Dr TeffyM4 unit

Prof Dr G Elangovan’s unit

Panjatcharam, 51/M, labourer, from Vyasarpadi

Admitted with , Fever - 7 days ,1 wk back Facial puffiness - 7 days Haematuria - 7 days,on& off Epistaxis - 3 days B/L leg swelling - 3 days

H/o fever for 7 days, I wk back - high grade,intermittent,not associated with chills/rigor - cough with minimal mucoid expectoration +; no hemoptysis

H/o facial puffiness - 7days, - periorbital,early morning

H/o haematuria - 7days - painless,early morning

• H/o epistaxis – 3 days - on &off,minimal bleed ,subsides spontaneously

• H/o B/L leg swelling – 3 days - minimal,progressive,

No H/o abdominal distension/breathlessness/decreased urine outputNo H/o loin pain/abdominal pain/dysuria/pyuriaNo H/o chest pain/palpitation/giddiness/syncopeNo H/o jaundice/nausea/vomiting

No h/o head ache/facial pain/rhinitisNo h/o other bleeding tendenciesNo h/o sore throat/skin lesions /jointpains/ rashes/ulcers/drug or native medicine intakeNo h/o trauma

Recently detected to be hypertensive one week backNo h/o DM/CAD/TB/CKD

Personal history: alcoholic & smoker – 30 yrsFamily history : non contributary

• ON EXAMINATION :• conscious , oriented to time,place&person• comfortable at rest• Hydration fair

• Periorbital puffiness +• B/L pitting pedal edema + (minimal)• Grade 1 clubbing +• No pallor/icterus/cyanosis/lymphadenopathy/ skin lesions• Bone & joints – normal; Eyes – normal• No paranasal sinus tenderness

Vital signs : Pulse - 82/min,regular,normal volume;all peripheral

pulses equally feltBP - 150/100 mmHg, Rt arm ,sittingRR -16/min,abdominothoracicTemp – NormalJVP – not elevated

SYSTEMIC EXAMINATION : within normal limit

Possibility of a renal disorder – ? Acute glomerulonephritis

INVESTIGATIONSCOMPLETE BLOOD COUNT

Hb 13

PCV 40

TC 9,800

DC N 60 L38 E2

Platelet count 3,00,000/mm3

ESR 30/64

MCV 86

MCH 29

RFT 16/10 22/10

RBS 104 98

UREA 50 48

CREATININE 1.7 1.6

Na 138 137

K 3.8 3.9

LFT

T Bil 1.0

SGOT 22

SGPT 19

S ALBUMIN 4.4

T CHOLESTEROL 160

URINE ROUTINE & MICROSCOPY

SPECIFIC GRAVITY 1.020

PH 5

GLUCOSE -

BILIRUBIN -

KETONE -

BLOOD 3+

PROTEIN 3+

RBC CASTS +

24 Hr URINE PROTEIN 400 MG/DAY

URINE C/S NO GROWTH

USG ABDOMEN & PELVIS: NORMAL STUDY RK- 10.3;LK – 10.9 Normal PCS,Echoes, CMD+

• ECG : NSR;WNL• ECHO:Normal

• Peripheral smear study : normal

OTHER INVESTIGATIONS :

CRP 25

ASO titre negative

Rheumatoid factor negative

ANA negative

HIV 1&2 Negative

HBs Ag Negative

Anti HCV Negative

S CALCIUM 10.2

S PHOSPOROUS 4.3

S URIC ACID 5.1

NEPHROLOGY OPINION : 16/10 – ? Acute Glomerulonephritis - to do C3,C4,C ANCA,P ANCA - continue antibiotics

C 3 121(90-180)

C4 23.45(10-40)

C ANCA POSITIVE ( IFA)

P ANCA Negative

ANCA vasculitis with epistaxis ? Wegener’s Granulomatosis -PLAN : CT chest CT PNS ENT opinion

CHEST X RAY PA VIEW : WNL

CT CHEST : WNL

CT PNS : B/L PANSINUSITIS –mucosal thickening +;no bony

erosions/expansion/fluid level

Chest X ray

CT Chest

X ray PNS

ENT opinion(23/10) : L/E : Ear,nose,throat -normal DNE with biopsy

NEPHROLOGY REVIEW : 24/10 – C/O ANCA Vasculitis; Epistaxis B/L Pansinusitis - ? Wegener’s Granulomatosis PLAN : Renal biopsy : To start IV methyl prednisolone followed by

oral prednisolone

Renal biopsy

Focal segmental glomerulonephritis ;focal necrosis +No immune deposition

Sinus mucosal biopsy- results pending

FINAL DIAGNOSIS ANCA vasculitis -renal & upper respiratory tract involvement ;

D/D1.Wegeners granulomatosis2.Microscopic polyangiitis3.Idiopathic necrotising glomerulonephritis4.CHURG strauss syndrome

possibly Wegener’s granulomatosis

TREATMENT givenINJ Cefotaxime 1g IV BDINJ Ranitidine 50 mg IV BDINJ Frusemide 20 mg IV BD , 2 daysINJ Methyl prednisolone 1 g in 100 ml NS IV infusion

over 1 hr , 3 days followed byTab Prednisolone 60 mg/day ( 1 mg/kg bw)

ANCA1982 –Davies & colleagues first described ANCA ;

Two types – c ANCA & p ANCA (IFA);

Antigens associated are -- proteinase 3-PR3 – c ANCA --myeloperoxidase –MPO-p ANCA• ANCA positivity by IFA should be confirmed by antigen specific testing for both PR3 & MPO

DISEASE ASSOCIATIONS Vasculitis :- : small vessel vasculitis – WG,MPA,CSS : idiopathic necrotising crescentic glomerulonephritis

Sensitivity of ANCA -50 to 90 % -Negative test does not rule out diagnosis in patients with high pretest probability

Specificity of ANCA ; : If IFA results are combined with antigen specific assays,the

specificity of both PR3-ANCA & MPO-ANCA is exceedingly high. • Influences disease phenotype -- PR3 – WG; MPO - MPA -- PR3 positive patients -> more relapse ->more granuloma -> more extrarenal

others..Rheumatoid arthritis ,SLE, myositis

Cystic fibrosis , endocarditis ,& HIV

Inflammatory bowel disease :UC > crohn’s Sclerosing cholangitis ,autoimmune heaptitis Drugs : Hydralazine ,propylthiouracil high MPO- D penicillamine ,minocycline ANCA

Wegener’s granulomatosis• First described in 1931 by Heinz Klinger ;

• Classic triad-Granulomatous necrotising vasculitis affecting the upper & lower respiratory tract and the kidneys; • Prevalence – 3/1,00,000 persons

• Affects both sexes equally ;

• Affects all ages –( mean age 41 yrs );

• More common in Caucasians

Pathogenesis Exact cause unknown;

HLA-DR1 & HLA-DQw7 association has been reported ;

PR3-ANCA antibodies are highly specific for Wegener’s (90-97%);

ANCA s cause neutrophil degranulation & also cause endothelial damage ;

Evidence of T cell involvement is less direct ;

Clinical featuresPredilection for upper,lower respiratory tract & the

kidneys ;

Mild forms of wegener’s without renal involvement have been described ;

Indolent or rapidly progressive course ;

Unexplained constitutional symptoms like fever and weight loss in one fourth of the patients

Upper airway featuresMost common presenting feature In 70 % of the patients at onset ,ultimately developing in

>90%Sinusitis(MC) initial presentation in 50 -67%;in85 %

during the course of the diseaseSecondary infection-S. aureus is predominant organism;Epistaxis -11-32%Biopsy - granulomatous inflammation with necrosis ;

vasculitis+/- - complete diagnostic triad in 3 – 16%

Renal manifestationsPresence or absence of renal disease defines generalised or

limited wegener’s ;

Early disease mey be clinically silentExtrarenal manifestations may precede renal disease11-18% at presentation & 80% over the course

mild focal & segmental glomerulonephritis with minimal haematuria & little dimunition of GFR tofulminant,diffuse,necrotizing &crescentic glomerulonephritis(RPGN) leading within days to wks to oligoanuria &dialysis

If untreated mean survival is 5 months ;Chronic renal failure in 42% despite treatment ;Urine microscopy most useful tool ;Presence of RBC casts 100% positive predictive value

for glomerulonephritis ;Fulminant WG - can manifest as pulmonary renal

syndrome ( alveolar haemorrhage & RPGN)

Accounts directly or indirectly for most of the mortality in this disease

PATHOLOGY:Focal ,segmental glomerulonephritisFibrinoid necrosis & proliferative changesEpiithelial crescentsSclerotic lesions

Vasculitis – focal in 5-10%

Granulomatous changes –only in 3-20%

Immune complex deposition unusual (pauci immune)

The degree of renal failure & serum creatinine do not always correlate with pathological features

picture

Frequency of Clinical features In 158 pts ; Studied at NIH

MANIFESTATION AT DISEASE ONSET DURING THE COURSE

KIDNEY

Glomerulonephritis 18 77

EAR/NOSE/THROAT 73 92

Sinusitis 51 85

Nasal disease 36 68

Otitis media 25 44

Hearing loss 14 42

Subglottic stenosis 1 16

Ear pain 9 14

Oral lesions 3 10

LUNG 45 85

Pulmonary infiltrates 25 66

Pulmonary nodules 24 58

Hemoptysis 12 30

Pleuritis 10 28

EYES

Conjunctivitis 5 18

Scleritis 6 16

Proptosis 2 15

Visual loss 8

Corneal/retinal lesions,iritis

OTHERS

Arthralgias/arthritis 32 67

fever 23 50

cough 19 46

Skin abnormalities 13 46

Wt loss 15 35

Peripheral neuropathy 1 15

CNS disease 8

Pericarditis 2 6

Venous thromboembolism,Accelarated atherosclerosis

ACR criteria(1990) : WG : atleast 2/4 criteria1. Nasal/oral inflammation2. Abnormal chest radiograph3. Microhaematuria4. Biopsy

Lab diagnosisGeneral :

- leucocytosis ,normochromic normocytic anemia , thrombocytosis

- raised ESR &CRP;

• Pathology : necrosis ; granulomatous changes ; vasculitis

: open lung biopsies – 90 %

ANCA & WG :1985 – Vander woude & colleagues – first to suggest

an association between ANCA & wegener’s

Most likely to be positive in pts with triad disease that is active & untreated

- PR3 ANCA -sensitivity –active disease – 90% remission -40% -specificity - > 95%High titre ANCA + PR3/MPO specific assay with high pretest probability is sufficient to diagnose

even in the absence of tissue confirmation

Regarding monitoring disease activity,

A substantial no of pts with rise in ANCA titre did not flare;hence rise in ANCA titre should not be the sole basis for therapeutic decision making

It was rare to see a flare in the absence of increased ANCA-strong negative predictive value

TREATMENTCYCLOPHOSPHAMIDE + GLUCOCORTICOIDS :

complete remission in 75 % of patientsCyclophosphamide – oral ; 2mg/kg/d - monitor leucocyte count (>3,000)/µl - S/e – haemorrhagic cystitis(30%);bladder

cancer(6%);myelodysplasia(2%); infertility-comtinued for 1 yr after the induction of complete

remission ,taper &discontinue

Glucocorticoids : -Oral;prednisone 1 mg/kg/d initially(1mth);then

alternate day schedule ;taper&discontinue - S/E –

diabetes,cataract,infections,osteoporosis;cushingoid features

- IV pulse methyl prednisolone (1g/d for 3 days ) especially for severe cases

• 50% of remissions are later associated with one or more relapses

Maintenance

Methotrexate – start at 0.3mg/kg single weekly dose - till 2 yrs past remissionAzathioprine- 2mg/kg/dayMycophenolate mofetil – 1000mg twice a day

OTHERS:Methotrexate induction for non severe disease RituximabTMP-SMX(upper airway disease)Organ specific treatment - isolated sinus or joint or skin disease - subglottic stenosis & endobronchial stenosis

Case reports :1. Unusual renal manifestation of Wegener’s -60 yr old female presented

with glomerulonephritis & ,mononeuritis multiplex 2 yrs before development of classic necrotizing granulomatous inflammation of sinuses & nose along with pulmonary nodules

The American Journal of medicine vol64,issue5,may 1978

2. Upper respiratory tract (maxillary & ethmoidal sinusitis) , renal involvement(pauci immune crescentic glomerulonephritis),vasculitis in a 15 yr old girl;c ANCA positive; responded well to steroids & cyclophosphamide

Journal of clinical medicine research vol 2,no 4,august 2010

REFERENCES1. Kellys textbook of Rheumatology2.Oxford textbook of Rheumatology3.Harrison’s Internal Medicine

THANK YOU for your patient listening

-------------------------