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PHM142 Fall 2016 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson Wegener’s Granulomatosis PHM 142H1 Tuesday, November 8, 2016 Rachel Anisman Mariana Klinovski Ivy Nguyen Habon Warsame What is Wegener’s Granulomatosis? Autoimmune disease Inflammation of blood vessels (often in respiratory tract) Restricts blood flow to organs and ultimately damages these organs At risk: ages 40 to 65 Cause: unknown Symptoms Deafness Nose bleeding Sinus pain Nasal ulcer Rhinorrhea Joint pain Weakness Lung and kidney inflammation Runny nose Coughing Shortness of breath Fever Fatigue Numbness (limbs, fingers, toes) Weight loss Hematuria Skin sores/bruising Ear infection Cyclophosphamide Alkylating agent Wegener’s Granulomatosis was a fatal disease before cyclophosphamide was introduced in the 1970s Taken with glucocorticoids Orally, IV, or IM High dose of 2mg/kg/day Crosslinking of DNA, RNA, and proteins causing cell death Cyclophosphamide Prodrug converted to aldophosphamide (liver, cytochrome P450) In lymphocytes: Aldophosphamide acrolein + phosphoramide mustard (a cytotoxic alkylating agent which causes apoptosis) In stem cells, liver, and intestinal epithelium: Aldophosphamide carboxyphosphamide (inactive non-toxic form) Aldehyde dehydrogenase 1 Cyclophosphamide Side effects Increased risk of infection Bone marrow suppression Sterility/infertility Teratogen Hemorrhagic cystitis (bladder bleeding) Bladder cancer Hair loss Glucocorticoid Co-administered with suppressive agents, such as Cyclophosphamide, Methotrexate, and Rituximab 1 mg/kg/day during remission induction, 10 mg/day during remission maintenance At low doses: anti-inflammatory and anti-allergic At high doses: immunosuppressant Exact mechanism of its anti-inflammatory and immunosuppressive actions is unknown Glucocorticoid Mechanism of action Binds to intracellular glucocorticoid receptor and causes: Transactivation: upregulation of anti-inflammatory genes by binding to the positive glucocorticoid responsive element (GRE) Transrepression: represses expression of proinflammatory genes by binding to transcription factors (mainly AP-1 and NF-ĸB) Reduces the production and proliferation of B and T lymphocytes, suppresses synthesis of cytokines, and decreases leukocyte infiltration at the inflamed sites Glucocorticoid Side effects Obesity Diabetes Cataracts Osteoporosis Change in mood/personality Increased infection risk Increased appetite Methotrexate (MTX) Alternative to cyclophosphamide In combination with Prednisone for remission Administration Orally once/week; or Injection under skin or muscle Caution: individuals with poor kidney function or liver disease avoid consumption with alcohol Side effects infection, lower blood count, nausea, soreness, ulceration of mouth lining, irritation of lungs, inflammation, scarring of liver Methotrexate (MTX) Mechanism of action: Reduced inflammatory process remission Inhibits dihydrofolate reductase interferes with DNA synthesis and cell reproduction Inhibits enzymes involved in purine synthesis accumulation and release of adenosine Adenosine Inhibits neutrophil adhesion to endothelial cells and generation of toxic oxygen metabolites Potent anti-inflammatory agent Methotrexate (MTX) Azathioprine Pro-drug Metabolized to 6-mercaptopurine (6-MP) Non-enzymatically by glutathione or cysteine Then to 6-thiouric acid, 6-methyl-MP, and 6-thioguanine (enzymatically) Purine analog that acts at the level of DNA Impairs leukocyte proliferation by: Blocking purine synthesis Incorporating itself into the DNA Safer than cyclophosphamide for maintaining remission. Alternative to Methotrexate. Patients can be transitioned to 2 mg/kg/day azathioprine Avoid many of the long-term toxic effects of cyclophosphamide Azathioprine Mechanism of action Blocks the de novo pathway for purine synthesis Inhibits GPA, first enzyme in the pathway Inhibition of purine synthesis hindered DNA synthesis impaired proliferation of fast-growing cells, such as T cells and B cells Causes T cell unresponsiveness Interferes with CD28 signaling Apoptosis of activated T-cells by way of inhibition of Rac1 Rac1 targeted by azathioprine metabolite 6-Thio-GTP 6-Thio-GTP binds to Rac1 instead of GTP. Suppression of Rac1 target genes such as Bcl-xL Azathioprine Side effects Serious side effects Nausea Severe stomach/intestinal symptoms Vomiting Fever Diarrhea Shaking Loss of appetite Chills Rash Itching/swelling Severe dizziness Trouble breathing Cough Wegener’s Granulomatosis and B Cell Response: Vasculitis resulting from Wegener’s Granulomatosis causes an autoimmune response whereby neutrophilic cytoplasm immune proteins release cytokines and chemokines This causes neutrophils to adhere to each other and to the endothelial cell wall B cells target damaging neutrophilic cytoplasm immune proteins by producing anti-neutrophilic cytoplasmic antibodies (ANCAs) B cell aggregation occurs around the neutrophils creating a granulocyte Rituximab Monoclonal anti-CD20 antibody therapeutic drug used in combination with glucocorticoids during remission Reduces the amount of B cells that circulate in the blood Rituximab down-regulates B cell CD20 receptor found on the surface of B cells This reduces the amount of overactive mature and immature B cells expressed Depletion of B cells only lasts for 6 months, levels return 9-12 months after treatment Cannot be used in patients with hepatitis B Rituximab Mechanism of action Increased thirst or urination 1. CD20 B cell apoptosis Swelling of the hands or feet 2. NK cell activation Tingling of the hands or feet 3. Complement-dependent cytotoxicity Serious side effects Summary Cyclophosphamide Glucocorticoid Transactivation of anti-inflammatory genes, and transrepression of pro-inflammatory genes Reduces production and proliferation of B and T lymphocytes, and cytokine synthesis Methotrexate Active phosphoramide mustard, an alkylating agent, causes crosslinking in DNA, leading to apoptosis Cells of liver, intestinal epithelium and bone marrow are resistant to cytotoxicity due to high levels of aldehyde dehydrogenase Remission maintenance drug that affects purine synthesis and increases the intracellular concentration of adenosine Adenosine is a potent anti-inflammatory agent (reduce inflammation & swelling) and inhibits neutrophil adhesion Azathioprine Remission maintenance drug that inhibits purine synthesis, impairing the proliferation of T cells and B cells Causes T cell unresponsiveness and apoptosis of activated T cells Rituximab Anti-CD20 antibody drug that down-regulates B cell CD20 receptor and thus B cell blood circulation Mechanism includes CD20 cell apoptosis, NK cell activation and complement-dependent cytotoxicity References "AZATHIOPRINE - ORAL (Imuran) Side Effects, Medical Uses, and Drug Interactions - Page 3." MedicineNet. N.p., n.d. Web. 04 Nov. 2016. Barnes, Peter J. "Inhaled Corticosteroids." Pharmaceuticals 3.3 (2010): 514-40. MDPI. Web. 4 Nov. 2016. "Cyclophosphamide (Rx)Brand and Other Names:Cytoxan." Cytoxan (cyclophosphamide) Dosing, Indications, Interactions, Adverse Effects, and More. N.p., n.d. Web. 05 Nov. 2016. Emadi, Ashkan, Richard J. Jones, and Robert A. Brodsky. "Cyclophosphamide and Cancer: Golden Anniversary." Nature Reviews Clinical Oncology 6.11 (2009): 638-47. Web. 4 Nov. 2016. “Granulomatosis with polyangiitis.” National Center for Advancing Translational Sciences. Web. 04 Nov. 2016. Kaltsonoudis E., Papagoras C., Drosos A. “Current and Future Role of Methotrexate in the Therapeutic Armamentarius for Rheumatoid Arthritis.” Int J Clin Rheumatol. 2012: 7(2): 179-189. Web. 04 Nov. 2016. Langford, Carol A. "Wegener's Granulomatosis: Current and Upcoming Therapies." Wegener's Granulomatosis: Current and Upcoming Therapies. Arthritis Res Ther, 29 May 2003. Web. 04 Nov. 2016. Langford, Carol A. "Wegener's Granulomatosis Treatment Today - The Rheumatologist." The Rheumatologist. N.p., 01 Oct. 2008. Web. 04 Nov. 2016. Maltzman, Jonathan S., and Gary A. Koretzky. "Azathioprine: Old Drug, New Actions." Journal of Clinical Investigation. American Society for Clinical Investigation, 15 Apr. 2003. Web. 04 Nov. 2016. Mayo Clinic Staff. "Granulomatosis with Polyangiitis." Overview. N.p., 22 Dec. 2015. Web. 04 Nov. 2016. "Methotrexate (MTX)." John Hopkins Vasculitis Center. N.p., n.d. Web. 04 Nov. 2016. Nelson, Harold S., Donald Y.m. Leung, and John W. Bloom. "Update on Glucocorticoid Action and Resistance." Journal of Allergy and Clinical Immunology 111.1 (2003): 3-22. Web. 4 Nov. 2016. Rhen, Turk, and John A. Cidlowski. "Antiinflammatory Action of Glucocorticoids — New Mechanisms for Old Drugs." New England Journal of Medicine 353.16 (2005): 1711-723. Web. 5 Nov. 2016. Rituximab mechanism. Digital image. N.p., n.d. Web. 3 Nov. 2016. "Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis — NEJM." New England Journal of Medicine. N.p., 15 July 2010. Web. 04 Nov. 2016. Rituximab-rituxan. Digital image. N.p., n.d. Web. 3 Nov. 2016. References "The Role of the Immune System in ANCA-associated Vasculitis." Role of the Immune System in ANCA-associated Vasculitis. N.p., n.d. Web. 04 Nov. 2016. Rudnicka, Dominika, Anna Oszmiana, Donna K. Finch, Ian Strickland, Darren J. Schofield, David C. Lowe, Matthew A. Sleeman, and Daniel M. Davis. "Rituximab Causes a Polarization of B Cells That Augments Its Therapeutic Function in NK-cell–mediated Antibody-dependent Cellular Cytotoxicity." Home. N.p., n.d. Web. 04 Nov. 2016. Shaw, T., J. Quan, and M. C. Totoritis. "B Cell Therapy for Rheumatoid Arthritis: The Rituximab (anti-CD20) Experience." Ann Rheum Dis 62 (2003): Ii55-i59. Print. Sistigu, Antonella, Sophie Viaud, Nathalie Chaput, Laura Bracci, Enrico Proietti, and Laurence Zitvogel. "Immunomodulatory Effects of Cyclophosphamide and Implementations for Vaccine Design." Seminars in Immunopathology 33.4 (2011): 369-83. Web. 5 Nov. 2016. Tracy, Christopher L. "Granulomatosis with Polyangiitis (Wegener Granulomatosis) Treatment & Management." Medscape. Ed. Herbert S. Diamond. N.p., 4 Nov. 2016. Web. 04 Nov. 2016. Tiede, Imke, Gerhard Fritz, Susanne Strand, Daniela Poppe, Radovan Dvorsky, Dennis Strand, Hans Anton Lehr, Stefan Wirtz, Christoph Becker, Raja Atreya, Jonas Mudter, Kai Hildner, Brigitte Bartsch, Martin Holtmann, Richard Blumberg, Henning Walczak, Heiko Iven, Peter R. Galle, Mohammad Reza Ahmadian, and Markus F. Neurath. "CD28-dependent Rac1 Activation Is the Molecular Target of Azathioprine in Primary Human CD4+ T Lymphocytes." Journal of Clinical Investigation. American Society for Clinical Investigation, 15 Apr. 2003. Web. 07 Nov. 2016. Valerie, Nicholas C.K., Anna Hagenkort, Brent D.G. Page, Geoffrey Masuyer, Daniel Rehling, Megan Carter, Luka Bevc, Patrick Herr, Evert Homan, Nina G. Sheppard, Pal Stenmark, Ann-Sofie Jemth, and Thomas Hellenday. NUDT15 Hydrolyzes 6-Thio-DeoxyGTP to Mediate the Anticancer Efficacy of 6-Thioguanine. Digital image. Home. N.p., 15 Sept. 2016. Web. 07 Nov. 2016. Vendemiati, Giulia, and Cecilia Capetti. "Methotrexate Efficacy In Rheumatoid Arthritis,Genetic Polymorphism in KeyMTX Pathway Genes." Methotrexate Efficacy In Rheumatoid ArthritisGenetic Polymorphism in KeyMTX Pathway Genes RSS. N.p., 4 Oct. 2015. Web. 04 Nov. 2016. V. H. J. Van Der Velden. "Glucocorticoids: Mechanisms of Action and Anti-inflammatory Potential in Asthma." Mediators of Inflammation 7.4 (1998): 229-37. Web. 4 Nov. 2016. "Wegener's Granulomatosis." Wegener's Granulomatosis (GPA) | Cleveland Clinic. N.p., 24 Feb. 2014. Web. 04 Nov. 2016. What You Should Know About Wegener ’s Granulomatosis (n.d.): n. pag. The Department of Immunology St. James’s Hospital, 2002. Web. 4 Nov. 2016. Wung, Peter K., and John H. Stone. "Therapeutics of Wegener's Granulomatosis." Nature.com. Nature Publishing Group, 24 Nov. 2005. Web. 04 Nov. 2016.
