Adverse effects of IBD therapies: how medica7ons work and what could happen while taking them

Adverse effects of IBD therapies: how medica7ons work and what could happen while taking them Chris7na Ha, MD Center for Inflammatory Bowel Diseases David Geffen School of Medicine at UCLA

Treatment Goals for IBD Induc7on of Remission Goals: Provide relief of GI symptoms Promote mucosal healing Treat complica:ons Improve quality of life Maintenance of Remission Goals: Maintain remission (absence of symptoms and maintenance of healed mucosa) Minimal adverse effects and adherence to therapy Maintaining quality of life Avoid hospitaliza:ons and surgeries Most pa:ents will require maintenance therapy to sustain remission

The Tradi7onal IBD Medicine Cabinet Over- the- Counter An7bio7cs Aminosalicylates Cor7costeroids Immunomodulators Biologics Slide courtesy of the CCFA

The Tradi7onal IBD Medicine Cabinet Over- the- Counter An7bio7cs Aminosalicylates Cor7costeroids Immunomodulators Biologics Slide courtesy of the CCFA

5- ASAs: commonly reported adverse effects Headache Muscle or joint pain Nausea/vomi7ng Heartburn Burping/gas/bloa7ng Cons7pa7on Slight hair loss Diarrhea. Consider: Electrolytes deficiencies: - Potassium, Magnesium - Can be associated with muscle cramps, bloa7ng/cramping,

Foods rich in magnesium and potassium Leafy greens (Mg, K) Nuts and seeds (Mg) Fish (Mg, K) Beans/len7ls (Mg, K) Whole grains/brown rice (Mg) Avocados (Mg, K) Dark Chocolate (Mg) Bananas (Mg, K) Low fat dairy e.g yogurt (Mg, K) Dried fruit e.g figs (Mg, K) Squash (K) Not always compa7ble with a low- residue diet Magnesium supplements may have a laxa7ve effect

5- ASAs: common adverse effects Headache Muscle or joint pain Nausea/vomi7ng Heartburn Burping/gas/bloa7ng Cons7pa7on Slight hair loss Diarrhea. Consider: Vitamin/Minerals- Check iron, B12, folate, Zinc levels - Iron deficiency may be associated with headaches, numbness, restless legs, fa7gue, weakness, hair loss - Folic acid deficiency may be associated with loss of appe7te, diarrhea, irritability - B12 deficiency may be associated with diarrhea, fa7gue, swollen tongue - Zinc deficiency may be associated with hair loss, eczema- like rash

5- ASA hypersensi7vity Sulfasalazine up to 30% of pa7ents are sensi7ve to the sulfa component Symptoms include nausea/vomi7ng, diarrhea, rashes Mesalamines/5- ASAs can also be associated with worsened symptoms of coli7s. If con7nued/worsened symptoms while on these agents, consider discon7nua7on

Help! There are tablets in my stool! Can occur with delayed- release tablets May be a factor of rapid gut transit Pills may not be readily dissolved to absorb in the colon If this happens frequently, may need to consider a different formula7on of medica7on Is this weird? My toilet bowl is stained purple Can occur with mesalamine enemas, occasionally tablets/suppositories

Safety Considera6ons of 5- ASA Agents: A Focus on Renal Func6on Nephrotoxicity impacts kidney func7on UNCOMMON à 0.26% per pa7ent- year Most oien reported within the first 12 months of therapy 1 Cau7on recommended when used in pa7ents with known (or history of) renal disease 2,3 FDA recommends monitoring blood urea nitrogen (BUN)/serum crea?nine 1. Gisbert JP et al. Inflamm Bowel Dis. 2007;13:629. 2. Asacol [prescribing information] Warner Chilcott (US) LLC.; Jan 2011. 3. Lialda (delayed release mesalamine) [package insert]. Wayne, PA: Shire USA; Jan 2007.

The Tradi7onal IBD Medicine Cabinet Over- the- Counter An7bio7cs Aminosalicylates Cor7costeroids Immunomodulators Biologics Slide courtesy of the CCFA

How do cor7costeroids work? Prevent the produc7on of mul7ple inflammatory proteins by blocking the genes that encode them Turn ac7vated inflammatory genes Nonspecific immunosuppressant off May also ac7vate an7- inflammatory genes Degrade inflammatory proteins Br J Pharmacol. 2006 Jun; 148(3): 245 254.

Poten7al adverse effects to STEROIDS Sleep disturbances, psychiatric effects Hyperac6vity, increased appe6te Glaucoma Cataracts Osteoporosis - Bone density tes6ng recommended Avascular Necrosis Myopathy GI upset Nausea FaDy liver Infec6on - Impact of vaccina7ons Diabetes Palpita6ons Hypertension Swelling Moon facies Abdominal striae Easy bruising Adrenal insufficiency

How do thiopurines work? Purines: framework for two of the four bases that occur in DNA Thiopurines: Block produc7on of purines Blocks produc7on of immune cells Deac7vate processes that lead to more inflamma7on Increased lymphocyte apoptosis: programmed cell death Excess # of ac7vated lymphocytes in IBD Adenine Guanine

Poten7al adverse effects to THIOPURINES Hair loss Drug reac6on: Fever, rash, arthralgias, myalgias GI disturbances Hepatotoxicity - Usually presents as abnormal liver tests - Rou7ne lab monitoring required Infec6on - Impact of vaccina7ons Skin cancers, Lymphoma - - - Pancrea66s Bone marrow Suppression - Usually the White blood count - Rou7ne lab monitoring required Sun protec7on Dermatology exams Rou7ne follow- up Slide courtesy of A. Kornbluth; Kornbluth A, Sachar DB. Am J Gastroenterol. 2004;88:1371. deboer N et al. Nature Clin Pract Gastroenterol Hepatol. 2007;4:686.

Thiopurines & lymphoma Overall incidence rates among current thiopurine users = 9 per 10,000 Hazard ra7o thiopurine exposed vs naïve = 5.3 (2.0-13.9) Yearly incidence rate per 1000 pa6ent- years 6 5 4 3 2 1 0 5.41 2.58 1.88 1.68 0.37 0.66 0.4 0 0 Current IMM Prior IMM No IMM < 50 yrs 50-65 yrs > 65 yrs Adapted from Cosnes et al. Lancet. 2010.

Thiopurines & lymphoma Overall incidence rates among current thiopurine users = 9 per 10,000 Hazard ra7o thiopurine exposed vs naïve = 5.3 (2.0-13.9) Yearly incidence rate per 1000 pa6ent- years 6 5 4 3 2 1 0 0.37 2.58 5.41 0.66 18/23 (78%) diagnosed with lymphoma were over 50 yrs old 10/18 (65%) current thiopurine use (range 1-10 yrs) 1.88 DURATION OF 1.68 IBD (OR 0 0 < 50 yrs Risk factors for 50-65 LPD: yrs OLDER AGE (OR 1.06 per 1- year increase) > 65 yrs 1.04 per 1- year increase CONTINUED 0.4 THIOPURINE THERAPY (OR 5.28) Current IMM Prior IMM No IMM Adapted from Cosnes et al. Lancet. 2010.

Hepatosplenic T- cell lymphoma: 36 cases reported as of 2010 Low ABSOLUTE risk (best es7mates <1: 22,000) Majority young males <35 years old Most pa7ents on combina7on therapy but more likely to be related to dura7on of thiopurine exposure Kotlyar et al. CGH, 2011.

Skin cancer risk and IBD therapies Non- melanoma skin cancer IBD overall Crohn s disease Ulcera6ve coli6s Melanoma 5- ASA 1.1 (0.8-1.5) 0.98 (0.6-1.5) 1.2 (0.8-2.0) Thiopurines 1.1 (0.7-1.7) 0.9 (0.5-1.6) 1.3 (0.7-2.6) Biologics 1.9 (1.1-3.3) 1.9 (1.0-3.7) 1.7 (0.5-5.6) Peyrin- Biroulet et al. Gastroenterology, 2011. Long et al. Gastroenterology, 2012.

An6- TNF How do an7- TNF medica7ons work? TNF tumor necrosis factor is an ac7vator/ regulator of inflamma7on Important for cell to cell communica7on Directs the produc7on of pro- inflammatory molecules An7- TNF therapies bind 7ghtly to TNF molecules, blocking communica7on pathways that s7mulate the produc7on of destruc7ve molecules by immune cells An6- TNF

How does Vedolizumab work? α4 β7 Vedolizumab MAdCAM- 1 Blocks the interac7on between α4 β7 and MAdCAM- 1 This interac7on allows for lymphocyte adhesion and trafficking through the blood vessel to the target sites Springer TA. Cell. 1994;76:301-314; Butcher EC et al. Science. 1996;272:60-66.

Poten7al adverse effects of BIOLOGICS Autoimmunity- (lupus, psoriasis) immunogenicity Conges6ve heart failure Hair loss Demyelina7ng disease (e.g mul7ple sclerosis) Infec6on - Impact of vaccina7ons Hepatotoxicity Skin cancers, Lymphoma - - - Sun protec7on Dermatology exams Rou7ne follow- up *Reported with natalizumab. Bone marrow suppression Infusion reac6ons, injec6on- site reac6ons PML, progressive mul7focal leukoencephalopathy Slide courtesy of A. Kornbluth; Clark M et al. Gastroenterology. 2007;133:312. Tysabri (natalizumab) [package insert]. South San Francisco, CA: Elan; Jan 2008.

Dermatologic side effects of biologic therapy Psoriasis Female predominance Es7mated incidence of 1:1000 pa7ent- years 50% of pa7ents are able to con7nue TNF therapy with the use of treatment for psoriasis

Drug- induced lupus due to an7- TNF therapies Syndrome of characteris7c lupus symptoms (arthralgias, myalgias, fevers, serosi7s) temporally associated with the an7- TNF therapy Uncommon 0.5-1% of treated pa7ents Costa et al. Semin Arthri7s Rheum, 2008.

Recommended vaccina7ons for IBD pa7ents on immunosuppression Vaccina6on Tetanus Influenza trivalent (inac6vated) vaccine Pneumonia vaccine (PPSV23 & PCV13): PCV13 (Prevnar), PPSV23 (Pneumovax) à superior efficacy than PVX alone Recommended schedule Ini7al dose with booster every 10 years Annually PPSV23: Ini7al vaccine at age 2+ years with revaccina7on 5 years later PCV13: 8 weeks before or 1 year aier PPSV23 HPV vaccina7on series Women and men aged 9-26 years Men who have sex with men Immunocompromised Hepa77s A and B Meningococcal vaccine Check 7ters if prior vaccina7on history College age, military, asplenic, travel to endemic country Varicella (live vaccine) If no evidence of immunity no or low- level immunosuppression only 2013 IDSA Clinical Prac7ce Guideline for Vaccina7on of the Immunocompromised Host. Moscandrew et al. Inflamm Bowel Dis. 2009;15:1399 1409. Maneesh et al. IBDJ. 2014;20:196-212.

Hair loss with IBD Vitamin/mineral deficiencies: Iron, B6, B12, Zinc Medica7on effect 5- ASAs, thiopurines, an7- TNF therapies, steroids Psoriasis associated alopecia Drug- induced lupus

Hair loss with IBD Telogen effluvium due to change in the number of hair follicles of growing hair Decreased # of hair follicles producing hair results in an increased # of dormant/res7ng hair follicles Results in shedding Seen in chronic disease states, usually transient Autoimmune condi7ons associated with IBD Alopecia areata

The Tradi7onal IBD Medicine Cabinet Over- the- Counter An7bio7cs Aminosalicylates Includes CAM Cor7costeroids therapies, An7- diarrheals, NSAIDs Immunomodulators (ibuprofen, naproxen) Biologics Slide courtesy of the CCFA

Complementary and Alterna6ve Medicine (CAM) ADJUNCTIVE Up to 60% of pa7ents with IBD use CAM 1 Two most common reasons IBD pa7ents use CAM 2 Wanted greater sense of control of self and their IBD Lack of efficacy or side effects from conven7onal therapy Ø Not regulated by the Food and Drug Administra7on Ø Only a handful have been studied in a controlled clinical trial se}ng Ø Efficacy based on mostly anecdotal evidence Ø No adverse event repor7ng system, no registries for safety Ø Uncertain poten7al for interac7ons with other medica7ons 1- Hilsden et al, IBD. 2011;17(2):655-662. 2- Li et al., Can J Gastro. 2005;19:567-573.

Weigh the Risks and Benefits of CAM Pros: Can provide benefit when used as adjunc?ve therapy, restores some sense of control Cons: Adverse effects not known, expense (most not covered by insurance), op7mal dosing may not be known, not FDA- regulated Takeaways Important to seek out good data to minimize poten7al risk Choose well- researched op7ons Consider the qualifica7ons of the informa7on resource Alterna7ve therapies should complement, not replace, tradi7onal therapies Tell your doctor everything you are taking!! Slide courtesy of the CCFA

Ques7ons to ask your healthcare team about IBD & medica7ons Where is my IBD located, how severe is it? What are my treatment OPTIONS? Why do you recommend this medica7on(s)? What is the likelihood I will respond to this medica7on(s) given my level of disease ac7vity? When and how will I know if it s working or not? How should this medica7on be stored and taken? Are there poten7al side effects? What should I look out for? When should I contact you? Are there any medica7on interac7ons? How do we monitor for adverse effects?