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 ❏ urinalysis ❏ measure renal function ❏ imaging studies ❏ X-Rays, CT scans, MRI ❏ tissue abnormalities  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

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* 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

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