Updates in ANCA Vasculitis

Adil Gasim, MDAssistant Professor

Pathology & Laboratory MedicineUNC Nephropathology Division

Julie McGregor, MDAssistant ProfessorUNC Kidney Center

4/16/2014 1

Anti‐neutrophil cytoplasmic antibodies (ANCA)‐associated diseases are a spectrum of phenotypically diverse but pathogenetically related autoimmune diseases characterized by small vessel vasculitis.

Disease categories include:Microscopic polyangiitis (MPA)Granulomatosis with polyangiitis (GPA) (Wegener’s)Eosinophilic granulomatosis with polyangiitis (EGPA)Renal limited pauci‐immune crescentic GN 

Circulating anti-GBMantibodies with linearglomerular IF staining

Paucity of glomerular IFimmunoglobulin

staining

CRESCENTIC GLOMERULONEPHRITIS 2013

Anti-GBM CGN

Glomerular immunecomplex localization with

granular IF staining

Immune ComplexCGN

ANCACGN

Frequency of Renal Biopsy Diagnoses vs Age at UNC from 1985-2007(Note: The relative frequency in the general population would be very different)

0

100

200

300

400

500

600

700

LupusIgA NepANCA GNTBM LesionFibrillary GNPost Infect GNAnti‐GBM GNHereditary Nep

Biopsy Diagnoses in Patients with Glomerulonephritic Syndrome

Age

Lupus GN

IgA GN ANCA

GN

Jennette JC, Falk RJ in National Kidney Foundation’s Primer on Kidney Disease, 6th Ed, Chap 16, 2014

Aorta Arteries

ArterioleCapillary Venule

Vein

ANCA Associated Vasculitis

Small Vessel Vasculitis

MicroscopicPolyangiitis

vasculitis withno asthma orgranulomas

Granulomatosis with Polyangiitis

(Wegener’s)

granulomasand noasthma

Eosinophilic Granulomatosis with

Polyangiitis(Churg-Strauss)

eosinophilia,asthma andgranulomas

ANCA Associated Vasculitis

MPA GPA EGPA

AAV

SVV

Pauci-immune crescentic

glomerulonephritis

renal limited

vasculitis

PICGN

Jennette et al., Heptinstall’s Pathology of the Kidney, 7th ed, 2014

Relative Frequency of ANCA Specificities in Different Clinicopathologic Expressions of ANCA Disease

* >75% MPO-ANCA positive when GN is present

*

• Acute ANCA‐associated glomerulonephritis is characterized by necrotizing lesions of the glomerular capillary tuft accompanied by extracapillary proliferation, inflammatory cell infiltration, and often rupture of the Bowman’s capsule.

• Necrotizing damage of small arteries is found in 10–30% of cases, and medullary capillaritis is occasionally observed.

• Chronic ANCA‐associated glomerulonephritis is characterized by sclerotic lesions.

Histologically unremarkable glomeruli in a patient with ANCA associated small 

vessels vasculitis.

Segmental fibrinoid necrosis

Cellular crescent with fibrinoid necrosis

Cellular crescent with early scaring Fibrous crescent

Necrotizing ANCA vasculitis 

Medullary ANCA angiitis

Red blood cell casts and acute tubular injury

The 2010 histopathological classification of ANCA associated GN was based on a total of 100 patients from various European centers.The goal was to identify pathologic features that has prognostic value for at the time of biopsy.

Berden AE, et al. J Am Soc Nephrol. 2010;21:1628-36

Pathologic Classification of ANCA Glomerulonephritis

Berden AE, et al. J Am Soc Nephrol. 2010;21:1628-36

Focal (n=16)

Crescentic (n=55)

Mixed (n=16)

Sclerotic (n=13)

0 2 4 6 8 10 12

0

20

40

60

80

100 Renal Survival

Years

%

Entry GFR 56.4

Entry GFR 11.2

Entry GFR 15.4

Entry GFR 10.8

Validation studies

• Chang et al 2012 (Chinese single center), Muso et al 2012 (Japanese study), Hilhorst et al 2012 (Maastricht University Medical Centre), Masaru Togashi et al 2014 (Japanese single‐center), and others.

• This classification needs to have more validation in patients with very low GFR or on dialysis at the time of presentation.

ANCA Vasculitis

Questions and Discussion on ANCA Glomerulonephritis

4/16/2014 20

Disclosures• I have blatantly “lifted” the majority of these

slides from Patrick Nachman and Will Pendergraft

• I used the fact that neither of them can say “no” to me to my advantage

• I plan on having Ron Falk, Patrick Nachman, and Will Pendergraft speaking as much as I do over the next 50 minutes in order to make this discussion really interesting

4/16/2014 21

4/16/2014 22

• Discuss Anti-neutrophil Cytoplasmic Antibody (ANCA) Disease in 2014

• Allow for • Questions and answers• Audience participation• Lots of interruptions

Objectives

How am I supposed to label the specific disease my patient with ANCA vasculitis has?

I’m sorry, I have been coming to these meetings for many years and it may just be me but I still don’t know what name I am supposed to label a patient with ANCA related disease. The names keep changing and frankly the name of it doesn’t seem to matter much anyway. I just want to converse intelligently with patients and colleagues about ANCA and be up with the current naming system.

4/16/2014 23

Question:

ANCA‐small vessel vasculitisNecrotizing vasculitis affecting capillaries, arterioles and venules, 

with few or no immune deposits

Microscopic Polyangiitis

(MPA)

‐May also affect small and medium 

size arteries.      ‐ GN and pulmonary 

capillaritis are common

Wegener’s Granulomatosis

‐ Granulomatousinflammation involving the 

respiratory tract.

‐ GN is common 

Churg‐Strauss Syndrome

‐ Eosinophil‐rich granulomatousinflammation involving the 

respiratory tract.‐ Associated with 

asthma and eosinophilia.

‐ ANCA in ~40% of patients (anti‐MPO).

Pauci‐immune necrotizing & crescentic GN

No extra‐renal manifestations

EosinophilicGranulomatosis w/ 

Polyangiitis(EGPA)

Granulomatosiswith Polyangiitis(GPA)

Falk RJ, Jennette JC. J Am Soc Nephrol 21: 745–752, 2010.

Frequency of C/PR3 and P/MPO ANCA by clinical phenotype

Genome-Wide Association Study

• GPA and MPA were genetically distinct; however strongest genetic associations were with the ANCA serotype.

• Genome-Wide Association Study supports categorization based on the ANCA antibody specificity rather than disease phenotype.

• “proteinase 3 ANCA-associated vasculitis” “myeloperoxidase ANCA-associated vasculitis” are two distinct autoimmune syndromes.

• Lyons PA et al N Engl J Med. 2012 Jul 19;367(3):214-23. PMID: 22808956 27

Serotype it is

• MPO- vs PR3-ANCA more applicable and useful categorization of patients with ANCA-small vessel vasculitis than phenotype-based disease categorization (MPA vs GPA).

• Classification systems that incorporate ANCA serotype more useful categorization based on clinical and pathologic criteria, notably in predicting relapse

• Mahr A et al. Ann Rheum Dis. 2013 Jun;72(6):1003-10. PMID: 22962314• Lionaki S et al Arthritis Rheum. 2012 Oct;64(10):3452-62

4/16/2014 28

How do I best treat newly diagnosed ANCA disease?

I have been hearing a lot about rituximab for the past few years- a lot of talk focused on ANCA disease. I’ve had a fair share of luck treating my ANCA disease patients with cyclophosphamide. I don’t want to be out dated in my treatment strategies but I also don’t want to be swept up by a passing trend.

4/16/2014 29

Question:

Induction Therapy

No life/organ‐threatening disease

Life/organ‐threateningdisease

Rituximab with Prednisone 6 months  or CyclophosphamideIV Q mo X 3 mo, Prednisone x 16 

wk

Solumedrol and/or plasma exchange, Prednisone x 16 wk, cyclophosphamide IV Q mo x 3‐6 

months

Remissionfollowing Cytoxan

Remissionfollowing Rituximab

Treatment resistance

Follow patient closely to detect 

disease early relapse

Remissionmaintenance with 

Azathioprine

Rituximab or oral cyclophosphamide

Remission

Rituximab ± Prednisone if relapse caught early orcyclophosphamide IV Q mo with  Prednisone for life/organ‐threatening disease

Relapse RelapseFollowing 12‐ 18 mo in remission, maintenance immunosuppression may be discontinued with close follow up

PULSE OR DAILY ORAL CYCLOPHOSPHAMIDE

Harper L et al. Ann Rheum Dis 2012:71:955–960.

4/16/2014 31

Pulse vs Daily Cyclophosphamide: Long‐term 

Harper L et al. Ann Rheum Dis 2012:71:955–960.

At last F/U:ESKD: Pulse13% vs DO 11%Median Cr:Pulse, 117 (89–185) μmol/l; DO, 117 (105–144) μmol/l; p=0.92)

RITUXIMAB?

4/16/2014 34

Rituximab for the Treatment of Wegener's Granulomatosis and MPA

197 patients with de novo or relapsing ANCA vasculitis WG 75%, MPA 25% PR3-ANCA 66%, MPO-ANCA 33%

Treatment: Rituximab 375 mg/m2 once weekly x 4 ; vs. Cyclophosphamide 2 mg/kg/day for months 1-3 then

Azathioprine 2 mg/kg/day for months 4-6 All patients received Methylprednisolone 1 g/day IV x 1-3 followed by Prednisone 1 mg/kg/day, with taper over 6 months.

Primary outcome: remission at 6 months off prednisone.Stone JH et al N Engl J Med. 2010;363(3):221-32.

Stone et al NEJM 2010;363(3):221-32.

Rituximab versus Cyclophosphamide for ANCA vasculitisResults at 6 months

Variable Rituximab (n=99)

Cyclophos. (n=98) P

ANCA-associated vasculitis type (%)Wegener’s granulomatosis (WG)Microscopic polyangiitis (MPA)Indeterminate

75241

76240

0.61

ANCA type (%)Proteinase 3 ANCAMyeloperoxidase ANCA

6732

6634

primary end point: BVAS/WG = 0 with no prednisone at 6 mos.

64% 53% 0.09(Non-infer. P<0.001)

Primary end point among WG pts (n=147) 63% 50% 0.11Primary end point among MPA pts (n=48) 67% 62% 0.76Primary end point among pts with relapsing disease

67% 42% 0.01

% PR3-ANCA pts who became ANCA neg 50% 17% <0.001% MPO-ANCA pts who became ANCA neg 40% 41% 0.95Rate of disease flares per patient-month 0.011 0.018 0.30Adverse events, n (%) 22 (22%) 32 (33%) 0.01

Extracted from Stone JH et al N Engl J Med. 2010;363(3):221-32.

HARD TO “RAVE” ABOUT TREATMENT OF ANCA VASCULITIS

Specks and colleagues, NEJM 369(5): 417-27, August 2013

Rituximab for ANCA vasculitis: Long term outcomes

Specks U et al. N Engl J Med. 2013;369(5):417-27.

Should I use rituximab and cyclophosphamide together?

It sounds like in many cases I could use either rituximab or cyclophosphamide. If one is good, isn’t two better? Why not use the best of both worlds?

4/16/2014 40

Question:

ONE ANCA VASCULITIS INDUCTION OF REMISSION REGIMEN

1. CYCLOPHOSPHAMIDE

4 mg/kg PO daily x 1 week*2 mg/kg PO daily x 7 weeks

CrCl 40-60 cc/min (reduce dose by 25%)CrCl 20-39 cc/min (reduce dose by 33%)CrCl <20 cc/min (reduce dose by 50%)NOTE: PO:IV equivalency (IV if non-compliant)* use 2 mg/kg PO daily x 8 weeks IF 1) on rituxan and 2) non-organ-threatening disease as defined in #4 below.

2. PREDNISONE

1000 mg IV daily x 3 days60 mg PO Q12h x 4 days60 mg PO daily x 1 week40 mg PO daily x 1 week30 mg PO daily x 1 week20 mg PO daily x 1 week15 mg PO daily x 1 month12.5 mg PO daily x 1 month10 mg PO daily x 1 month7.5 mg PO daily x 1 month5.0 mg PO daily x 1 month2.5 mg PO daily x 1 month2.5 mg PO every other day x 1 month

3. RITUXIMAB: DOSE 1: 1 gram IV x 1 during week 1, DOSE 2: 1 gram IV x 1 within three weeks after DOSE 1- 1 gram IV x 1 Q4 months after DOSE 2 x 2 years thereafter followed by Q6 months (hold if IgG < ½ lower limit of normal)

4. PLASMA EXCHANGE: performed if severe renal and/or pulmonary involvement (7 exchanges over 10-12 days)- severe involvement defined as Cr > 5 and/or dialysis-dependence for no more than 2 weeks and/or alveolar hemorrhage- NOTE: will also be performed for 2.5-fold increase in ANCA titer and/or doubling of serum creatinine within one week of presentation

0

200

400

600

800

1000

1200

050

100150200250300350400

1 14 27 40 53 66 79 92 105

118

131

144

157

170

183

196

209

222

235

248

261

274

287

300

313

326

339

352

012345

1 14 27 40 53 66 79 92 105

118

131

144

157

170

183

196

209

222

235

248

261

274

287

300

313

326

339

352

GFR > 60 cc/min

GFR 40–60 cc/min

GFR 20‐39 cc/min

GFR < 20 cc/min

mg/kg

prednisone

rituximab

milligrams

day

4/16/2014 42

Cyclophosphamide(N=178)

Rituximab + cyclophosphamide

(N=77)P values

ESKD n (%) 44 (25%) 9 (12%) 0.0189Death n (%) 30(17%) 5(6%) 0.0128ESKD or death (%) 64 (36%) 12 (16%) 0.0009

Addition of rituximab to cyclophosphamide therapy reduces death and ESKD

Should my patient receive plasma exchange/pheresis?

I can provide plasma exchange/plasmapheresis at my hospital. What are the exact indications for using PLEX in ANCA? Are there risks and benefits?

4/16/2014 43

Question:

Jayne and colleagues. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. JASN 18(7): 2180-8, 2007.

THE MEPEX TRIAL 137 patients with ANCA vasculitis and Cr > 5.8 mg/dL

treatment arms: plasma exchange x 7 sessions OR IV methylprednisolone

plasma exchange

methylprednisolone

P = 0.008

THE MEPEX TRIAL: LONG-TERM OUTCOMES

Walsh M et al Kidney Int. 2013 Aug;84(2):397-402

PEXIVASplasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasmic autoantibody-associated vasculitis (n=500)

What can I say to my patient about lifespan prognosis and quality of life?

My patient is devastated to receive a diagnosis of ANCA disease. She is worried she won’t see her grandchildren grow up and won’t complete her bucket list.

4/16/2014 47

Question:

4/16/2014 48

Any Infection 489 206 141 107 81 66

Relapse 489 329 229 153 116 91

Severe Infection 489 318 251 196 149 119

ESRD 489 374 298 226 173 144

Death 489 387 309 240 181 149

Any Infection

Relapse

Severe Infection

ESRD

Death

Relapse rates of patients with ANCA vasculitis at Massachusetts General Hospital

undergoing continuous B cell depletion

Pendergraft et al. CJASN, 2014

Survival of ANCA vasculitis patients at MGH undergoing continuous B cell depletion mirrors the general population

Age-, gender- and ethnicity-matched United States population

ANCA vasculitis patients undergoing continuous B cell depletion

Cum

ulat

ive

Sur

viva

l (%

)

Time from start of remission maintenance therapy (years)Number at risk 172 140 102 69 49 24 7

Pendergraft et al. CJASN, 2014

What, if any, remission maintenance therapy should I be giving my patients?

Ok good, my patient is in remission. Now what? I feel like the idea of remission maintenance therapy has been a moving target every time it is discussed at this meeting. Should patients stay on therapy? Is it safe to stop treatment altogether? Is there a best remission maintenance therapy?

4/16/2014 51

Question:

Sequential treatment with cyclophosphamide and azathioprine

144 patients who attained a remission with oral CyP and prednisolone

Continue CyP

azathioprine

Switch to azathioprine

Months 3 to 12

Month 12

No significant difference in the rate of relapses (13.7 % vs. 15.5%, P=0.65).

No significant difference in the rate of severe adverse events (11 vs. 10%, P=0.94)

Jayne D. N Engl J Med. 2003;349:36-44. Relapse occurred in 8% of pts with MPA, vs. 18% of pts with WG (p=0.03)

adjusting for age, sex, diagnosis, route of cyclophosphamide & renal function at entry, HR 1.8, 95%CI 1.1-2.93, P=0.02) .

MMF vs Azathioprine (IMPROVE)

Hiemstra TJAMA. 2010;304(21):

• 117  patients: – 23 MPA, 89 GPA, 5 Kidney limited disease– 93 newly diagnosed, 24 with relapsing disease– 58 in rituximab gp, 59 in azathioprine gp

• 56% males• The two groups were well balanced with respect to organ involvement, lung manifestation, baseline kidney function.

Rituximab vs. Azathioprine for Maintenance in ANCA‐Vasculitis

Guillevin L. et al International Vasculitis Workshop, Paris, May 2013

Rituximab vs. Azathioprine for Maintenance in ANCA‐Vasculitis

• Randomized controlled trial• All patients received induction therapy with

Methylprednisolone pulse + prednisone + pulse Cyclophophamide x 6 months

• Maintenance therapy randomized to – Rituximab 500 mg on days 1, 15, month 5.5 and every 6 months thereafter for total of 18 months

– Azathioprine 2 mg/kg/day x 22 months• Primary outcome: frequency of major relapses at 28 months

Guillevin L. et al International Vasculitis Workshop, Paris, May 2013

RituximabN=58

AzathioprineN=59

Relapse 3 (5.4%) 15 (24.5%)Deaths 0 2 Serious Adverse Events

15 (25.8%) 18 (30.5%)

Infections 11 (0 fatal) 12 (1 fatal)

Event free survival Rituximab >> Azathioprine, p=0.002ANCA +ve: 

at remission: similar in the two groupsat month 28: Aza 64% vs Rituximab 27%

Rituximab vs. Azathioprine for Maintenance in ANCA‐Vasculitis: Results

Guillevin L. et al International Vasculitis Workshop, Paris, May 2013

http://www.newevidence.com/rheumatology/entries/Rituximab_versus_azathioprine_for_maintenance_in/

MAINRITSAN 1RTX vs. AZA

http://clinicaltrials.gov/ct2/show/NCT01731561

MAINRITSAN 2 RTX and wait vs. continuous RTX

ARM 1

ARM 2

RTXANCA status and CD19+ B cells monitored Q3 months and patients receive 500 mg RTX either if:1. CD19>0/mm3 or 2. ANCA positive again or 3. ANCA titer rises significantly

RTX RTX RTX RTX RTX

d1 d15 Month 6 Month 12 Month 18

RITAZAREMDAVID JAYNE & PETER MERKEL 

An international, open label, randomized controlled trial comparing rituximab with azathioprine as maintenance therapy in relapsing ANCA‐associated vasculitis 

RITAZAREMKey Inclusion criteria

Subjects must meet all of the following criteria: 1. Age 15 years and above 2. GPA or MPA 3. Current or historical positive ANCA4. Disease relapse in patients that have previously achieved remission following induction therapy 

Key Exclusion criteria

1. Age < 15 years2. Previous therapy with any biological B cell depleting agent (e.g.; rituximab or belimumab) within the past 6 months 

When do I re-dose rituximab?

I gave my patient rituximab. When do I give it again? Is it safe to wait for B cells to return before I redose my patient with rituximab? If I find that B cells are back then do I need to redose with rituximab? Do B cells need to have repopulated (CD 19 and 20 >1) in order to have a relapse?

4/16/2014 63

Question:

Information from RAVE Trial• Circulating B cells detectable in 21 of the 24

patients (88%) who relapsed in the rituximab group and in 11 or the 20 relapsers (55%) in the control group. » Not all people who relapsed had B cells» Cyclophosphamide makes B cells undectable,

too and perhaps for longer??????• Increases in ANCA titers did not predict

relapses in either treatment group» only 3 of the 44 patients relapsed without

either ANCA or detectable circulating B cells.

4/16/2014 64Specks and colleagues, NEJM 369(5): 417-27, August 2013

• Disease unresponsive to maximum tolerated doses of cyclophosphamide or disease for which cyclophosphamide was deemed necessary but could not be given.

• 53 patients with refractory GPA (median age 46 years IQR 30–61y).  anti‐PR3 in 52

• Received a median of 4 courses of RTX (IQR 3–5); median time to return of B cells: 8.5 months (IQR 6–11). 

• All patients treated for relapses with the combination of RTX and glucocorticoids (85 courses) achieved complete remission.

• Observed relapses (32) occurred after reconstitution of B cells and were accompanied/preceded by an increase in ANCA levels (except for 1).

Cartin‐Ceba R et al. Arthritis Rheum 2012;64:3770–3778

BUT ALL B CELLS MAY NOT BE BAD

You have heard us say this before…

4/16/2014 66

The Percentage of CD5+ B Cells Decreases in Active Disease and Normalizes in Remission

Figure from Bunch DO, et al., CJASN 2013 Mar;8(3):382‐91

%CD5+ B Regulatory Cells and IL-10 Normalize as Patients During Remission

Clinical CD5 Cohort

Patients Who Repopulate with ≥30 %CD5+ B Cells have a Longer Time to Relapse After Rituximab

Includes CD5+ B cell data acquired from clinical Rituxan panels

p = 0.0002

What is the best treatment for relapsed disease?

Unfortunately my patient has relapsed.

4/16/2014 71

Question:

Relapse treatment• Treatment with corticosteroids and

cyclophosphamide is associated with similar remission rates as for de novo disease.

• RAVE trial: superiority of Rituximab over cyclophosphamide among patients with relapsing ANCA vasculitis. » Allows cyclophosphamide avoidance in those who

have previously received cyclophosphamide therapy.

• Choice of therapy for the treatment of relapse should take into consideration the severity of the disease activity. » Use of rituximab is not well established for patients

with severe pulmonary hemorrhage or severe renal failure nearing or requiring dialysis. 4/16/2014 72

How should I treat late onset neutropenia?

I gave rituximab (with or without cyclophosphamide) and now months later my patient has a very low white blood cell count (absolute neutrophil count ≤1.5x109/L).

4/16/2014 73

Question:

PROPOSED LATE-ONSET NEUTROPENIA GUIDELINES FORANY RITUXIMAB-TREATED INDIVIDUAL

1. Educate patients and check CBC with differential:- every 2 months x 4 after any RTX infusion and- immediately at the onset of fever

2. If ANC < 1000 on repeat blood work and afebrile, then- Filgrastim (G-CSF, neupogen) 300 mcg SC x 1- repeat CBC with differential in 1-3 days

3. If ANC < 1000 and febrile, then NEUTROPENIC FEVER- admit, check cultures, administer antibiotics + filgrastim

4. If ANC < 1000 on multiple occasions, then STOP RTX- consider alternative remission maintenance agent(s)

What can I tell this patient about fetal risk from exposure to rituximab during pregnancy?

I had a young woman present 15 months ago with ANCA disease that I treated with rituximab for induction and remission maintenance to preserve her fertility. Well, it worked and now she is pregnant.

4/16/2014 75

Question:

FETAL OUTCOMES AFTER RITUXIMAB EXPOSURE

Pendergraft, et al Annals of Rheumatic Diseases 72(12): 2051-3, December 2013

WHAT ABOUT RITUXIMAB USE IN PREGNANCY?

GROWING COHORT AT MGH OF PREGNANT ANCA PATIENTS…

Currently n = 7

EXAMPLE:

29 F with GPA in 2002 characterized by fever, fatigue, sinus congestion and RPGN- treated with steroids and azathioprine- Cr 0.7 (baseline) by 2006- transitioned to rituximab 10/19/2010 for maintenance- delivered healthy baby two weeks ago

WHAT ABOUT RITUXIMAB USE IN PREGNANCY?

GROWING COHORT AT MGH OF PREGNANT ANCA PATIENTS…

Currently n = 7

EXAMPLE:

29 F with GPA in 2002 characterized by fever, fatigue, sinus congestion and RPGN- treated with steroids and azathioprine- Cr 0.7 (baseline) by 2006- transitioned to rituximab 10/19/2010 for maintenance- delivered healthy baby two weeks ago

MOM’S CIRCULATIONG CD20+ B cells: < 0.01 %BABY’S CORD BLOOD CD20+ B cells:

WHAT ABOUT RITUXIMAB USE IN PREGNANCY?

GROWING COHORT AT MGH OF PREGNANT ANCA PATIENTS…

Currently n = 7

EXAMPLE:

29 F with GPA in 2002 characterized by fever, fatigue, sinus congestion and RPGN- treated with steroids and azathioprine- Cr 0.7 (baseline) by 2006- transitioned to rituximab 10/19/2010 for maintenance- delivered healthy baby two weeks ago

MOM’S CIRCULATIONG CD20+ B cells: < 0.01 %BABY’S CORD BLOOD CD20+ B cells: 6.0 %

Try me…

Ok, I think I’ve got it.

4/16/2014 80

Now for a case:

History of Present Illness

56 year old woman with HTN and three months of- arthralgias and - night sweats

Past Medical History: • Diabetes• CVA resulting in left-sided

hemiparesis• Spinal Stenosis

4/16/2014 81

Medications

HCTZHydralazine

LisinoprilAtenolol

Ibuprofen

4/16/2014 82

PHYSICAL EXAM:VITALS: 200 lbs (down from baseline of 225 per patient) 98 78 170/100 18 98% RA

GENERAL: ill-appearing, overweight, NAD, pleasant

HEENT: anicteric, moist membranes, good dentition, no lymphadenopathy

CV: warm and well-perfused, no JVD, PMI non-displaced, normal S1/S2, rrr, no audible mrg, no edema

PULM: clear bilaterally

ABDOMEN: protuberant, +bs, soft, nt, nd

NEURO/MSK: weak on left compared to right, no arthritis or synovitis

GU: no CVA tenderness

SKIN: no visible rash 83

4/16/2014 84

144

4.5

93

28

30

(1.2)1.9130 1.9

9.6

7.97.2 212

10.1

30.0

albumin = 4.2

URINALYSIS: 1.025/5.0, 3+ blood, 3+ protein

RENAL ULTRASOUND: unremarkable, no hydronephrosis

ANA 1:640, anti-dsDNA negative C3 93 (86-184), C4 16 (16-38), SPEP OK

HBV sAg/sAb negative, HCV negative, HIV negative, ARMPIT cryos negative

Laboratory Values

Case QuestionAdditional testing shows:

- MPO-ANCA = 11,000 units- anti-GBM immunoblot is negative

This patient most likely has:

A. granulomatosis with polyangiitis (formerly Wegener’s)

B. pulmonary-renal syndrome NOSC. microscopic polyarteritis nodosum articulumD. drug-associated ANCA vasculitis4/16/2014 85

Case QuestionAdditional testing shows:

- MPO-ANCA = 11,000 units- anti-GBM immunoblot is negative

This patient most likely has:

A. granulomatosis with polyangiitis (formerly Wegener’s)

B. pulmonary-renal syndrome NOSC. microscopic polyarteritis nodosum articulumD. drug-associated ANCA vasculitis4/16/2014 86

Pendergraft et al. Curr Opin Rheum, 2014

DRUG CULPRITS ASSOCIATED WITH ANCA VASCULITIS

Pendergraft and Niles, ANCA Meeting 2013 abstract

Discussion• Cases in your practice you have questions

on?• Other questions not yet addressed?• Differing opinions from those already voiced?

4/16/2014 89