1.
WEGENERS GRANULOMATOSIS: a.
necrotizing, granulomatous vasculitis that classically involves the upper and lower respiratory tract and the kidney b.
Pathology : 3 types of vasculitis i.
Infiltration and destruction of capillaries, venules and arterioles by neutrophils  microvasculitis or capillaritis

leads to diffuse alveolar hemorrhage, palpable purpura, and necrotizing glomerulonephritis ii.
granulomatous vasculitis that involves small or medium sized arteries and veins  seen in granulomatous inflammation of lung parenchyma with multinucleate giant cells in vessel wall iii.
necrotizing vasculitis involving small to medium sized arteries or veins without giant cells or granulomatous inflammation  can occur in any organ system iv.
any form of vasculitis can lead to thrombosis and occlusion of blood vessel  necrosis v.
can be mimicked by mycobacterial or fungal infections c.
Clinical : any organ system can be affected by vasculitis or granulomatous inflammation i.
Organ system:
1.
upper resp tract
2.
lower resp tract
92%
85%
3.
kidney
4.
musculoskeletal
5.
eye/orbit
77%
67%
52%
6.
skin 46%
7.
PNS (mononeuritis) 15%
8.
CNS 8% ii.
nasal involvement : inflammatory rhinitis, mucosal ulceration, recurrent epistaxis, destruction nasal cartilage, perforation of nasal septum, saddle nose, 90% sinusitis

nasal and sinus biopsies are frequently nondiagnostic iii.
trachea : gran. inflammation of mostly subglottic region in 20%
 tracheal stenosis iv.
pulmonary : >80%, cough, dyspnea, chest pain, and hemoptysis v.
CXR : single or multiple (more common) nodular infiltrates that tend to cavitate , often associated with fever and systemic signs of infection vi.
Glomerulonephritis : 20% at onset and 75% at some point in illness , focal segmental necrotizing GN with crescent formation and paucity of immune complex d.
ANCA : deposition, rapidly progressive and can lead to irreversible renal failure if untreated i.
serum autoantibodies that react with certain neutrophil cytoplasmic proteins ii.
target antigen responsible for c-ANCA is serine proteinase = proteinase-3 iii.
c-ANCA are dominant in WG

is positive in >90% of pts with active granulomatous inflammatory disease of resp tract and active GN iv.
in absence of renal disease (“limited WG”) 
c-ANCA sensitivity = 65-70% v.
high specificity, especially in setting of active GN vi.
false positives seen in infectious and neoplastic disorders

does not obviate tissue diagnosis vii.
play a role in pathogenesis?

1.
YES : proteinase-3 exists in azurophilic cytoplasmic granules and when neutrophils are activated by TNF
 
proteinase-3 containing granules move to cell membrane where they can interact with extracellular ANCA

activation and degranulation
2.
NO : significant number of pts have localized gran vasculitis of resp tract in absence of c-ANCA, height of titer does not correlate with disease activity, many in remission continue to have high titers e.
Treatment and Prognosis : i.
if untreated

WG runs a rapidly fatal course with mean survival = 5 mths and
90% die within 2 yrs of diagnosis ii.
Steroids : may decrease inflammation and temporarily improve systems

BUT will NOT control disease iii.
Fauci and Wolff 1970’s developed combined steroids and low dose daily cyclophosphamide

>90% with marked improvement, 75% with complete remission , BUT relapse is common and requiring prolonged courses with serious side effects iv.
Monthly high dose IV cyclophosphamide appears to be less effective and is not recommended v.
Azathioprine is less effective in inducing remission, but may play a role in maintaining remission if cannot tolerate cyclophosphamide vi.
Cyclosporine show some benefit, but frequent relapses, especially when <5mg/kg used and also nephrotoxic effects make it difficult to use in GN vii.
TMP/SMX : only anecdotal and uncontrolled trials viii.
MTX/Prednisone : complete remission in 71% with 23% relapse in 1 yr and 40% in 2 yrs ix.
Special situations :
1.
isolated sinus: topical steroids, daily nasal saline irrigations, empiric Abx if suspect superimposed infection
2.
refractory sinus disease: low dose ( 10-20mg/d) steroid
3.
isolated subglottic stenosis: mechanical dilation, local steroid injection, tracheostomy
4.
arthralgias/arthritis: not associated with systemic disease , NSAIDs f.
Complications of Cyclophosphamide : 43% cystitis , 3% bladder cancer (33 times increase than gen’l population, latency pd = 7 mths to 12 yrs, early manifestation may be hematuria which may be easily confused with GN – all should get cystoscopy), 2% MDS,
57% infertility in 158 pts at NIH
2.
GOODPASTURES SYNDROME: a.
refers to the combination of alveolar hemorrhage and glomerular hemorrhage b.
production of an autoAb to basement membrane antibodies c.
Clinical : i.
Pulmonary : cough, SOB, hemoptysis, hilar pulmonary infiltrates on CXR with hypoxia, increased DLCO, possibly provoked by viral URI/hydrocarbon inhalation/cocaine inhalation, increased risk of alv bleeding in cigarette smokers ii.
Renal : range from normal to focal proliferative and necrotizing GN with crescents, rapidly progressive renal failure, Bx = linear deposits of IgG (or rarely
IgA) anti–BM-Ab often accompanied by C3 deposition iii.
fever, arthralgias, and other systemic symptoms are mild or absent d.
Anti-BM-Ab : i.
circulating Ab to glycopeptide antigens related to noncollagenous domains on type
IV (basement membrane) collagen

ii.
found in >90% iii.
level does not correlate well with severity of disease
  diagnostic, NOT prognostic iv.
complement levels always normal v.
occasionally, ANCA may develop often in assoc with systemic features of vasculitis e.
Treatment and Prognosis : i.
Pulmonary Course : if survive initial bout of hemoptysis

long term remission or repeated bouts of hemoptysis ii.
Renal Course : mild forms may not progress, but more commonly renal disease is progressive and sometimes fulminant leading to renal failure in wks to mths iii.
high doses IV Solumedrol (10-15 mg/kg) given over short pds of time – for life threatening pulm hemorrhage iv.
intensive plasma exchange (daily or every other day for 1-2 wks, NO help if long standing renal disease requiring HD) and cytotoxic drugs and steroids – see dramatic remissions in pulm hem and glomerular disease v.
long term therapy usually not required: steroid and immunosuppressive agents may be withdrawn after 6 mths with careful monitoring of clinical and anti-
BM-Ab and ANCA levels  relapses are uncommon, but usually due to emergence of ANCA associated vasculitis vi.
Renal Transplant : delay until levels of circulating anti-BM-Ab decrease to undetectable
3.
SYSTEMIC LUPUS ERYTHEMATOSUS : a.
Pulmonary : i.
Lupus Pneumonitis:
1.
Acute : fever, dyspnea, cough, cyanosis, and pleuritic pain with bilateral infiltrates and often accompanied by pleural effusion  when attack subsides, infiltrates may clear completely or not ( with abnormal PFT’s), histo – alveolar damage/ IS edema/ hyaline membranes, Rx= steroids
2.
Chronic : behaves like ISLD – DOE, nonprod cough, and basilar crackles, restrictive PFT’s, histo – alveolar fibrosis/ focal necrosis/ plasma cell infil/ desquamation  poor prognosis ii.
LIP : benign proliferative process, seen also in Sjogrens iii.
Pulmonary Hemorrhage : dyspnea, hemoptysis, transient diffuse IS infil, may be precipitated by a pulmonary infection, needs early recognition and aggressive treatment, Rx= high dose steroids +/- cycloph/Aza iv.
PE : via lupus anticoagulant v.
Pulmonary HTN : infrequent, assoc with Reynauds, early inflammatory phase with vasculitis and immune complex depostion

irreversible fibrosis vi.
Pleuritis vii.
Diaphragmatic weakness : elevation of diaphragms with sluggish movements via localized myositic process viii.
Pneumonia : bacterial or fungal ix.
Drug toxicity – MTX b.
Renal : range from mild hematuria to massive proteinuria to RPGN to chronic indolent GN
4.
CHURG-STRAUSS DISEASE (ALLERGIC ANGIITIS and GRANULOMATOSIS): a.
allergic granulomatous vasculitis of multiorgan systems, particularly lung

b.
Constellation of symptoms: severe asthma, eosinophilia, eosinophilic PNA, eosinophilic arteritis, granulomas in multiple organs (PAN – no asthma, eosinophilia, and granulomas) c.
Histology : asthmatic changes, eosinophilic PNA, vasculitis (effects small and medium size vessels, may show necrosis and thrombosis), and necrotizing granulomas i.
67% - heart, kidney, spleen ii.
50% - lung, liver iii.
less – GI, muscle, skin, CNS d.
Clinical : i.
resp manifestations in all patients and may precede other manifestations by years ii.
systemic illness with eosinophilic infiltration of organs iii.
cardiac dz cause of death in 50% iv.
renal disease less severe than PAN e.
CXR : fleeting infiltrates – peripheral, patchy, hilar LAN, pleural effusions f.
different than PAN b/c involves lung, blood vessels of all types and sizes (PAN= small and med arteries), associated with asthma and peripheral eosinophilia g.
Treatment : Prednisone 40-100 mg/day , if resistance add Azathioprine h.
5 year survival = 62%
5.
IDIOPATHIC PULMONARY RENAL SYNDROME: a.
unexplained pulmonary hemorrhage and RPGN in absence of other organ involvement b.
most are pauci-immune and are associated with pANCA
6.
HENOCH-SCHONLEIN PURPURA : a.
Minor flu-like illnes/viral URI precedes nonthrombocytopenic purpura, arthralgias, abdominal pain, and glomerulonephritis b.
Usually children, but any age. Leukocytoclastic vasculitis in children c.
Renal manifestation is hematuria and proteinuria

rapidly progressive GN. IgA nephropathy (Berger’sDisease) may represent monosyptomatic form d.
Respiratory tract – DAH, patchy peri-hilar infiltrates
7.
ESSENTIAL MIXED CRYOGLOBULINEMIA: a.
purpura, weakness, arthralgias, multi-organ involvement b.
Increased cryoglobulins with RF activity c.
Leukocytoclastic vasculitis (Ig and Complement) in blood vessels and GBM
8.
AMYLOIDOSIS
9.
SARCOIDOSIS