This presentation is about pulmonary manifestations of systemic vasculitis,in it m discussing about WEGNER,S GRANULOMATOSIS, churg-strauss syndrome and MPA

1. PULMONARY
VASCULITIS
By Dr. RATAN LAL MEENA
Moderator Dr. MOHAMMED JAVED QURESHI

2. Introduction
• Pulmonary vasculitis is usually manifestation of a systemic
disorder leads to inflammations of different sizes vessels by
variety of immunological mechanism.
• Primary vasculitis are a heterogeneous group of syndromes
of unknown etiology, which share a clinical response to
immunosuppressive therapy.
• Secondary vasculitis may represent significant management
problems in the context of a well-defined underlying disorder
like SLE ,RA etc.

3. When to think about vasculitis?
 Feature alone or in combination to other are suggesting vasculitis
• Constitutional illness (fever, fatigue, weight loss, myalgias , arthralgia)
• Ulcerative upper airways lesions
• Cavitary or nodular lesion
• Microscopic heamaturia
• Diffuse alveolar hemorrhage
• Palpable purpura
• Mononeuritis multiplex
• Peripheral eosinophilia

5. Classification (CHCC Nomenculature 2012)
Primary vasculitis
Small vessels vasculitis
• ANCA(antineutrophilic cytoplasmic autoantibody) associated
Granulomatosis with polyangitis (GPA)
Microscopic polyangitis (MPA)
Eosinophilic granulomatosis with polyangitis (EGPA)
• Immune complex mediated
Anti-GBM Disease
IgA vasculitis
Cryglobulinemic vasculitis
Hypocomplementemic urticarial vasculitis

6. Classification (CHCC Nomenculature 2012)
 Medium vessels vasculitis
Polyarteritis nodosa
Kawasaki disease
 Large vessels vasculitis
Giant cell arteritis
Takayasu arteritis
 Variable vessel vasculitis
Behcet disease
Secondary vasculitis
Systemic lupus erythematus
Rheumatoid artheritis
Scleroderma
Antiphospolipid antibody syndrome
Inflamatory bowel disease
Drug induced vasculitis

7. Etiopathogenesis
 Environmental association
• Infectious agents:
Staph. Aureus
E- coli., Klebsiella
• Silica
• Drugs
PTU, Allopurinol, Hydralazine,
Minocycline, Levamisole
 Genotypic associations
• HLA-DP
• SERPIN A1 Gene-code for α1-
antitrypsin
• PRT3 Gene- code for PR3
• HLA-DQ

8. Etiopathogenesis
 Immune complex mediated
• HSP
• SLE &other collagen vascular disease
• Polyarteritis nodosa
• Essential mixed cryoglobulinaemia
 T-lymphocyte mediated –with Granuloma formation
• Giant cell arteritis
• Takayasu arteritis
• GPA
• EGPA
 ANCA mediated
• GPA
• MPA
• EGPA

9. ANCA
ASSOCIATED VASCULITIS

10. ANCA associated vasculitis
• ANCA associated vasculitis are characterised by more
frequent lung invovement.
• ANCAs are antibodies directed against the intracellular
antigens (protienase-3,myloperoxidase)of neutrophils and
monocytes.
• Depends upon immunofluorescence pattern on ethanol fixed
neutrophils that react with neutrophil granules
• c-ANCA ( cytoplasmic pattern)
• P-ANCA (perinuclear pattern)

11. P-ANCA
• Antibodies to strong cations
• Target antigen is
myeloperoxidase(MPO)
• Positive in >50% patients
with MPA &EGPA
• Also positive in <10 %
patients GPA
C-ANCA
• Antibodies to neutral
proteins or weak cations
• Target antigen is
protienase-3(PR3)
• Positive in > 80% patients
with GPA
• Rarely positive in MPA &
EGPA

12. Pathophysiology
Predisposing factor (microbs,genetics,environment,drugs)
Productions of pro-inflammatory cytokins
Priming of neutrophil (exposure of cytoplasmic proteins to cell surface of PMN)
Interctions with ANCA
Activation of primed neutrophil
Activated primed neutrophil attached to and transmigration
through endothelium and accumulate within vessels wall
These neutrophil degranulates and produce reactive oxygen radical
Results in inflammation and apoptosis endothelial cells and tissue
injury (fibrinoid necrosis)

13. Pathophysiology

14. Granulomatosis with polyangitis
• Also known as wegener’s granulomatosis
• The Chapel Hill Consensus Conference defined GPA as
“necrotizing granulomatous inflammation usually involving
the respiratory tract, and necrotizing vasculitis affecting
predominantly small- to medium-sized vessels
• It is characterized clinically by triad;
o Upper airway disease(nasal,oral,sinus inflammation)
o Lower respiratory tract disease
o Kidneys(glumerulonephritis)

15. Granulomatosis with polyangitis
 Limited GPA (non severe)
• Pathology is predominantly a necrotizing granulomatous
inflammation, and the vasculitis seen on biopsy is of lesser
clinical significance
• No immediate threat either to the patient’s life or that the
affected organ is at risk for irreversible damage.
 Severe GPA
• Threatens to the patient’s life
• Vital organ with the risk of irreversible damage

16. Clinical feature
NOSE
• Nasal
congestion
• Epistaxis
• Nasal septum
perforation
• Saddle nose
ORAL
• Gingival
hyperplasia
• Oro-
pharyngeal
ulceration
Upper airways involvement
(in 90-95% patients)
• Chronic
serous ottitis
THROAT
• Subglottic
stenosis
• approx 20%
of patient
EAR

17. Clinical feature
Upper airways involvement

18. Clinical feature
 Parenchymal involvement (in 54-85% patients)
• Cough
• Dyspnea
• Chest pain
 Diffuse alveolar heamorrhage(in 5-15% patients)
• Progressive dyspnea
• Hemoptysis
• Anaemia
 Hemoptysis may be absent in about 1/3 patients
 With DAH patient deteriorate rapidly and experience respiratory failure
which has mortality rate up to 50%
lower respiratory tract

19.  Glomerulonephritis (in 51-80% patients)
• Is most concerning disease manifestation of GPA as it can progress to
complete renal failure in the absence of symptoms
• Usually detected by abnormal lab. Results such as
o Microscopic heamaturia (>5 RBC/HPF)
o Red cell cast
o Protienuria
o Declining renal functions
Clinical feature
Renal invovement

20. Clinical feature
EYE
• In 35-52%
patients
• Conjunctivitis
• Scleritis
• Keratitis
• Uveitis
• Retroorbital
pseudotumor
CNS
• In 20-50%
patients
• Mononeuritis
multiplex
• Pachy-
meningitis
Other system involvement
• In 8-16%
patients
• Pericarditis
• Valvulitis
• Regional wall
motion
abnormality
frequent Echo
finding
SKINCARDIAC
• In 33-46%
patients
• Palpable
purpura

21. Criteria of the American College of Rheumatology
(ACR1990)
(presence of at least 2 out of the 4 of following)
Criterior
• Nasal or oral inflamation
• Abnormal chest radiograph
• Urinary sediment
• Granulomatous inflammation
on biopsy
Definition
• Development of oral ulcer or
nasal discharge
• Nodules fixed infiltrates or
cavities
• Microhematuria(> 5 RBCs/HPF
or red cell cast)
• Granulomatous inflammation
within the wall of artery or in
the perivascular or
extravascular area

22. Radiology
 Pulmonary
• Nodule /mass
Cavitating /non-cavitating, single /multiple
• Alveolar opacities
Ground glass opacities
Consolidation
• Airways
Subglotic stenosis
• Pleural effusion
• Mediastinal lymphadenopathy
 Extrapulmonary
• Paranasal sinuses
• Ophthalmic

25. Granulomatosis with polyangitis
 Pulmonary capillaritis
• Usually causes fibrinoid necrosis of alveolar and vessels wall
• Leukocytoclasis; presence of pyknotic cells and nuclear fragments from
neutrophils undergoing apoptosis
 Lung nodule
• Small necrotising microabcesses appears to be earliest lesion.
• Typical geographical and basophilic appearance of necrosis after enlarge
and coalsce to each other.
• Necrotic centre is surrounded by palisading histiocytes and scattred giant
cell
• Mixed cellular infiltrates containing lymphocytes, plasma cell ,eosinophil
Histopathology

26. Granulomatosis with polyangitis
 Gross pathology
• Lung specimen showing
cavitating grey white lesion
Histopathology
 Alveolar capillaritis
• showing alveolar hemorrhage
 Lung nodule
• Showing geographical basophilic
necrosis with palisading histiocytes

27. Granulomatosis with polyangitis
Histopathology

28. Granulomatosis with polyangitis
• C-ANCA pattern on indirect
immunofluorescence
• Staining in the cytoplasm
while the multi-lobulated
nuclei (clear zone ) are
nonreactive
• Positive in >80% of patients
• P-ANCA pattern on indirect
immunofluorescence
• Perinuclear staining of the
multi-lobulated nucleus
with poorly defined cell
border
• Positive in <10% of patients
ANCA testing

29. Microscopic polyangitis
• It is non-granulomatus necrotising small vessels ANCA
associated vasculitis
• More common in male,average age 50 years
• Incidence ; 10 to 12 per million
• Most patients (40% to 80%)have P-ANCA variety, reacting with
MPO.
• C-ANCA reacting with PR3 is seen less frequently
• Several cases of MPA in association with severe obstructive
airway disease or bronchiectasis have also been described.

30. Microscopic polyangitis
RENAL
• M/C up to
80%
involvement
• Glomerulone
phritis
Hematuria
Red cast
proteinuria
Muskulo- skeletal
• 30 to 60%
involvement
• Myalgias
• arthralgias
Clinical feature
• Parenchymal
disease
(in 20% patients)
Cough
Chest pain
Dyspnea
• Alveolar –
hemorrhage
(in 10-50% patients)
hemoptysis
anaemia
SKIN
• Up to 62%
invovement
• Palpable
purpura
PULMONARY

31. Microscopic polyangitis
• Constitutional symptoms such as fever, malaise, and weight
loss.
• Gastrointestinal involvement occurs in about one-third of
patients
• MPA and GPA seem to be a part of a clinical
spectrum,however
 Absence of granuloma formation
 Sparing of the upper repiratory tract are feature of MPA
• In contrast to EGPA there is no H/O ASTHMA and no
eosinophilia
Clinical feature

32. Eosinophilic granulomatosis with polyangitis
• Also known as CHURG-STRAUSS SYNDROME
• Annual incidence; 1-3/million
• Male>female
• It is ANCA associated small vessels vasculitis Where pANCA
are predominant type and cANCA positivity is rarely seen
• Other association are in patient using leukotriene receptor
antagonists due to unmasking of vasculitic symptoms in
asthma, by allowing dose reductions or discontinuation of oral
glucocorticoid therapy
• Late age of onset(mean age of 32) asthma allow us to distin-
guish EGPA asthma from typical asthma in general population.

33. Eosinophilic granulomatosis with polyangitis
1. Churg and strauss(1951)
• H/O asthma
• Tissue eosinophilia
• Extravascular granuloma formation
• Systemic vasculitis
• Fibrinoid necrosis of connective tissue
2. Lanhaman & colleagues(1984)
• Asthma
• Peripheral blood eosinophilia(1.5x 109)
• Systemic vasculitis involving 2 or more extrapulmonary
organ
Clinical criteria

34. Eosinophilic granulomatosis with polyangitis
3. American college of rheumatology criteria (1990)
(4 out of 6 in following below)
• Asthma
• Eosinophilia(>10%)
• Neuropathy
• Transient pulmonary infiltrates
• Paranasal sinus abnormality
• Extravascular eosinophil infiltration
4. Chapel Hill Consensus updated (2012)definition
“eosinophil-rich and necrotizing granulomatous inflammation often
involving the respiratory, and necrotizing vasculitis predominantly
affecting small- to medium-sized vessels, and associated with
asthma and eosinophilia.”
Clinical criteria

35. Eosinophilic granulomatosis with polyangitis
Prodromal
Late -onset allergic
disease
• Evidence of
asthma
Cough
, Wheeze
Dyspnea
• Allergic rhinitis
• Nasal polyposis
Vasculitic
• Vasculitis of small
or medium size
vessels
• Vascular or
extravascular
granuloma
• Constitutional
symptoms
Clinical phases
• Marked peripheral
eosinophilia
• Eosinophilic tissue
infiltration of LUNG
,GI tracts or SKIN
Eosinophilic

36. Eosinophilic granulomatosis with polyangitis
 Pulmonary
• Parenchymal involvement occurs in 30 -40% of patients
• Alveolar hemorrhage is exceedingly rare
 Renal involvement less prominent (<25%) than GPA& MPA
 Peripheral nerve invovement(70-80%)
• In form of mononeuritis multiplex result from capillaritis and direct
toxicity from eosinophil granules
 Skin, heart and abdominal viscera may also be involved
 Prognosis of EGPA is better than that of GPA and MPA, as the overall
mortality is lower ,Most deaths are secondary to cardiac involvement.

37. Eosinophilic granulomatosis with polyangitis
Skin rashes Subcutaneus nodule

38. Radiology
• Transient alveolar type of
infiltrates are most common
• Predominantly peripheral
distribution
• Nodular lesions occasionaly
• Sinusitis

39. Eosinophilic granulomatosis with polyangitis
• Necrotising vasculitis
• Eosinophilic tissue infiltration
• Extravascular granuloma
Histology

40. System GPA MPA EGPA
Pulmonary •70–95%;
•Tracheobronchial
10–50%
•fixed nodules,
cavitation
•10–30%,
•most of the pts
will have alveolar
hemorrhage
•Asthma is universal;
Renal RPGN in 50–80% of
patients
RPGN -universal RPGN in 10–25%
Upper Airway 90–95% of pts;
Ulcerating and
destructive lesions
Almost none Sinusitis - 20–70% of
pts but lacks
destructive nature

41. System GPA MPA EGPA
Constitutional Common Very common and
often precedes
RPGN
Common
Ocular Common,35–52% <5% Uncommon
Cardiac 5–16%. 10–15% 30–50% and a
major cause
of mortality
Gastrointestinal Uncommon Common,up to 35% 30-60%
Neurologic 20 – 30% Mononeuritis
multiplex 40–60%
Mononeuritis
multiplex > 70%

42. System GPA MPA EGPA
Chest
Imaging
Abnormal-80%.
alveolar, interstitial
or mixed infiltrates,
or nodular / cavitary
lesions
Pulmonary infiltrates
occur in 10–30%
Transient infiltrates
- 40-75%
Peripheral
distribution
ANCA c-ANCA positive in 90%
and
p-ANCA in 10%
positive-50–75%
p-ANCA
positive in 45–70%
most of these being
p-ANCA
Biopsy Necrotizing palisading
(coagulative)
granulomas dominates
necrotising vasculitis
with No granuloma
formation
biopsy containing a
blood vessel with
extravascular
eosinophils.

43. Treatment
• Principle of therapy
1. Remission induction
2. Remmision maintenance
3. Monitoring
• Disease activity assesment
• Drug toxicity/adverse events
• Superimposed infection
• Disease recurrence after achieving drug free remmision
• Disease complication(e.g. tracheal stenosis)

44. Remmision induction therapy
Localised GPA
• Trimethoprim/sulfamethoxazole (T/S) 160/800 mg BD
• It related to antimicrobial effects on S. aureus, the organism most
frequently cultured from the nostrils of patients with GPA
• continued long-term observation required, as some will later
develop more severe disease manifestations
Limited GPA or MPA
• oral prednisolone at doses of 0.5 to 1 mg/kg per day
• in combination with methotraxate with a target dose of 20 to 25
mg once a week.
• To minimize toxicity and the risk of Pneumocystis pneumonia
folic acid, 1 mg/d and standard PCP prophylaxis should be added.

45. Severe GPA or MPA
• Oral prednisone in combination with oral cyclophosphamide at a
dose of 2 mg/kg /day for 3 to 6 months
OR
• IV pulse therapy with cyclophosphamide three pulses of 15 mg/kg
given 2 weeks apart
• followed by 15 mg/kg pulses given every 3 weeks for 6 months .
OR
• Rituximab (375 mg/m2 of body surface ) once weekly 4 doses.

46. Rapidly progressive fulminant disease,
• Such as those presenting with alveolar hemorrhage or rapidly
deteriorating renal function,
• IV methylprednisolone, 1000 mg per day for 3 to 5 days
• If this therapy does not generate the desired effects,
plasma exchange should be implemented
Severe disease relapse,
• Rituximab was found to be superior to cyclophosphamide
Refractory GPA
• 10% of patients do not respond adequately to therapy with
cyclophosphamide and fail to achieve remission
• rituximab has now become standard of care for refractory
GPA.

47. Remmision maitenance therapy
• For at least 12 months beyond achievement of remission,
and longer in patients who have suffered relapses
• limited or “nonsevere” disease should be maintained on
methotrexate
• Patients treated with cyclophosphamide for remission
induction should be switched to either methotrexate or
azathioprine(1-2mg/kg/day)
• Azathioprine is preferred in patients with any degree of renal
insufficiency

48. Treatment of EGPA
•EGPA usually responds to prednisolone alone.
•Induction of remission with oral prednisolone (40-60 mg/day).
•After the first month prednisone is gradually tapered down.
•Other immunosuppressive drugs in steroid resistant cases ,
• azathioprine,
• methotrexate, or
•cyclophosphamide.
•High doses of i.v. methylprednisolone with severe or refractory
•The course of therapy can last for 1 to 2 years
•steroid therapy has increased the 5-yr survival more than 50%.

49. EUVAS Grading of ANCA associated vasculitis
(Disease Severity and first line management)
Class - Consti.Symp.- Renal Fns - Vital Organ DysFn- Therapy
Limited No Creat≤1.4 mg/dl No Steroids/ MTX/AZT
Early gen. Yes Creat≤1.4 mg/dl No Steroids+Cyclo/MTX
Active gen. Yes Creat ≤ 5.7 mg/dl Yes Cyclo + steroids
Severe Yes Creat≥5.7 mg/dl Yes Cyclo+steroids+
Plasmapheresis
Refractory Yes Any Yes Newer agents

50. Supportive Therapy
• Pneumocystis pneumonia still carries a mortality of up to 35%.
So, T/S (180/600) is recommended for all non sulpha allergic
patients
• To minimize toxicity of immunosuppressive regimen it should
be supplemented by folic acid, 1 mg/d
• Patients undergoing intense immunosuppression during the
remission induction phase so prophylactic antifungal therapy.
• Patient treated with glucocorticoids for AAV should receive
osteoporosis prophylaxis with calcium and vitamin-D
supplementation.

51. OTHER
VASCULITIS

52. Giant cell arteritis
• A generalized inflammatory disorder involve large and medium
sized arteries.
• M/C in white population, elderly patients
• Annual incidence ; 13 per million
• Respiratory symptoms have been reported up to 25% of patients
Cough
Horseness
Throat pain
• Symptoms are usually resolve with prednislone therapy

53. Takayasu arteritis
• A large vessels vasculitis predominantly affecting aorta and
branches.
• Annual incidence ;1-2 per million , young patients
• Pulmonary complication in half of patients result from unique
arteriopathy
• Progressive defects in the outer media of the arteries and ingrowth
of granulation tissue–like capillaries associated with thickened
intima and sub-endothelial smooth muscle proliferation
• Which lead to pulmonary artery stenosis and occlusion as well as
pulmonary hypertension in up to one-half of all patients.

54. Behcet disease
• It is immune complex mediated chronically relapsing systemic
inflammatory disorder.
• Characterised by aphthous oral ulcers
(>2 time/year)
• and at least two or more of the following;
aphthous genital ulcers, uveitis,
cutaneous nodules, meningoencephalitis.
• Respiratory manifestation;
Cough, hemoptysis ,chest pain ,dyspnea
• Pulmonary artery aneurysm; on CT or MR angiography
Due to massive hemoptysis there is destruction of elastic lamina of
pulmonary artery

55. AntiGBM disease
• Also known as “Good pasture syndrome”
• Caused by autoantibodies directed against the NC1-domain of the α3
chain of basement membrane collagen type IV.
• This epitope is only accessible for autoantibodies in the basement
membranes of kidneys and lungs.
• Diffuse alveolar hemorrhage is common in Inhalational
injury(smoking,hydrocarbon exposure)
• A definitive diagnosis depends on the documentation of linear anti-GBM
deposits in the kidney or lung
• Early implementation of immunosuppressive therapy in conjunction with
plasma exchange is the key to a favorable outcome.

56. AntiGBM disease
1.Diffuse alveolar hemorrhage 2. Glomerulonephritis

57. Antiphospholipid syndrome
• Defined by arterial and venous thromboses, or recurrent miscarriages
occurring in patients with antiphospholipid antibodies (anticardiolipin
antibodies, lupus anticoagulant, or both)
• Capillaritis of APS appears to be immune complex mediated
• Tissue necrosis from microthrombosis as well as pulmonary capillaritis has
been implicated as the cause of alveolar hemorrhage

58. Drug induced vasculitis
 Small- to medium-sized vessels are usually affected
 Propyl-thiouracil, D-penicillamine, hydralazine, sulfasalazine,
minocycline, allopurinol, and others can induce ANCA-associated
vasculitis
 All-trans-retinoic acid (ATR) used in acute promyelocytic leukemia
can cause a fever, leukocytosis, fluid retention, hemorrhage,
thrombosis, and organ failure
 Chronic nasal cocaine abusers develop severe midline destructive
lesions.
• In early stage, such a lesion is clinically and histopathologically
difficult to differentiate from limited Wegener granulomatosis.
• The presence of ANCA reacting with human neutrophil elastase
(HNE) appears to be an immunological marker separating patients
with cocaine-induced midline destructive lesions from those with
Wegener granulomatosis.
• The clinical picture of patients exposed to levamisole can mimic systemic
vasculitis

59. Systemic lupus erythematous
• The development of pulmonary capillaritis in SLE is thought to be immune
complex mediated
• The onset of diffuse alveolar hemorrhage in patients with SLE is usually
abrupt, and it is seldom the first sign of SLE majority of Patients
• The rapid development of pulmonary infiltrates is associated with fever
• Hemoptysis may be absent in up to one-half of the patients
• Lung biopsy of a patient with lupus erythematosus and alveolar hemorrhage
showing so-called lumpy, bumpy deposition of immune complexes as
demonstrated by direct immunofluorescence
• Treatment consists of glucocorticoids and cyclophosphamide.
• The use of plasma exchange has been suggested,but its benefit
remains unproved.