organ threatening AAVNORAM 2005

CYCLOPS 2009

Rituximab = IVCYRITUXIVAS 2010

Rituximab > oral CYrelapse AAV, DAHRAVE 2010

PE > methylpredsevere renal AAVMEPEX 2007

Etanercept add-on WGET 2005

oral CY

CYCAZAREM 2003

Pagnoux 2008

Leflunomide > MTXmore AEMetzler 2007

MMF > IVCYmild renal MPA

IMPROVE(terminated)

Weixin 2010open RCT n=35

MMF < Aza

Bactrim add on

Nat Rev Rheumatol. 2010 Nov;6(11):653-64 .

Treatment - DAHTreatment - DAH

Pulse methylprednisolone + steroid + cyclophosphamide

Induction + Plasma exchange Induction with Rituximab + steroid

Factor VIIa Extracorporeal membrane oxygenation

Thank You

Further readings

ANCA-associated vasculitides--advances in pathogenesis and treatment . Nat Rev Rheumatol - . 2010 Nov;6(11):653 64.

Imaging of pulmonary vasculitis .Radiology -. 2010 May;255(2):322 41.

Microscopic polyangiitis : Clinical presentation . Autoimmun Rev . 2010 Oct;

- 9(12):812 9.

Education

case microscopic polyangiitis