MCQs on TMAs and Vasculitis

Dr Jian Cheng, MBBS, MPH, FRACP

Nephrologist

Orange Base Hospital

Parameter AdmissionHaemoglobin (g/L) 145 (162)Platelets (x109/L) 22 (302)MCV (fL) 90Blood film SchistocytesLDH (U/L) 7020Bilirubin 78Coagulation profile NormalPotassium (mmol/L) 3.3Bicarbonate (mmol/L) 26Urea (mmol/L) 34.3Creatinine (umol/L) 344 (56)

Q1. A 55yo Indigenous female

presents with agitation, dark urine,

fever, and diarrhoea. This is on the

background of a recent chest

infection, COPD and drug eluting

stents 6 months ago. Her

investigations demonstrate:

Should this person receive plasma exchange?

A. Yes. There is evidence of microangiopathic haemolysis and AKI without any other clear cause

B. Yes. She is likely to have complement mediated HUSC. No. Her haemoglobin is normalD. No. Her labs are consistent with DIC

Should this person receive plasma exchange?

A. Yes. There is evidence of microangiopathic haemolysis and AKI without any other clear causeA. Qualifies under the PLASMIC score

B. Yes. She is likely to have complement mediated HUSA. Platelets >30 and/or Cr >150 makes cHUS more likely than TTP

(https://pubmed.ncbi.nlm.nih.gov/20436664/)B. Treatment for cmHUS is eculizumab

C. No. Her haemoglobin is normalA. The presence of schistocytes, high LDH and relatively lower Hb are concerning for

haemolysisD. No. Her labs are consistent with DIC

A. Coags are normal

PLASMIC Score

Patient

Platelet count <30x109/L 1

Haemolysis (reticulocytes >2.5%, haptoglobin undetectable, bilirubin > 34.2umol/L

1

Active cancer (No=1) 1

Transplant (No=1) 1

MCV <90fL 0

INR <1.5 1

Creatinine <176.8umol/L 0

Further history and investigations:

Medications include:• Paroxetine 60mg mane• Thyroxine 50mcg mane• Clopidogrel 75mg mane• Aspirin 100mg mane• Atorvastatin 20mg/ezetimibe 10mg • Diltiazem 240mg mane• Quinine 300-600mg nocte• Varenicline 1mg mane• Furosemide 40mg mane

Parameter ResultUrineLeucocytes (x106/L)Erythrocytes (x106/L)

10-100<10

Faeces PCR NegativeADAMTS-13 activity (%) 38DAT Negative

In addition to withdrawal of drug, what is the best treatment?A. Plasma exchange aloneB. Eculizumab and plasma exchangeC. EculizumabD. Prednisolone

In addition to withdrawal of drug, what is the best treatment?A. Plasma exchange

A. 2C cat IV (Weak recommendation, ineffective/harmful) recommendation for quinine, gemcitabine

A. PLEX is relatively ineffective at removing quinine from blood. Insufficient evidence for PLEX over supportive care (https://onlinelibrary.wiley.com/doi/10.1002/jca.21470)

B. 2B cat I (Weak recommendation, 1st line therapy) for ticlopidineC. 2B cat III (Weak recommendation, unestablished treatment) for clopidogrel, CNI

B. Eculizumab and plasma exchange• Often inefficient, as PLEX removes eculizumab

C. Eculizumab• This patient has drug induced TMA (DITMA) likely secondary to quinine (clopidogrel is also a

rare cause of DITMA)• This is the growing treatment of choice for DITMA in those with persistent non immune DITMA,

or those with acute, severe immune mediated DITMA with risk of kidney failureD. Prednisolone

A. No data

Eculizumab Side Effects

Side effect % (n=78)

Leucopaenia 5

Nausea / vomiting 5

Headache 5

Cough 2.5

Hypertension 3.8

Drug induced TMA

• Immune mediated• <21/7 of exposure or intermittent exposures for years• Quinine is the most common immune mediated DITMA –

• Mechanisms of complement activation (https://pubmed.ncbi.nlm.nih.gov/28052232/ ):• Quinine antibodies binding to antigens on cells• Apoptosis from microvascular thrombosis à loss of complement regulators• Depletion of nitric oxide à increased expression of soluble P selectin • Microvascular thrombosis stimulate fibrinolysis and plasmin generation. Plasmin may act as a C5

convertase à activation of alternative complement pathway• Symptoms - Sudden, severe systemic sx incl chills, fever, abdo pain, D/N/V w/in hours of

quinine exp. Anuria is usually abrupt. Neuro symptoms range from mild confusion – coma. May also mimic sepsis.

• Non immune mediated• >21/7 of exp• Develops over weeks-months with weakness, fatigue, hypertension, renal failure

Q2. A 39yo man presents with increasing shortness of breath, lethargy over the past year. This is associated with a week of bilious vomiting and decreased urine output. This is on the background of ulcerative colitis, and ceasing alcohol (usually drinking 12-15 beers a day) a month ago. Investigations demonstrate:

Parameter AdmissionHaemoglobin (g/L) 56Platelets (x109/L) 59MCV (fL) 89Blood film Mild fragmentsReticulocytes (%) 7.1LDH (U/L) 2933Bilirubin (umol/L) 36Coagulation profile NormalPotassium (mmol/L) 4.3Bicarbonate (mmol/L) 18Urea (mmol/L) 38.6Creatinine (umol/L) 684

Should this person receive plasma exchange?

A. Yes. PLEX is the best therapy to improve renal failure in CMHUSB. Yes. This could reflect TTPC. No. There are only mild schistocytesD. No. The reticulocyte count is not high enough

PLASMIC ScorePatient

Platelet count <30x109/L 0

Haemolysis (reticulocytes >2.5%, haptoglobin undetectable, bilirubin > 34.2umol/L

1

Active cancer (No=1) 1

Transplant (No=1) 1

MCV <90fL 1

INR <1.5 1

Creatinine <176.8umol/L 0

Should this person receive plasma exchange?A. Yes. PLEX is the best therapy to improve renal failure in CMHUS• Historically PLEX was used in both TTP and CMHUS• PLEX induced remissions in 25-88% of CMHUS depending on genetic abnormality

(https://ashpublications.org/blood/article/123/16/2478/32643/How-I-treat-the-clinical-differentiation-and)• CR/PR in 2/3 of those w/ CFH mutations. Only ¼ of those with CFI respond• Cr usually remains uncorrected, though LDH improves in 80%

• Eculizumab is now the standard of careB. Yes. This could reflect TTPC. No. There are only mild schistocytes

A. Schistocytes are often absent at the beginning D. No. The reticulocyte count is not high enough

A. Normal range is between 0.5-2.5%

Further investigations return. In addition to definitive therapy, what other therapy is required?A. FFP to replace intravascular

oncotic pressure during plasma exchange

B. Meningococcal BC. Meningococcal ACWY, B

and antibiotic prophylaxis D. Prophylactic calcium to

prevent hypocalcaemia on plasma exchange

Parameter ResultUrine protein : creatinine (mg/mmol)

301

Faeces PCR NegativeADAMTS-13 activity (%) 41DAT Negative

Further investigations return. In addition to definitive therapy, what other therapy is required?A. FFP to replace intravascular oncotic pressure during plasma exchange

• FFP would be the usual substitution fluid on PLEX in TTP (to replace ADAMTS13/remove causative antibody) or risk of bleeding (eg pulmonary haemorrhage)

• Albumin or FFP are the usual substitution fluids on PLEXB. Meningococcal B vaccinationsC. Meningococcal ACWY, B vaccinations and antibiotic prophylaxis

• C5 targeted agents are associated with increased risk of encapsulated bacteria, especially Neisseria

• Ciprofloxacin for 2 weeks, +/- phenoxymethylpenicillin for duration on Eculizumab (note meningococcal can still breakthrough vaccinations)• There are penicillin resistant strains of meningococcal, and penicillin alone does not reliably eliminate

nasopharyngeal carriage

D. Prophylactic calcium to prevent hypocalcaemia on plasma exchangeA. Maybe used if citrate anticoagulation is used on PLEX

The most common gene mutation in complement mediated haemolytic uraemic syndrome is:A. CFHB. MCP (CD46) C. CFID. DGKE

The most common gene mutation in complement mediated haemolytic uraemic syndrome is:

A. CFH• The most common mutation with worst prognosis

• >100 mutations (auto dominant or recessive) are known and are usually heterozygous. Therefore may only slightly decrease CFH and C3 levels (normal in 50%)

• Usually present <20yo with severe hypertension and haemolytic anaemia• Action: Cofactor with CFI to accelerate C3 convertase decay, and competes with CFB for C3b binding

B. MCP (CD46) • Usually seen in childhood with favourable renal outcome, frequent relapses but a ow rate of

recurrence after transplant• Action: Accelerates decay of C3 and C5 convertases; and is a cofactor with CFI to degrade C3b and C4b

on cell surfaceC. CFI

• Intermediate prognosis between CFH and MCP• Action: Cofactor for CFH, MCP

D. DGKE• <1% of cases

C3 C3b C3bBb C5b-C9

CFHCFIMCPThrombomodulinCFHR

DGKECFBC3Gain of function àEnhanced stability

Loss of function àRegulatory loss

C5

Summary of Known Genetic MutationsGene Frequency in CM-HUS Recurrence (%) Recurrence post

transplant (%)

CFH 20-25 30-50 70-90

MCP (CD46) 5-23 60-90 11-20

CFI 6-17 10-30 70-80

CFB 2-4 Rare Rare

C3 6-9 50 40-50

CFHR 5-35 23-60 20

Thrombomodulin 2-5 23-30 Rare

DGKE <1% Unclear Unclear

Match pathology with description

A. TTP

B. DIC

C. Complement mediated

D. STEC HUS

1. Abnormal coagulation profile

2. Fever, anaemia thrombocytopaenia, neurological changes, renal impairment

3. Severe renal impairment with diarrhoea

4. Severe renal impairment after contaminated food

DifferentialsTMA Phenotype Coagulation Other testsCMHUS Preceding infection

Severe renal impairmentNormal Platelets >30 but <75% baseline

Genetic testing

STEC HUS Food exposure Severe N/V/DSevere renal impairment

Normal Stool

TTP Fever uncommonNeurologicLess severe kidney injury

Normal ADAMTS13 <10%Platelets <30Cr<200

DIC Sepsis, malignancyFever / chills

Abnormal Low fibrinogenHigh d dimer

Match pathology with description

A. TTP

B. DIC

C. Complement mediated

D. STEC HUS

1. Abnormal coagulation profile

2. Fever, anaemia thrombocytopaenia, neurological changes, renal impairment

3. Severe renal impairment with diarrhoea

4. Severe renal impairment after contaminated food

Vasculitis

What is the likely diagnosis?A 71yo Filipina female presents with widespread

cramps, and loss of 10Kg over 6 months. She denies any

rash or IV drug use. Pulses are equal with no carotid

bruits. UACR is 185mg/mmol, with red blood cell casts

in urine. Creatinine is 198umol/L (50umol/L 2 years

prior), PR3>221IU/mL. Renal biopsy demonstrates 50%

interstitial fibrosis and 3/10 glomerulosclerosis. What is

the likely diagnosis?

A. PANB. Takayasu’sC. LupusD. ANCA vasculitis

What is the likely diagnosis?• PAN

• Investigations:• Biopsy – Inflammation of medium sized arteries• Arteriogram – Multiple aneurysms• Urine – Can have subnephrotic proteinuria due to glomerular ischaemia, but no inflammation

• Takayasu’s• Patient >40yo, with normal pulses, no bruits

• Lupus• No mention of complement or consistent biopsy findings (eg full house staining on

immunofluorescence)• ANCA vasculitis

• Sensitivity >80%, specificity 98%in a carefully selected population – Glomerulonephritis, pulmonary haemorrhage, cutaneous vasculitis, multiple lung nodules, destruction of upper airways, sinusitis, tracheal stenosis, peripheral neuropathy, retro-orbital mass. Can also be positive in IBD, rheumatoid arthritis, infections, malignancy. Higher titres >4x ULN are associated with an increased probability of AAV https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/211811

What is the ideal treatment regime to induce remission?A. MethotrexateB. IV CYC + pulse methylpredC. Ritux + steroidD. PLEX

What is the ideal treatment regime to induce remission?

A. Methotrexate• Used if no organ damaging disease. LT outcomes (eg relapse) worse than CYC

B. IV CYC + pulse methylpred• IV – 15mg/kg q2/52 until 3-6/12• Pulse methylpred 500-1000mg/d x3 (7mg/kg/d) for severe disease (though no RCT data).

C. Ritux + steroid• Rituximab 375mg/m2 x4 as good as CYC (RAVE, RITUXVAS)

• If week 8-10, can see if ritux has worked. CYC should have worked by month 3• Superior to CYC for remission induction in PR3 (RAVE). Similar response to CYC in MPO vasculitis

D. PLEX• Potential indications: Positive antiGBM*, pulmonary haemorrhage*, Cr >500 (especially if AKI on

dialysis)• MEPEX – Increased rates of renal recovery at 3 and 12 months, but no difference in mortality, rates of ESKD or

relapses• 7 exchanges w/in 14/7

• PEXIVAS – No difference. Pts had eGFR <50 but did not need to have bx unlike MEPEX. Therefore may have included pts with high fibrosis to explain ineffectiveness. There was trend to benefit in those w/ pulmonary haemorrhage

Further bloods demonstrate the patient is positive for HB core antibody; and negative for HBV DNA, HB surface antigen. Which is the preferred prophylaxis regime?A. LamivudineB. TenofovirC. None. The patient has had previous immunisation to hepatitis BD. Entecavir

A. LamivudineA. Can be used, but causes Fanconi’s in 1%, and is less efficacious than entecavir

https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-meta-analysis-prophylactic-entecavir-or-lamivudine-S166526811931138X

B. TenofovirA. Can be used, but is associated with proximal tubular injury. Therefore avoid in those with renal

dysfunctionC. None. The patient has had previous immunisation to hepatitis B

• Serology is consistent with previous exposure to virus (HBcAb positive) but is not chronically infected (HBsAg negative)

D. Entecavir• High risk (>10% risk of reactivation) – Prophylaxis https://www.gastrojournal.org/article/S0016-

5085(14)01331-6/pdf• AntiCD20 (ie rituximab) regardless of HBsAg• HBsAg +ve on anthracyclines OR >10mg/d prednisone for ≥ 4 weeks

• Moderate risk (1-10% reactivation pa)– Prophylaxis• HBsAg +ve on cytokine / integrin / TK inhibitors / <10mg/d prednisone for ≥4 weeks • HBsAg –ve on >10mg/d prednisone for ≥4 weeks OR on anthracyclines

• Low risk (<1% reactivation pa) – No prophylaxis• Azathioprine, 6MP, methotrexate regardless of HBsAg• Any dose steroid for ≤1 week regardless of HBsAg• HBsAg –ve on <10mg/d prednisone for ≥4 weeks

She also complains of a chronic dry cough. Quantiferon Gold was positive. A CT scan was performed (right). Bronchoalveolar lavage was negative for tuberculosis. What is the appropriate regime?A. Isoniazid + pyridoxine for 6-9 monthsB. Rifampicin for 12 monthsC. Rifampicin, isoniazid, pyrazinamide,

ethambutol for 2 months, then 4 months of rifampicin and isoniazid

D. None – Granulomata can be explained by GPA, and the IGRA may be a false positive

A. Isoniazid + pyridoxine for 6-9 months• 10mg/kg up to 300mg• Watch for hepatitis and peripheral neuropathy

B. Rifampicin for 12 months• Can be used if there is toxicity or TB resistance to isoniazid. • Used in a 4 month course. Noninferior with higher treatment completion and better

safety (https://www.nejm.org/doi/full/10.1056/NEJMoa1714283) • Not licensed in Australia

C. Rifampicin, isoniazid, pyrazinamide, ethambutol 2 months, then 4 months of rifampicin and isoniazid• 98% cure rate with 5 year relapse <1%

D. None – Granulomata can be explained by GPA, and the IGRA may be a false positiveA. TST will be falsely positive (IGRA will not be affected) in those who have had the BCG

vaccine

The patient reaches remission. However she is intermittently inadherent to her medications. Preferred strategy of maintenance is:

A. RituximabB. AzathioprineC. MethotrexateD. Mycophenolate

The patient reaches remission. However she is intermittently inadherent to her medications. Preferred strategy of maintenance is:A. Rituximab

• MAINRITSAN, RITAZEREM –Rituximab is superior to Azathioprine to prevent relapses in those induced on either rituximab or cyclophosphamide Methotrexate

• Additional advantages of increased induction in PR3 disease (RAVE), and observed therapy• Disadvantage: Hepatitis B reactivation, though this occurs early in therapy

B. Azathioprine• Agent of choice in those who want to become pregnant• 4 years of maintenance is better than 2 years (MAINTAIN)

C. Methotrexate• MTX 0.3mg/kg q weekly then increased slowly to 25mg q weekly – Usu used for nonrenal

disease. Avoid in those with eGFR<60mL/min/1.73m2

D. Mycophenolate• MMF as 3rd line because less effective than Azathioprine

What is the best method of decreasing cyclophosphamide toxicity?A. Prophylactic antibioticsB. Mesna useC. Lower cumulative doseD. Allopurinol

What is the best method of decreasing cyclophosphamide toxicity?A. Prophylactic antibiotics

• Most require PCP prophylaxisB. Mesna use

• HR 1.24 for haemorrhagic cystitis for every 10g of cyclophosphamide used (1-2% treated for rheumatic diseases)

• Prevention of haemorrhagic cystitis – IV pulse cyclophosphamide, aggressive hydration, MesnaC. Lower cumulative dose

• IV pulse therapy (usually ~10g in vasculitis) generally results in less cumulative dosing than PO dosing

• If patient is on daily PO cyclophosphamide, blood count should be checked every 2 weeks• If patient is on IV pulse cyclophosphamide on a monthly basis, leukopaenia nadirs 7-14 days after administration

• Gonadal toxicity occurs >5g https://www.uptodate.com/contents/general-principles-of-the-use-of-cyclophosphamide-in-rheumatic-diseases?sectionName=Prevention%20of%20drug-induced%20cystitis&topicRef=7987&anchor=H388498&source=see_link#H1114349736

D. Allopurinol• This increases CYC toxic metabolites

Compared with PR3, MPO ANCA is related to all but the followingA. Silica exposureB. Less lung and ENT symptomsC. A poorer kidney and patient survivalD. Higher relapse rate

Compared with PR3, MPO ANCA is more associated with all but the followingA. Silica exposure

• 40% of PR3 vs 67% of MPO AAV have high silica exposure (https://cjasn.asnjournals.org/content/2/2/290)

• Silica activates T cells, and is also responsible for other autoimmune diseases eg RA, SSc, SLE

B. Less lung and ENT symptoms• Lung and ENT symptoms fit with GPA (PR3 is more common)

C. Poorer kidney survivalA. There are usually more normal glomeruli, less interstitial fibrosis and less fibrous

crescents in PR3 compared with MPO AAVD. Higher relapse rate

A. PR3 relapse more often (HR 1.6-3.2) more than MPO AAV https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587702/

A 20yo presents with fever,

arthralgia and rash. He admits to

injecting IVDU and cocaine use.

There is no stigmata of

endocarditis, and blood cultures

are negative. MPO and PR3 are

positive. What is the likely cause?

A. Adulterated cocaineB. Staphylococcus sepsisC. HydralazineD. Primary ANCA

associated vasculitis

A 20yo presents with fever, arthralgia and rash. He admits to injecting IVDU and cocaine use. There is no stigmata of endocarditis, and blood cultures are negative. MPO and PR3 are positive. What is the likely cause?

A. Adulterated cocaine• Cocaine is often cut with levamisole (an antiparasitic) for synergy

B. Staphylococcus sepsis• Staph related GN (and case reports of other bacteria) may also have dual ANCA

positivity

C. Hydralazine• Associated with positive ANA, antidsDNA and hypocomplementaemia• Occurs in 5% using 100mg/d for >3 years

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6229221/

D. Primary ANCA associated vasculitis

ANCA Antibodies and AssociationsANCA Type GPA EGPA MPA Renal

limitedPR3 (%) (Higher relapse) 75 5 25 20

MPO (%) (Worse prognosis) 20 40 65 70

Negative ie atypical antigens (%)

5 55 10 10

PR3 and MPO Cocaine/levamisole

ANCA and antiGBM 1/3 of those with antiGBM disease have a positive ANCA1/10 of those with ANCA vasculitis have a positive antiGBM

A 60yo presents 6 months of

fatigue, polyarthritis and

fever. ANCA is PR3 positive.

CT sinuses and chest do not

demonstrate any granulomas.

Eosinophil count is normal.

What is the likely diagnosis?

A. Granulomatosis with polyangiitis (Wegener’s)

B. Microscopic polyangiitisC. Eosinophilic granulomatosis with

polyangiitis (Churg Strauss)D. Renal limited vasculitis

• Granulomatosis with polyangiitis (Wegener’s)• Epi – 2.5/100 000• Lung (>90%) and ENT (>90%) involvement

• If patient has a saddle nose you can likely attribute this to GPA. Otherwise differentiation from MPA difficult

• Hallmark – Granulomas (Renal granulomas are in only 5%)• Microscopic polyangiitis

• Epi – 2.5/100 000• Diagnosis of exclusion if not GPA and EGPA

• Eosinophilic granulomatosis with polyangiitis (Churg Strauss)• Epi – 1/100 000• Hallmark - Asthma (>95%) involvement, eosinophilia >1.5

• Renal limited vasculitis• Epi – Much younger (mean age 40yo)• Fewer extrarenal sx à delay in diagnosis à advanced glom and tubulointerstitial

scarring à poorer renal survival

Summary

• Thrombotic microangiopathies• PLEX based on PLASMIC score• ADAMTS13 is key• Meningococcal prophylaxis for Eculizumab• Genetics

• ANCA vasculitis• Prophylaxis for immunosuppression• Phenotype, ANCA subtype (including dual positivity)• Induction: Rituximab / Cyclophosphamide• Maintenance: Rituximab / Azathioprine