This document summarizes the treatment of granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis. It describes initial immunosuppressive therapy including glucocorticoids combined with cyclophosphamide or rituximab for moderate to severe disease. Maintenance immunosuppressive therapy options include methotrexate, azathioprine and low dose glucocorticoids, typically continued for 12-18 months after remission is achieved. Prophylactic treatments and management of organ system involvement are also outlined.

1. DR ASHRAF AHMAD
PULMONOLOGIST
KAASH – Taif
2015

2. INTRODUCTION
a complex, immune-mediated disorder in which tissue injury
results from the interplay of an initiating inflammatory event
and a highly specific immune response. Part of this response
is directed against previously shielded epitopes of neutrophil
granule proteins, leading to high-titer autoantibodies known
as antineutrophil cytoplasmic antibodies (ANCA). these
antibodies produce tissue damage via interactions with
primed neutrophils and endothelial cells.

3. RISK FACTORS AND POSSIBLE
INITIATING EVENTS
 Infection
 Anti-LAMP-2 Ab — A subtype of ANCA Ab are directed
against lysosome-associated membrane protein-2 (LAMP-2)
and are present in over 90 %of patients
 Anti-plasminogen Ab: increasing VTE
 Genetic factors :MHC class II allele HLA-DRB1-15 markedly
increases the risk
 AAT deficiency
 Exposures: silica,mercury &lead
 Drugs: Rifampicin,Allopurinol &Hydrlazine

4. CLINICAL PRESENTATION
 ENT: saddle nose deformity , upper airway and orbital
masses , cranial nerve entrapment and subglottic disease
,rhinorhea,crusting , ulcers
 Tracheobronchial disease :subglottic and lower tracheal
and bronchial stenoses, tracheal and endobronchial mass
lesions,
 Pulmonary nodules
 DAH

6. cont.
 Renal: RPGN( Haematuria, protienuria )&CRF
 Skin :The most common skin lesion is
leukocytoclastic angiitis, which causes purpura
involving the lower extremities that may be
accompanied by focal necrosis and ulceration. Skin
lesions may also include urticaria, livida reticularis,
and tender nodules. Occasional patients with
erythema nodosum, pyoderma gangrenosum and
Sweet syndrome may also have ANCA-positive disease

7. Cont.
 Eyes :conjunctivitis, corneal ulceration,
episcleritis/scleritis, optic neuropathy, nasolacrimal duct
obstruction, proptosis, diplopia, retinal vasculitis, and
uveitis
 Nervous system mononeuritis multiplex, cranial nerve
abnormalities, central nervous system mass lesions,
external ophthalmoplegia, hearing loss. Meningeal disease
is most commonly associated with granulomatous
inflammation of the central nervous system.
 Increased risk of DVT

8. INVESTIGATIONS
 Lab: c-ANCA, ESR,CRP,TLC,Platlets
 Urine: hematuria and proteinuria.
 CXR & CT chest
 Tissue biobsy: renal,skin,nasal or lung

12. Initial immunosuppressive therapy

13. Overall approach to initial
therapy
 Mild disease - No evidence for "active" GN(ie, normal
serum creatinine and no red cell casts or proteinuria)
and no organ-threatening or manifestations . we suggest a
regimen of glucocorticoids in combination with
either rituximab or methotrexate.
 Moderate to severe disease – Other patients. we
recommend a regimen consisting of glucocorticoids in
combination with either cyclophosphamide or rituximab.
.

14. Cyclophosphamide-based
regimen
 Daily oral cyclophosphamide:
dose of 1.5 to 2 mg/kg per day until a stable remission is
induced, (3-6m).WBC count should be closely
monitored,
 Monthly Iv cyclophosphamide: 0.5 g/m2 2weeks
for 3-6 m
Rituximab-based regimen:
375 mg/m2 per week for four weeks.

15. Glucocorticoid dosing
 Begin with pulse methylprednisolone (7 to 15 mg/kg to
a maximum dose of 500 to 1000 mg/day for 3 days)
inthose with necrotizing or crescentic
glomerulonephritis or more severe respiratory disease.
Oral glucocorticoid therapy, either from day 1 or from
day 4 if pulse methylprednisolone is given, typically
consists of 1 mg/kg per day (maximum of 60 to
80 mg/day)

16. Role of plasma exchange
 Severe active and rapidly progressive renal disease,
which has been variably defined
 Concurrent anti-GBM antibody disease, usually when
the Scr is <5.7 mg/dL
 Severe pulmonary hemorrhage (eg, life threatening or
ventilatory dependent)

17. PCP prophylaxis
 For patients treated with cyclophosphamide and
glucocorticoids, we use trimethoprim-sulfamethoxazole (one
single-strength [80 mg/400 mg] tablet daily or one double-
strength tablet [160 mg/800 mg] three times per
week). Atovaquone is preferred in patients who are allergic to
sulfonamides or do not tolerate trimethoprim-
sulfamethoxazole.
 For patients treated with methotrexate and glucocorticoids,
the addition of trimethoprim-sulfamethoxazole is associated
with an increased risk of pancytopenia.Atovaquone may be
used for prophylaxis in such patients.
 After cyclophosphamide is discontinued and maintenance
immunosuppressive therapy is initiated, we continue PCP
prophylaxis until the CD4-positive T cell count
exceeds 300/microL.

18. MANAGEMENT OF UPPER AIRWAY
INVOLVEMEN
 bronchial stenosis :airway dilation with or without
stenting.
 subglottic stenosis, intralesional injection of
glucocorticoids in combination with endoscopic
dilation

19. Maintenance immunosuppressive therapy

20. Methotrexate
 started within one to two days of
thelast cyclophosphamide dose at an oral dose of 0.3 mg/kg
week (max. dose 15 mg). If tolerated, the dose was increased
in 2.5 mg increments each week to a dose of 20 to 25 mg per
week. If remission was sustained for two years or longer,
methotrexate was tapered by 2.5 mg each month until
discontinuation.
 In patients with impaired renal function, azathioprine is
preferred to methotrexate in patients with an estimated GFR
less than 50mL/min.

21. Azathioprine
 Starting at 2 mg/kg per day, then reduced to 1.5 and 1.0
mg/kg per day after 12 and 18 months, respectivly
 Azathioprine is preferred in women who want to
become pregnant, since methotrexate is
contraindicated in pregnancy.

22. Initiation of maintenance therapy
 Cyclophosphamide induction therapy is usually continued
for one to two months after the first documentation of
remission.
 For patients treated with daily oral cyclophosphamide ,
maintenance therapy can be started as soon as the following
criteria are met after the cessation of cyclophosphamide:
WBC>4000 cells/microL; and the absolute neutrophil count
is >1500 cells/microL.
 For patients treated with monthly IV cyclophosphamide,
maintenance therapy is started at 2-4W (the time of the
leukocyte nadir) after the last dose of cyclophosphamide if
the above criteria are met.

23. DURATION OF MAINTENANCE TTT
 Maintenance therapy in patients with newly diagnosed GPA or
MPA is usually given for 12 to 18 months after stable remission has
been induced
Glucocorticoids:
 Low-dose oral prednisone is initially continued in most patients
receiving maintenance therapy. The goal is to attain the minimum
prednisone dose required for control of systemic symptoms
 The median duration of glucocorticoid therapy is less than six to
eight months .