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Granulomatosis with Polyangiitis (Wegener’s Granulomatosis)
PHM Fall 2018 Instructor: Ms. Maya Latif Coordinator: Dr. J. Henderson Granulomatosis with Polyangiitis (Wegener’s Granulomatosis)
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Introduction Autoimmune disease : effects nose, trachea, lungs and kidneys Swelling leads to lack of blood flow and damage Granulomatosis with polyangitis- formerly named Wegener’s Granulomatosis is an autoimmune response which causes the inflammation of blood vessels in the body, mainly affecting the sinuses, nose, trachea, lungs, and kidneys. The swelling can cause lack of blood flow to those areas, thereby leading to damage
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History First clinical analysis of condition was conducted by Friedrich Wegener (1907–1990), a German pathologist, from 1936 and 1939, where disease was named Wegener's granulomatosis -Scottish otolaryngologist Peter McBride (1854–1946) first described the condition in 1897 in a BMJ article entitled "Photographs of a case of rapid destruction of the nose and face". -First clinical analysis of condition was conducted by Friedrich Wegener (1907–1990), a German pathologist, from 1936 and 1939, where disease was named Wegener's granulomatosis -Due to Wegener being allegedly tied to the Nazi regime, the scientific community has since renamed the condition granulomatosis with polyangiitis -Can be sometimes confused with lethal midline granuloma and lymphomatoid granulomatosis
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Symptoms Most Common (upper respiratory): Inflammation of sinuses
Runny/bloody nose Sores around the nose Ear infections Related to lungs: Cough up blood Shortness of breath Chest pain Most common symptoms occur in the upper respiratory tract: Inflammation of the sinuses, bacterial infection in the sinuses runny/blood nose Sores around the opening of the nose Ear infactions Symptoms which are usually present are in the lungs: Cough up blood, shortness of breath, chest pain
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Biochemistry Symptoms of GPA caused by vasculitis: damage and inflammation of small-medium sized blood vessels Cause of damage to vascular tissue thought to be from antibodies known as anti-neutrophil cytoplasmic antibodies (ANCAs) Abs target antigens found in neutrophil granules ANCAs lead to neutrophil activation -> degranulation -> damage to blood vessels
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Biochemistry Unclear mechanism for activation of neutrophils
One possible mechanism: ANCA interacts with target antigen on neutrophil, causing activation Neutrophil degranulates Proteases and ROS released, cause endothelial and vascular damage NETs also potentially cause damage to endothelial tissue
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Biochemistry T cell involvement?
Cytokines that signal T cell proliferation lead to development of granulomas Granulomas appear to be the source of ANCAs When CD4+ T cell count reduced, symptoms also reduced Cytokine release also leads to persistent inflammation, more damage
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Biochemistry (continued)
Other putative mechanisms/pathways found to be correlated with symptoms ANCAs inactivate key antigens on neutrophils Prevents neutrophil inhibitors from complexing with neutrophils -> activation Activation of complement pathway, leads to production/release of proteases
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Causes/Pathogenesis Not well studied, like many other autoimmune diseases Staphylococcus aureus infection found to be strongly correlated with incidence of disease S. aureus may have antigens that mimic neutrophil antigens PR3 and MPO No known genetic markers, environmental factors, etc.
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Causes Other potential causes/contributing factors:
Failure to downregulate antibody production via regulatory T cells Activation of complement, leading to increased production of proteases Defective clearing of NETs
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Diagnosis Can clinically present itself in a wide range of ways
At least 2 out of 3 areas (upper airway, lungs, and kidneys) should be affected Biopsies: Urinary sediment containing RBC cast Abnormal chest radiograph Oral ulcers or nasal discharge Inflammation Diagnosis is often delayed due to the wide range that it can clinically present itself For Granulomatosis with polyangiitis - symptoms in 2 out of the 3 areas (upper airway, lungs, and kidneys) should be effected then laboratory tests will be ordered to confirm doctor suspicion of the disease when the patient is observed to have a recurrent respiratory infection, weightloss, unexplained fevers and fatiques. Tests include: Blood test to check for swelling and ANCAs- antineutrophil cytoplasmic antibodies Chest x ray or CT scan to determine if there is inflammation in the lungs ** tests alone are not conclusive and cannot be the sole evidence to show that the patient has Granulomatosis and polyangiitis but it can be used as supporting evidence for the presence of the disease. The American College of Rheumatology established criteria to aid in the diagnosis- the biopsies include: Urinary sediment containing RBC cast Abnormal chest radiograph Oral ulcers or nasal discharge inflammation
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Diagnosis ELK: E for ears, nose, and throat L for lungs K for kidneys
Positive cytoplasmic ANCA There is another testing method named ELK- E standing for ears, nose and throat, L for lungs, and K for kidneys. If a granulomatosis manifestation occurs in either of the 3 areas and is supported by a positive cytoplasmic ANCA test then it can be diagnosed.
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Treatment Treatment of this condition depends on the severity of progression and presence of organ damage. In advanced stages, common treatment of GPA is inducing remission with immunosuppressants such as rituximab or cyclophosphamide in combination with high-dose corticosteroids. When disease progression is limited, a combination of methotrexate and corticosteroids, with reduced steroid dose after an incident of remission has been achieved + methotrexate as maintenance therapy.
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Similar Diseases In family of diseases called ANCA-related vasculitis (but different antigen target) Microscopic polyangiitis Churg-Strauss syndrome
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Summary
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Summary Autoimmune disease affecting nose, trachea, lungs and kidneys
Symptoms: mainly affect upper respiratory tract Diagnosis: 2 out of 3 areas should be effected (upper airway, lungs, and kidneys) then biopsy will be ordered to confirm **biopsies /tests are NOT sufficient for a diagnosis Symptoms caused by neutrophil activation -> degranulation -> damage to endothelial cells Other mechanisms include T cells, complement, defective regulation Unknown cause, but strong correlation to S. aureus infection For advanced stages of GPA, common treatment is immunosuppressants such as rituximab or cyclophosphamide in combination with high-dose corticosteroids. For limited stages of GPA, treatment is corticosteroids with reduced dose to induce remission, followed by methotrexate as maintenance therapy In family of diseases known as ANCA-associated vasculitis, which have similar mechanisms and symptoms
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References Friedmann I . "McBride and the midfacial granuloma syndrome. (The second 'McBride Lecture', Edinburgh, 1980)". The Journal of Laryngology and Otology. 96 (1): 1–23. (January 1982). doi: /s Hua, F., Wilde, B., Dolff, S. & Witzke, O. T-Lymphocytes and Disease Mechanisms in Wegener’s Granulomatosis. Kidney and Blood Pressure Research 32, 389–398 (2009). Kubaisi, B., Samra, K. A. & Foster, C. S. Granulomatosis with polyangiitis (Wegeners disease): An updated review of ocular disease manifestations. Intractable & Rare Diseases Research5,61–69 (2016). Lally, L; Spiera, R (2015). "Current therapies for ANCA-associated vasculitis". Annual Review of Medicine (Review). 66: 227–40. doi: /annurev-med Lintermans, L. L., Stegeman, C. A., Heeringa, P. & Abdulahad, W. H. T Cells in Vascular Inflammatory Diseases. Frontiers in Immunology 5, (2014). Lungs and Breathing. MedlinePlus(2015). at < Nakazawa, D., Tomaru, U. & Ishizu, A. Possible implication of disordered neutrophil extracellular traps in the pathogenesis of MPO-ANCA-associated vasculitis. Clinical and Experimental Nephrology 17, 631–633 (2012). Noone, D., Hebert, D. & Licht, C. Pathogenesis and treatment of ANCA-associated vasculitis—a role for complement. Pediatric Nephrology 33, 1–11 (2016).
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References Pakalniskis, MG; Berg, AD; Policeni, BA; Gentry, LR; Sato, Y; Moritani, T; Smoker, WR . "The Many Faces of Granulomatosis With Polyangiitis: A Review of the Head and Neck Imaging Manifestations". AJR. American Journal of Roentgenology (Review). 205 (6): W619–29. (December 2015). Schonermarck, U., Csernok, E. & Gross, W. L. Pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis: challenges and solutions Nephrology Dialysis Transplantation (2014). doi: /ndt/gfu398 Sharma, S. Granulomatosis with Polyangiitis (Wegener's) Symptoms, Life Expectancy, Treatment. eMedicineHealthat < Tracy CL and Papadopoulos PJ. Granulomatosis with Polyangiitis (Wegener Granulomatosis). Medscape Reference. December 2, 2017; Weeda, L. W. & Coffey, S. A. Wegeners Granulomatosis. Oral and Maxillofacial Surgery Clinics of North America 20, 643–649 (2008). Wegener's granulomatosis stock photos. Wegener's Granulomatosis Images, Stock Photos & Vectors | Shutterstockat < granulomatosis> Willcocks, L. C., Lyons, P. A., Rees, A. J. & Smith, K. G. The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis. Arthritis Research & Therapy 12, 202 (2010).
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