1. Granulomatosis with Polyangiitis (Wegener’s Granulomatosis)
PHM Fall 2018
Instructor: Ms. Maya Latif
Coordinator: Dr. J. Henderson
Granulomatosis with Polyangiitis (Wegener’s Granulomatosis)

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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

11. 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

12. 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.

13. 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.

14. Similar Diseases
In family of diseases called ANCA-related vasculitis (but different antigen target)
Microscopic polyangiitis
Churg-Strauss syndrome

15. Summary

16. 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

17. 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).

18. 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).