1. Causes and Treatments for Granulomatosis with Polyangiitis (GPA)
October 24, 2017
Syed Danial Akif
Edwin Cheung
Semon Striganov
Noorulla Syed
PHM Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson

2. Also commonly known as Wegener’s Granulomatosis (until 2011) after German Pathologist Friedrich Wegener in 1930s.
A systemic disease (autoimmune) of inflammation and necrosis of small- medium sized blood vessel endothelia.
Sub-categorized under ANCA-associated vasculitides.
Incidence rates of cases per million yearly.

3. Symptoms
Symptoms:
Long term, flue like (fever, inflammation)
otalgia (ear pain)
rhinorrhoea (bloody)
sinusitis (inflammation of sinuses)
hematouria (progressed)
Typically presents itself like respiratory infection, with possibility of bloody sputum.
Saddle nose deformity common in GPA.
Otalgia = ear pain.
Hematouria = blood in urine.
Berden, A; Göçeroglu, A; Jayne, D; Luqmani, R; Rasmussen, N; Bruijn, JA; Bajema, I (January 2012). "Diagnosis and management of ANCA associated vasculitis.". BMJ. 344: e26. PMID   

5. Diagnosis
Blood tests for increased leukocytosis, C reactive protein, raised serum creatinine.
Chest radiography (x-ray) will reveal bilateral infiltrates, nodules. Difficulty breathing.
ANCA assay (Anti-neutrophil cytoplasmic antibody) (Commonly via ELISA)
Berden, A; Göçeroglu, A; Jayne, D; Luqmani, R; Rasmussen, N; Bruijn, JA; Bajema, I (January 2012). "Diagnosis and management of ANCA associated vasculitis.". BMJ. 344: e26. PMID   

6. Unclear Causes…
There is mutual agreement that this disease may have genetic and environmental factors, with most cases of PGA surfacing after an infection.
Initially treated with corticosteroids, however survival rates were low(1950s ~ 90% mortality within 2 years due to renal failure) as it did not address cause of endothelial damage.

7. ANCA Plasma B Cells Target antigens derived from Neutrophils
Anti-Neutrophil Cytoplasmic Antibodies
IgG
Target antigens derived from Neutrophils
ANCA

8. Neutrophil Most common Leukocyte Granulocyte Azurophilic Granules
60% of Leukocytes
Granulocyte
Same class as: Eosinophil, and Basophil
Enzymes
Azurophilic Granules
“primary granules”
Myeloperoxidase, Proteinase 3, etc.
Phospholipase A2, Acid Hydrolases, Elastase, Defensins, Serine Protease, Lysozyme, Proteoglycnas
Neutrophil

9. Types of ANCA C-ANCA P-ANCA Targets Proteinase 3 Cytoplasmic staining
Polyangiitis with Granulomatosis
P-ANCA
Targets Myeloperoxidase
Perinuclear staining
Both Antigens from Azurophilic Granules – readily stainable with Romanowsky stain
Proteinase 3 –
Myeloperoxidase – H2O2 + Cl - HOCl bacterialcidal
Types of ANCA

10. Neutrophil Response Stimulates Neutrophils Associated Inflammation
Attach vessel walls
Degranulate
Damage to walls
Associated Inflammation
Cytokines prime Neutrophils
Surface expression of antigens
ANCA binds the accumulating Neutrophils
Neutrophil Response

11. Vasculitis

12. ANCA related disorders
Granulomatosis with Polyangiitis
Lungs, sinuses
Microscopic polyangiitis
Lungs, skin, kidney and nerves
Eosinophilic Granulomatosis with polyangiitis
Involves high levels of Eosinophils
Glomerulonephritis
Glomeruli swelling
ANCA related disorders

13. Factors such as organs affected, individual medical history and disease severity should be considered before treatment
Individuals who have a severe case of GPA are usually given immunosuppressants (cyclophosphamide) and glucocorticosteroids (prednisone)
Cyclophosphamide (CYC) is usually given for 3 to 6 months and it could either be injected or orally administered
Treatments

14. Individuals who improve could then switch to alternative medications such as azathioprine and methotrexate which can be administered for 2 or more years
Other options also exist for treating GPA
For instance Rituximab can be combined with glucocorticoids
Rituximab injected via the vein can eliminate organ and blood vessel inflammation
Treatments cont.

15. Cyclophosphamide mechanism of action
Drug classes: Immunosuppressant, Alkylating Agent, Cancer Chemotherapeutic
Potent immunosuppressant which decreases immune response by reducing DNA production in cells.
CYC is a nitrogen mustard which has alkylating abilities because its from the oxazophosphorine group
Undergoes extensive metabolism by cytochrome p450 which results in the two main active and inactive metabolites being formed: Phosphoramide mustard and acrolein respectively.
Cyclophosphamide mechanism of action

16. Cyclophosphamide mechanism of action cont.
Phosphoramide mustard is degraded while acrolein is excreted in the urine
The active ingredients mentioned in the previous slide crosslink with DNA, which is done by adding alkyl groups to the guanine base of DNA (number seven nitrogen of the imidazole ring)
This inhibits DNA replication which leads to cell death
CYC affects both dividing and resting lymphocytes
The exact mechanism by which CYC treats autoimmune diseases is still not well understood
Cyclophosphamide mechanism of action cont.

17. Prednisone mechanism of action
Drug class: glucocorticoid, immunosuppressant and anti-inflammatory steroid
Prednisone is inactive in its initial state, it must be converted to prednisolone by 11- beta hydroxysteroid dehydrogenase 1 (hepatic enzyme) before it can bind to glucocorticoid receptors
The resulting physiological effect is: inhibition of PLA2, downregulation of COX-2 and inflammatory cytokines and reduction in activity of the immune system
Prednisone mechanism of action

18. Side effects Cyclophosphamide
Nausea, vomiting, hair loss and skin rashes.
Reduce in number of WBC
Can cause infertility in both males and females
May result in the formation of blood in urine because of scarring in bladder
Increase risk factor of developing some kinds of cancers such as lymphoma, skin and bladder cancer
Prednisone
Blurred vision, swelling, depression, low potassium and high blood pressure
Side effects

19. Current Research

20. How GPA is treated Induction phase Maintenance phase Primary treatment
3 to 6 months
Put drug into remission
systemic corticosteroid and immunosuppressant combination
Prednisone plus cyclophosphamide (CYC) or rituximab (RTX)
Maintenance phase
18 to 24 months after remission
Oral corticosteroids plus azathioprine(AZA) or methotrexate (MTX)
Prevent relapse
How GPA is treated

21. Pre-emptive Maintenance Therapy using RTX
Use chronic pre-emptive RTX therapy to treat GPA
Evaluate long term efficacy and safety
Long term RTX maintenance therapy – reduce relapse rate from 30.9% to 6.6%
Lower relapse rates than maintenance using AZA with CYC induction therapy (8%)
However, 37% of patients discontinued– hypogammaglobulinemia and infections
26% of patients have severe infections
Therefore, RTX can’t be used for maintenance therapy
Pre-emptive Maintenance Therapy using RTX

22. Using RTX with/without a maintenance agent
Treat patients with RTX – they go into remission
One group is given a maintenance agent, another group isn’t
No maintenance therapy – 39% relapse free after 18 mths
Maintenance therapy – 65% relapse free after 18 mths
Using RTX with/without a maintenance agent

23. Commentary on this Study
AZA and MTX treatment could increase risk of infection
26% of patients had severe infections, 28% of patients discontinue due to hypogammaglobulinemia
Commentary on this Study

24. Other Future Research Reducing dose of CYC
Reduce dose of corticosteroids
Alternatives to CYC – use RTX
Predicting relapse using biomarkers – many patients are immunosuppressed longer than needed
ANCA amount not good predictor of relapse
Duration of maintenance therapy
BIOMARKERS - McKinney et al have discovered a CD8 T cell messenger RNA signature detectable at diagnosis, which was associated with relapse in patients with AAV and a range of autoimmune conditions.81 This signature was only discernible in isolated leukocyte subsets and not in whole blood. If a clinically applicable test could be devised based on these findings it could have some utility in predicting relapse in GPA. Calprotectin (S100A8/S100A9) is a damage associated molecular pattern produced by neutrophils and monocytes, and is commonly raised in inflammatory conditions.
DURATION: In one retrospective study, withdrawal of corticosteroid treatment at 6 months was associated with reduced infections and no increase in relapse rate compared with those maintained on corticosteroids.94 However, in other studies, early withdrawal of steroids has been associated with increased relapse rates
Other Future Research

25. A systemic disease (autoimmune) of inflammation and necrosis of small-medium sized blood vessel endothelia.
Typically presents like long-term flu-like symptoms.
Saddle nose deformity common in GPA.
Mainly affects respiratory tract and kidneys.
Diagnoses includes elevated creatinine, bilateral lung infiltrates, ANCAs.
Anti-Neutrophil Cytoplasmic Antibodies target specific granular enzymes to activate neutrophils
Affinity of ANCA for Proteinase 3 (PR3) causes Granulomatosis with Polyangiitis
Summary

26. Individuals who have a severe case of GPA are usually given glucocorticoid (steroid) medications, which include: prednisone and cyclophosphamide
Cyclophosphamide Undergoes extensive metabolism by cytochrome p450 which results in the two main active and inactive metabolites being formed: Phosphoramide mustard and acrolein respectively.
The active ingredients crosslink with DNA, which is done by adding alkyl groups to the guanine base of DNA (number seven nitrogen of the imidazole ring)
This inhibits DNA replication which leads to cell death
CYC affects both dividing and resting lymphocytes
Prednisone is inactive in its initial state, it must be converted to prednisolone by 11- beta hydroxysteroid dehydrogenase 1 (hepatic enzyme) before it can bind to glucocorticoid receptors
The resulting physiological effect is: inhibition of PLA2, downregulation of COX-2 and inflammatory cytokines and reduction in activity of the immune system
Alternatives to CYC are being researched – RTX
RTX is not a viable long term solution if used alone
RTX use with maintenance therapy is much more effective
However, with both RTX and maintenance agents, there is still an increased risk of infection
Future research must be done on reducing dose, biomarkers, duration of therapy
Summary

27. Cartin-Ceba, R. , Peikert, T. , Specks, U. 2012
Cartin-Ceba, R., Peikert, T., Specks, U Pathogenesis of ANCA-associated vasculitis. Current Rheumatology Reports. 14 (6): 481–93.
Berden, A., Göçeroglu, A., Jayne, D., Luqmani, R., Rasmussen, N., Bruijn, JA., Bajema, I Diagnosis and management of ANCA associated vasculitis. BMJ. 344: e26. 
Strzepa, A., Pritchard, K.A. and Dittel, B.N., Myeloperoxidase: A New Player in Autoimmunity. Cellular Immunology.
Kallenberg, C.G., Pathogenesis of ANCA-associated vasculitides. Annals of the rheumatic diseases, 70(Suppl 1), pp.i59-i63.
Jennette, J.C. and Nachman, P.H., ANCA Glomerulonephritis and Vasculitis. Clinical Journal of the American Society of Nephrology, 12(10), pp
ANCA Vasculitis. UNC School of Medicine. disease/anca-vasculitis (accessed Oct )
(n.d.). Retrieved October 21, 2017, from
Cyclophosphamide. (n.d.). Retrieved October 21, 2017, from
Cyclophosphamide (Cytoxan). (n.d.). Retrieved October 21, 2017, from
Granulomatosis with Polyangiitis (Wegener's). (n.d.). Retrieved October 21, 2017, from Polyangitis-Wegners
Prednisone (Prototype). (n.d.). Retrieved October 21, 2017, from
Prednisone Uses, Dosage, Side Effects, Warnings. (n.d.). Retrieved October 21, 2017, from
References

28. Azar, L. , Springer, J. , Langford, C. , & Hoffman, G. (2014)
Azar, L., Springer, J., Langford, C., & Hoffman, G. (2014). Rituximab With or Without a Conventional Maintenance Agent in the Treatment of Relapsing Granulomatosis With Polyangiitis (Wegener's): A Retrospective Single-Center Study. Arthritis & Rheumatology, 66(10),
Besada, E., & Diamantopoulos, A. (2015). Does Concomitant Methotrexate During Rituximab Treatment in Granulomatosis With Polyangiitis (Wegener's) Increase the Risk of Severe Infection? Comment on the Article by Azar et al. Arthritis & Rheumatology, 67(7),
Besada, E., Koldingsnes, W., & Nossent, J. (2013). Long-term efficacy and safety of pre-emptive maintenance therapy with rituximab in granulomatosis with polyangiitis: results from a single centre. Rheumatology, 52(11),
Comarmond, C., & Cacoub, P. (2014). Granulomatosis with polyangiitis (Wegener): Clinical aspects and treatment. Autoimmunity Reviews, 13(11),
Pusey, C., & Tarzi, R. (2014). Current and future prospects in the management of granulomatosis with polyangiitis (Wegener's granulomatosis). Therapeutics And Clinical Risk Management,
References