Causes and Treatment of
Wegener’s granulomatosis
Alicia Yu
Yifan (Emily) Hu
Grace Tang
Jessica Wu
PHM142
October 20, 2015
PHM142 Fall 2015
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
Case Study
A 45 year-old male goes to the physician, complaining of
nasal congestion, cough, chest discomfort and dyspnea. He
thinks it is just a common cold, but also reports finding bloody
nasal discharge, and experiences painful swelling in his lower
eyelid. The physician orders a blood and urine test.
Case Study: Laboratory Results
Blood Test shows:
❏Leukocytosis [Inflammation]
❏Elevated erythrocyte sedimentation rate [Inflammation]
❏C-reactive protein levels:50 mg/L [Inflammation]
❏ANCA positive (Anti-Neutrophil Cytoplasmic Antibodies)
[Autoimmune response]
Urine Test
❏Elevated RBC components [Kidney disease]
What is Wegener’s Granulomatosis?
❏ a.k.a. granulomatosis with polyangiitis (GPA).
❏ An uncommon systemic disorder that causes inflammation of blood vessels.
❏ This inflammation is accompanied by granuloma formation which restricts the supply of blood to
various organs.
❏ GPA is characterized by an close association with ANCA (anti-neutrophil cytoplasm antibody)
targeted against PR3 (proteinase 3).
❏ About 80-90% of patients with GPA are ANCA-positive.
❏
The levels of PR3-ANCA is highly specific for GPA and thus is a valuable tool for the
diagnosis of this disease.
❏ Today, our knowledge pertaining the cause and pathogenesis of GPA
are still incomplete. The clue to the initiating event in GPA is
considered to be a combination of environmental and genetic factors.
Infected Organs and Symptoms
❏ The major sites of infection usually involve the upper and lower respiratory tracts and kidneys. The
symptoms at these infected sites include:

recurrent infections of the nose
❏ sinus pain and inflammation
❏ mucosal thickening
❏ cough
❏ shortness of breath
❏ chest pain
❏ blood in urine
❏ During active disease, patient may have other non-specific symptoms such as weight loss, joint
pain, skin sores, malaise, eye swelling, and some forms of hearing loss.
Diagnosis
 no test specific for GPA
 physical symptoms
❏ non-specific: e.g. cold-like symptoms
❏ other symptoms: renal failures, ocular
inflammations
❏blood tests
❏ positive for ANCA
❏ presence of PR3-ANCA
❏urinalysis
❏ measure renal function
❏imaging studies
❏ X-Rays, CT scans, MRI
❏ tissue abnormalities
Pathogenesis
❏ Dual morphology - necrotizing vasculitis and extravascular granulomatous inflammation
❏ Usually starts as granulomatous disease before it converts to systemic autoimmune vasculitis
Hypotheses regarding the pathogenesis of GPA concentrate
on PR3-ANCA, TNF-alpha, neutrophils, T and B cells in
granuloma formation and induction of vasculitis.
Pathogenesis - proposed
mechanisms
Some in vitro and in vivo studies support the concept that
PR3-ANCA and TNF-alpha interaction activate neutrophil
granulocytes, thereby inducing subsequent endothelial
damage in blood vessels and further leukocyte recruitment
resulting in vasculitis.
Causes
❏ Genetic Factors
❏ MHC:
❏ particularly HLDPB1*0401 - significant risk factor
❏ HLA-DPB4
❏ risk factor for GPA but not for other AAV (anca-associated vasulitis)
❏ Environmental Factors
❏ infections
❏ bacterial: Staphylococcus aureus
❏ exposure to inhaled substances
❏ fume and particulate
❏ drugs
❏ evidence suggesting that some drugs may induce ANCA production
Treatment
❏Cyclophosphamide (Trade name: Cytoxan)
❏ Anti-cancer and Immunosuppressant
❏Prednisone (Cortisone)
❏ Corticosteroid: prevents inflammation, immunosuppressive
❏Methotrexate (Trade name: Rheumatrex)
❏ Anti-cancer and immunosuppressant
❏Trimethoprim/sulfamethoxazole (Trade name: Bactrim)
❏ Antibiotics to prevent relapse
Treatment: Rituximab
❏Trade Name: Rituxan
❏Chimeric monoclonal antibody that
binds to CD20 protein, destroying B cells
❏IV administration, 10 mg/mL
❏Used in combination with glucocorticoids
❏Studies found it to be effective in adults patients with
refractory GPA
❏Other uses: treatment of Non Hodgkin’s
Lymphoma, and Rheumatoid Arthritis
Summary
❏Wegener’s granulomatosis, a.k.a. granulomatosis with
polyangiitis (GPA), is an autoimmune disease characterized by
granuloma formation-induced inflammation and necrotic vasculitis
❏Undefined etiology and pathogenesis
❏ Risk factors: genetic and environmental
❏ Models of pathogenesis have been proposed
❏ inconclusive due to lack of supporting evidence
❏Pathological hallmark: presence of PR3-ANCA
❏Treatment: immunosuppressants (eg. Cyclophosphamide,
Prednisone)
❏Rituximab : Chimeric monoclonal antibody that binds to CD20
protein to destroying B cells, found to be effective in refractory
cases
References
Arning L, Holle JU, Harper L et al. Are there specific genetic risk factors for the different forms of ANCA-associated vasculitis? Ann. Rheum. Dis. 70(4), 707–708 (2011).
CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2015. Rituxin [product monograph]. Available from: http://www.e-therapeutics.ca. Also available in paper copy
from the publisher.
Holle JU, Gross WL, Holl-Ulrich K et al. Prospective long-term follow-up of patients with localised Wegener’s granulomatosis: does it occur as persistent disease stage? Ann.
Rheum. Dis. 69(11), 1934–1939 (2010).
Laudien M, Gadola SD, Podschun R et al. Nasal carriage of Staphylococcus aureus and endonasal activity in Wegener s granulomatosis as compared to rheumatoid arthritis and
chronic rhinosinusitis with nasal polyps. Clin. Exp. Rheumatol. 28(1 Suppl. 57), 51–55 (2010).
Ntatsaki E, Watts RA, Scott DG. Epidemiology of ANCA-associated vasculitis. Rheum. Dis. Clin. North Am. 36(3), 447–461 (2010).
Oristrell, J., Bejarano, G., Jordana, R., Monteagudo, M., Marí, B., Casanovas, A., & Tolosa, C. (2009). Effectiveness of Rituximab in Severe Wegener’s Granulomatosis: Report of
Two Cases and Review of the Literature. The Open Respiratory Medicine Journal, 3, 94–99. http://doi.org/10.2174/1874306400903010094.
Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CG. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in
Wegener granulomatosis. Ann. Intern. Med. 120(1), 12–17 (1994).
Wieczorek S, Holle JU, Epplen JT. Recent progress in the genetics of Wegener’s granulomatosis and Churg-Strauss syndrome. Curr. Opin. Rheumatol. 22(1), 8–14 (2010).
Witko-Sarsat, V., Reuter, N., & Mouthon, L. (2010). Interaction of proteinase 3 with its associated partners: Implications in the pathogenesis of Wegenerʼs granulomatosis. Current
Opinion in Rheumatology, 22(1), 1-7. doi:10.1097/BOR.0b013e3283331594.
Lamprecht, P., Csernok, E., & Gross, W. L. (2006). Effector memory T cells as driving force of granuloma formation and autoimmunity in wegener's granulomatosis. Journal of
Internal Medicine, 260(3), 187-191. doi:10.1111/j.1365-2796.2006.01698.x.
[Untitled photograph of Rituximab Vial ]. Retrieved from http://rheumatoidarthritisnews.com/2015/01/06/rheumatoid-arthritis-drug-rituximab-delays-need-for-re-treatment-from-
disease-flares/.