Vasculitic pearls for the general internist Simon Carette, MD, - - PowerPoint PPT Presentation

Vasculitic pearls for the general internist

Simon Carette, MD, MPhil, FRCPC Professor of Medicine University of Toronto CSIM Nov 3, 2017

Disclosures

• Investigator in the following trials:

– PEXIVAS – BREVAS – AGATA – RITAZAREM – TAPIR

Objectives

• 1. Integrate new concepts in the diagnosis and

management of patients with systemic vasculitis

• 2. Recognize the mimickers of vasculitis

Case 1

• 62 year old woman with no significant past

medical history is transferred from another hospital to your ICU

• Unwell x 3 weeks
• Cough X 2 weeks
• No response to a 7 day course of clarythromycin

500 mg BID

• Hemoptysis X 3 days
• Progressive SOB X 24 hours

Case 1

• Intubated on arrival, PEEP 10 cm H2O
• T 37.5o, BP 110/75, 88/min, O2 sat 98% (40%
• xygen)
• Diffuse crackles
• ENT, heart, abdomen normal
• MSK: no synovitis
• Neuro: sedated, neck supple, DTR 2+

symmetrical

Case 1

• Hemoglobin 78 (110)
• WBC 12.3
• Platelets 453
• Creatinine 312 (115)
• Urine: blood 3+, proteins 2+
• Urine sediment: 50-80 RBC/hpf, ? 2 RBC casts

CXR

What is the most likely diagnosis?

Pulmonary-renal syndrome

Etiology of Pulmonary-renal syndrome

Critical care 2007;11:213

What test(s) would be most helpful at this point?

Biopsy or ANCA?

ANCA testing

• Sensitivity of ANCA: 95%
• Specificity: 95%
• Pre-test probability: 70%

ANCA-Related Vasculitis No vasculitis ANCA + 66 1.5 ANCA - 4 28.5 70 30

PPV: 66/67.5 = 98%

How would you treat this patient?

Management

• Corticosteroids

– IV pulse 1000 mg/day x 3 – Equivalent of prednisone 1 mg/kg (up to 80 mg/day)

• Cyclophosphamide or Rituximab

Cyclophosphamide

Oral or IV pulse?

Annals Intern Med 2009;150:670-80

Inclusion criteria

• NEWLY diagnosed WG, MPA or renal-limited

MPA

• Renal involvement due to active vasculitis

– serum creatinine level >150µmol/L – biopsy showing necrotizing GN – red cell casts or hematuria (> 30 RBC/HPF) and proteinuria (>1 g/day)

• Confirmatory histology or ANCA positivity

Interventions

• IV CYC 15 mg/kg q 2 weeks x 3 and q 3 weeks

until 3 months after remission* * or oral pulses 5 mg/kg x 3 consecutive days

• Oral cyclophosphamide

– 2 mg/kg/day until remission – 1.5 mg/kg/day for another 3 months

Time to remission

HR 1.098 95% CI 0.78 to 1.55 P= 0.59

Relapse

• 19 (14.5%) of the 131 patients who

achieved remission had a relapse

– Pulse CYC: 13 (7 major, 6 minor) – Oral CYC : 6 (3 major, 3 minor) HR: 2.01 (CI, O.77 to 5.30)

Harper L et al Ann Rheum Dis 2012;71:955-960

Patient population

• 134/149 patients
• Median follow-up: 4.3 years (2.95-5.44)

Risk of death by treatment allocation

HR 1.04, 95% CI 0.47-2.29 p= 0.92

12 DO, 13 IV Median time to death 2.23 years IQR, 0.32-3.13

Risk of relapse by treatment allocation

HR 0.50 95% CI, 0.26 to 0.93 P= 0.029

Risk of relapse depending on limb and ANCA status

Pulse CYC reductions for renal function and age

Age (years) Creatinine 150-300 µmol/l Creatinine 300-500 µmol/l <60 15 mg/kg/pulse 12.5 mg/kg/pulse >60 and <70 12.5 mg/kg/pulse 10 mg/kg/pulse >70 10 mg/kg/pulse 7.5 mg/kg/pulse

Algorithm for Adjusting CYC

Creatinine clearance

(ml/minute)

CYC dose

(mg/kg/day)

> 100 2.0 50-99 1.5 25-49 1.2 15-24 1.0 <15 or on dialysis 0.8

Rheum Dis Clin N Am 2001:863

What about Rituximab for this patient?

The RITUXIVAS TRIAL

Study design

• Open-label, two group, parallel-design,

randomized trial

• 44 patients
• Eight centers in Europe and Australia

Jones RB et al. NEJM 2010; 363: 211-220

Inclusion criteria

• New diagnosis of ANCA-related vasculitis
• ANCA positive
• Renal involvement

– Necrotizing GN on biopsy or, – Red-cell casts or, – Hematuria (≥ 30 red cells per HPF)

• Randomization in a 3:1 ratio, stratified for age,

diagnosis, baseline renal function

Treatments

• Patients in rituximab group (33):

– Rituximab 375 mg per square meter/week x 4 weeks – IV cyclophosphamide 15 mg/kg with the first and third Rituximab infusions

• Patients in cyclophosphamide group (11):

– Validated regimen of IV cyclophosphamide for 3 to 6 months followed by azathioprine

12 month Data

Two-year follow-up of RITUXIVAS

Jones RB et al Clin Exp Imunol 2011;164S1:57

24 month Data

NEJM 2010; 363: 211-220

Study design

• Double-blind, double dummy, randomized,

non-inferiority controlled trial

• 197 patients
• Nine clinical sites from the USA

Stone JH. et al NEJM 2010; 363: 221-232

Inclusion criteria

• WG or MPA
• ANCA positive
• Manifestations of severe disease and a

BVAS/WG score of 3 or more

• Patients with newly diagnosed disease or

relapsing disease were eligible

• Randomized in a 1:1 ratio
• Stratification clinical site and ANCA type

Treatments

• Patients in Rituximab group:

– 375 mg per square meter/week x 4 weeks – Placebo-cyclophosphamide – Placebo azathioprine after 3-6 months

• Patients in the control group:

– Daily cyclophosphamide 2 mg/kg – Placebo rituximab infusions – Azathioprine 2 mg/kg after 3-6 months

Results

• Primary outcome

BVAS/WG=0 and off prednisone at 6 months Rituximab: 63/99 patients 64% Cyclo: 52/98 patients 53 %

• 11 (95% CI -3.2 to 24.3, P=0.09)

Results

Sub-group analyses for primary outcome:

• Relapsing patients:

– Rituximab: 67% – Controls: 42% P=0.01

Long-term follow-up RAVE

• 197 patients
• Mean follow-up: 35 months (SD 14.6)
• Primary outcome (BVAS/WG=0 and no

prednisone):

6 months 12 months 18 months RTX 64% 48% 39% CYC 53% 39% 33%

Specks U et al. NEJM 2013; 369:417-427

Long-term follow-up RAVE

• Relapsing Disease versus Newly Diagnosed

Disease

6 months 12 months 18 months RTX 67%* 49%** 37% CYC 42% 24% 20%

Specks U et al. NEJM 2013; 369:417-427 * p= 0.01 ** p= 0.009

Long-term follow-up RAVE

• No difference in:

– Number of flares – Number of patients suffering at least one flare – Overall, serious or selected adverse events

• Difference in

– Leucopenia CYC (23%) versus Rituximab (5%) – Pneumonia CYC (11%) versus Rituximab (3%)

What about Plasma Exchange?

MEPEX Trial

• Biopsy-proven ANCA necrotizing GN with

acute renal failure (creatinine > 500µmol/l)

• 7 PE (60 ml/kg) in 2 weeks vs 3 MPP (15

mg/kg) + standard therapy (CYC + pred)

• 151 patients from 9 countries
• MPA was the most common diagnosis

Jayne DRW et al. J AM Soc Nephrol 2007:18:2080

Outcome at 3 months Alive and

• ff dialysis

ESRD Death PE n=70 48 (69%) 11 (16%) 11 (16%) MPP n=67 33 (49%) 23 (34%) 11 (16%) Difference 95% CI 20% 18 to 35

MEPEX RESULTS

Outcome at 12 months Alive and

• ff dialysis

ESRD Death PE n=70 41 (59%) 10 (14%) 19 (27%) MPP n=67 29 (43%) 22 (33%) 16 (24%) Difference 95% CI 16% 4 to 40

MEPEX RESULTS

Long-term follow-up MEPEX

• 137 patients
• Mean follow-up: 4 years
• ESRD: 70 (51%); Death: 56 (41%) Relapse:

26 (19%)

Casian A. Clin Exp Immunol 2011;164 S1:52

Long term follow-up MEPEX

• HR for ESRD/Death:

0.81 (0.53-1.23; P= 0.32)

• HR for ESRD:

0.67 (0.39-1.13)

• HR for death:

1.08 (0.67-1.72)

• HR for relapse:

0.57 (0.26-1.21)

Plasma exchange and glucocorticoid dosing in ANCA associated vasculitis: a randomized control trial (PEXIVAS)

Michael Walsh1, Peter Merkel2, and David Jayne3 for the PEXIVAS Study Group

1University of Calgary; 2Boston University; 3Addenbrooke’s Hospital

Severe AAV Cyclophosphamide Or Rituximab Adjunctive Plasma Exchange No Plasma Exchange Standard-Dose GC Reduced Dose GC Standard-Dose GC Reduced Dose GC ESRD or Death

Follow-Up

PEXIVAS Factorial Design

Glucocorticoid Dosing

10 20 30 40 50 60 70 1 3 5 7 9 1113151719212325 Prednisone (mg/day) Weeks PEXIVAS PEXIVAS (Reduced)

PEXIVAS Sample Size

• 700 patients
• Powered to measure absolute risk

reduction of 12% at 5 years

• For GC non-inferiority hypothesis
• 80% power to detect 11% difference in

mortality at 5 years

• 80% power to detect 10% reduction in

infections in first year

Principles of management

• The use of cyclophosphamide should be

restricted to 3-6 months Jayne D. et al NEJM

2003;349:36

• Metotrexate or azathioprine can be used

interchangeably to maintain remission Pagnoux

• C. et al NEJM 2008;359:2790
• Methotrexate can be used to induce remission

in patients with non life and/or organ threatening manifestations de Groot K. et al Arthritis

Rheum 2005;52:2461

Principles of management

• Mycophenolate mofetil is inferior to

azathioprine to maintain remission

Hiemstra TF. et al JAMA 2010;304:2381

• Patients maintained on low dose-

prednisone (<10 mg/day) may have a lower rate of relapse

Walsh M. et al Arthritis Care Res 2010;62:1160

Can we devise more effective strategies to prevent relapses?

NEJM 2014; 371: 1771-1780

MAINRITSAN

• 115 newly diagnosed (92) or relapsing (23)

patients with GPA or MPA who achieved remission with CS+CYC

• Randomized to:

– 500 mg RTX infusion on D1, D15, 5.5 months and every 6 months x 2 (total of 5 infusions over 18 m) – AZA 2 mg/kg x 12m, 1.5 mg/kg x 6 m, 1 mg/kg x 4 m

• Primary outcome: rate of major relapse at 28 m

Guillevin et al. NEJM 2014;371:1771-80

Results

Hazard ratio of major relapse for patients randomized to AZA, was 6.61 (95% CI, 1.56 to 27.96; P=0.002). Hazard ratio of major or minor relapse in patients in the AZA group was 3.53 (95% CI, 1.49 to 8.40; P=0.01).

Guillevin L et al. N Engl J Med 2014;371:1771-1780.

Long term follow-up of MAINRITSAN

• 60 months
• n= (110/115 patients 96%)
• Overall survival rate:

RIT: 100% AZA: 93 % p=0.045

Terrier et al. A&R 2016 abs 1955

Long term follow-up of MAINRITSAN

• Relapse-free survival rates:

RIT: 58% AZA: 37% p= 0.012

• Major relapse-free survival rates:

RIT: 72% AZA: 49% p= 0.003

• NO difference in survival without SAEs
• NO difference in the cumulative GC dose

Long term follow-up of MAINRITSAN

• For RIX-treated patients, predictors of major

relapse were:

– PR3-ANCA positivity – ANCA persistence 12 months after starting maintenance therapy

How long should we keep patients

• n maintenance therapy?

The REMAIN Trial

Randomized Controlled trial of Treatment Withdrawal in the Remission Phase of ANCA Vasculitis

Karras et al J AM Soc Nephrol 26:2015 TH-OR025

REMAIN Trial

• AAV patients
• Remission induction with CYC + prednisone
• Maintenance with azathioprine
• Randomized at month 18 (1:1)

– AZA/PRED until 48 months (C) – Discontinuation of AZA/PRED by 24 months (W)

• Primary outcome: rate of relapses during 30-

months follow-up

REMAIN Trial

22% 66% 121 patients ESRD in 5 cases in W group versus 0 in C group

Summary

• Corticosteroids + Cyclophosphamide remain

the medication of choice in life and/or organ- threatening GPA (WG)

• Rituximab has the same efficacy as

cyclophosphamide in severe disease. It may be superior in relapsing disease. It does not increase the risk of infertility or malignancy

Summary

• The role of plasma exchange in organ and/or

life threatening manifestations of GPA remains to be determined

• Maintenance of remission with rituximab may

be the best approach to reduce disease relapse

• Withdrawing IS drugs too early after remission

is associated with a higher rate of relapses

Case 2

• 25 year old man
• Presents with a 2 month history of:

– Fatigue – Progessive weight loss of 5 kg (60 kg)

• 2 week history of:

– Numbness in both feet and right hand

Case 2

• Past history

– Asthma confirmed by PFT x 3 years – No hospitalization

• Habitus

– 5 pack year of smoking – Use of cocaine 1-2/month X 2 years. None x 3 years

• Medications:

– Advair 250, I puff BID – Montelukast (Singulair) 10 mg OD x 1 year

Physical examination

• 370, 120/80, 72/min. 98% O2 sat on room air
• ENT normal
• Chest: good A/E. Mild wheezes
• Heart, abdomen, MSK: normal
• Hypoesthesia right D1-3, weakness thumb

abduction, opposition: grip R 120/20, L: 320/20. Hypoesthesia both feet. R ankle dorsiflexion and eversion 3.5/5, inversion 5/5

Laboratory

• Hemoglobin: 110
• WBC 7.2

– Neutro 2.0 – Eosinophils: 4.3

• Urine: normal
• Creatinine: 78
• CXR normal

What is your diagnosis?

What further investigation(s) would you like in this patient?

ANCA in EGPA

• The prevalence of ANCA in patients with

eosinophilic granulomatosis with polyangiitis (EGPA) (Churg and Strauss syndrome) is only 40-60%

• The sensitivity of a nerve biopsy for the

diagnosis of vasculitis is only 50%

What is the role of montelukast in triggering EGPA?

Thorax 2008;63:677-682

• Medication histories in 78 patients with CSS
• Case-crossover research design
• Exposure to montelukast and other asthma

medications during the 3 month “index” period preceding the onset of CSS compared with those of four previous 3-month “control” periods

Montelukast and the risk of CSS

Drug OR (95% CI) Montelukast 4.5 (1.5-13.9) Inhaled long-acting beta (2) agonists 3.0 (0.8-10.5) Inhaled corticosteroids 1.7 (0.5-5.4) Oral corticosteroids 4.0 (1.3-12.5) Hauser T et al. Thorax 2008;63:677-82

How would you treat this patient?

What is his Five Factor Score?

What is his five factor score?

• Cardiac involvement
• GI involvement
• CNS involvement
• Creatinine > 140 mμol/l
• Proteinuria > 1 gm/24 hours

Guillevin et al. Medicine 1996;75:17-28

Five Factor Score

Arthritis Rheum 2008;58:586-594

Results

• 72 patients
• 93% achieved remission with CS alone
• 35% relapsed
• Survival at 1 and 5 years were 100% and 97%

respectively

Case 3

• 45 year old man
• Bipolar disorder, schizophrenia, asthma
• Presents to the ER with a new rash on his

lower extremities

• Meds: Advair, risperidone, amoxicillin
• No fever, chills, sore throat
• Some nasal congestion and occasional

epistaxis.

Case 3

• Intermittent SOB and chest discomfort x 2

months.

• No cough or hemoptysis
• No abdominal pain or diarrhea
• No numbness or weakness in his extremities
• Mild recent joint pain in his knees and ankles

Examination

• Rapid Atrial fibrillation 150/min
• BP 105/70, SaO2: 97% RA
• ENT: no oral or nasal ulcer
• Lungs: normal
• Heart: normal
• Abdomen: soft, no visceromegaly
• MSK: no synovitis
• Neuro: normal

Skin examination

Investigations in the ER

• Hgb: 13.6
• WBC: 3.3
• Plt: 207
• Cr: 85
• INR 0.9
• ALT/AST: N
• Urine: normal

Course

• Admitted to hospital
• IV cardizem. Converts to NSR
• Further blood work ordered by rheumatology
• Skin biopsy
• Started on prednisone 60 mg/day for probable

vasculitis

Further investigation

• HepBsAg/HepC Ab: negative
• Cryoglobulins: negative
• ANA: positive 1:320
• Positive IgM ACL
• MPO-ANCA: 2.7
• PR3-ANCA: 4.0
• TTE: normal
• CXR: normal

What do you think?

Would it be easier if he also had these lesions?

Cocaine/levamisole –induced vasculopathy (CLIV)

Arthritis Care & Research 2011;63:1195-1202

Clinical history

• 8 patients seen in one year
• Non specific constitutional symptoms 8/8
• Weight loss 3/8
• Overt arthritis 6/8 (ankles, wrists, knees,

hands)

• Duration of cocaine sue: 2.5-32 years

Physical examination

• Extremities and/or

torso 8/8

• Mouth ulcers 5/8
• Ear lesions 3/8
• Face lesions 3/8
• Livedo reticularis 3/8
• Purpuric lesions 4/8
• Ulcers 5/8
• Bullous lesions 5/8
• Papular or puslular

lesions 4/8

• Skin necrosis 4/8
• Tender erythematous

papules on ext fingers 3/8

Examples of lesions

Papules on extensor surfaces of fingers

Skin necrosis

Laboratory abnormalities

• Elevated ESR/CRP: 8/8
• Anemia: 6/8
• Neutropenia: 4/8
• Lymphopenia: 8/8
• ANA: 6/8 (1:160-1:320)
• Anti-DNA: 5/8
• P-ANCA: 8/8
• C-ANCA: 5/8
• MPO ANCA: 7/8
• PR3-ANCA: 6/8
• aPL: 7/8

– LAD 3/8 – IgM ACL 6/8 – IgG ACL 1/8

• Cold agglutinins: 6/6

Skin biopsies

• Thrombotic microangiopathy: 3/7
• Neutrophilic dermatosis: 2/7
• Leucocytoclastic vasculitis: 1/7
• Neutrophulic dermatosis→thrombotic

microangiopathy: 1/7

The many faces of cocaine-induced vasculopathy

Outcome

• Improvement of skin lesions only in patients

who appear to have stopped cocaine use

Pathophysiology of CLIV

• Cocaine itself?

– Vasoconstrictor – Association with APL antibodies

• Levamisole is the most likely culprit…

– Known to cause lesions of the ear lobes and face – Associated with ANCA, ANA and aPL

Case 4

• 46 year old man
• Saddle nose deformity
• Perforation of hard palate
• P-ANCA positive

Does this patient has GPA?

Cocaine induced midline destructive lesions (CIMDL)

Arthritis Rheumatism 2004;50:2954-2965

• 25 patients with cocaine-induced midline

destructive lesions (CIMDL)

• P-ANCA:17/25 (76%); C-ANCA: 2/25 (8%)
• PR3-ANCA: 11/19
• MPO-ANCA: 0/19
• HNE-ANCA: 18/19
• 3/6 patients with negative ANCA had + HNE-

ANCA (human neutrophil elastase)

Case 5

• 78 year old man
• Past history of CAD, COPD and type 2 DM
• Was admitted to hospital 2 months previously

for treatment of a PE (LMWH followed by warfarin)

• Referred for assessment of fever, 10 pound

weight loss, myalgias, new rash on his lower extremities and ischemic lesions on his feet

Case 5

Case 5

Investigations

• Hgb 98
• WBC 8.5 (1.8 eosino)
• Plt 340
• Creatinine 300 μmol/L (125)
• Urine: 20-30 RBC/hpf; no RBC casts
• C3 0.84 (0.9-1.8)
• C4 0.08 (0.1-0.4)

Does he have vasculitis?

Atheroembolism (Cholesterol crystal embolism)

Atheroembolism

• Different than thromboembolism

– Results from thrombus superimposed on a complex atherosclerotic plaque (>4mm) – TIA, stroke (left carotid territory) – Acute ischemia of an extremity – Acute bowel ischemia

Atheroembolism

• Results from disruption of an atherosclerotic

plaque that results in the release of cholesterol crystals within the plaque

• Multiple occlusions by these small debris

(<200 micrometers in diameter) in multiple

• rgans

Risk factors

• Male gender
• Age (> 60)
• Smoking, hypercholesterolemia, hypertension,
• besity, diabetes→ atherosclerosis
• Spontaneous in 25% of cases
• In the remainder, precipitated by vascular

instrumentation (arteriography, surgery, trauma)

• Anticoagulant/thrombolytic therapy?

Clinical manifestations

• Skin (35%):

– Livedo reticularis (50%) – Gangrene (35%) – Cyanosis (30%) – Ulcers (20%) – “Blue toe syndrome” (15%) – Purpura or petechiae – Painful erythematous nodules

Clinical manifestations

• Renal (25-50%)

– Acute kidney injury

• GI (10%)

– Abdominal pain, diarrhea, bleeding

• CNS

– Amaurosis, TIA, stroke, confusion, headache

• Ocular

– Hollenhorst plaques

Hollenhorst plaque

Diagnosis

• Non specific laboratory abnormalities

– Anemia, leucocytosis – Elevated ESR, CRP – Transient eosinophilia – Transient hypocomplementemia

• Imaging: TEE, CTA, MRA
• Biopsy: only definitive diagnostic modality

Cholesterol clefts

Treatment

• Risk factor management

– Lipid-lowering therapy – Antithrombotic therapy? – Plaque removal?

SVV mimickers

• Atheroembolism

– Atherosclerosis

• Endovascular procedure

– Warfarin therapy?

• Thromboembolism

– Aortic atherosclerotic complex plaques

• Atrial mxyoma
• Bacterial endocarditis
• APL syndrome
• TTP
• DIC
• Malignant hypertension