Slide 1. Slide 2. Slide 3. Complications of Medical Therapy and How to Prevent Them. Objectives. Complications of IBD Medical Therapy

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1 Slide 1 Complications of Medical Therapy and How to Prevent Them Hamed Khalili, M.D., MPH MGH Crohn s and Colitis Center Harvard Medical School Slide 2 Objectives 1. To identify common preventable infectious risks from IBD medications 2. To understand vaccination recommendations 3. To learn about preventable non-infectious risks from IBD medications Slide 3 Complications of IBD Medical Therapy IBD patients on immunosuppressive monotherapy have OR 2.9 for infection; combination therapy OR = 14.5 Preventable Infections TB reactivation Hepatitis B reactivation Pneumoccocal infection Influenza Chickenpox, shingles Infections that may not be preventable Preventable cancers Skin cancers

2 Slide 4 Influenza Vaccine Types: Trivalent inactivated vaccine: Two common Type A strains H1N1 & H3N2 and one type B strain Quadrivalent inactivated vaccines: one additional type B strain Fluzone Quadrivalent, Fluarix Quadrivalent, FluLaval Quadrivalent Not studied in immunocompromised patients Live, attenuated intranasal vaccine, quadrivalent: FluMist Quadrivalent For pts aged 2-49, not pregnant or on immunosuppression Slide 5 Influenza Vaccine Benefit: Milanovic et al. Tohoku J Exp Med 2013;229:29-34 Vaccinated patients with SLE, RA, and Sjogren s had lower rate of influenza infection and/or total viral infections Negative correlation between vaccination & onset of influenza, severe forms of influenza, total viral infections, bacterial complications Slide 6 Influenza Vaccine Efficacy in IBD Lu Y et al. Am J Gastroenterol 2009; 104(2): consecutive children with IBD Vaccination response similar regardless of IM status Subanalysis revealed impaired seroprotection against strain B in those on anti-tnf agents debruyn et al. Inflamm Bowel Dis 2012; 18(1): children with IBD and 53 sibling healthy controls 98% tolerated the vaccine In children with IBD: Serologic protection 95%, 98%, and 85% to H3N2, H1N1, and influenza B components, respectively, compared to 96%, 98%, 94% in controls Those on IM less likely to achieve serologic protection to influenza B than those not on IM (79% versus 100%, P = 0.02)

3 Slide 7 Influenza Vaccine Efficacy in IBD debruyn et al. Inflamm Bowel Dis 2012; 18(1):25-33 Slide 8 Influenza Vaccine Efficacy in IBD H1N1 influenza vaccine: Cullen G. et al. Gut 2012; 61(3): Seroprotection: immunosuppressed (44%) vs. no immunosuppression (64%), p=0.06 Combination therapy (36%) vs. no immunosuppression (64%) p=0.02 Combined immunosuppression lower fold increase in geometric mean titers than monotherapy (3.5 vs 11.5, p=0.03) Slide 9 Influenza Vaccine Efficacy in IBD Cullen G. et al. Gut 2012; 61(3):

4 Slide 10 Influenza Vaccine Safety No large studies in IBD Small pediatric studies (e.g. Mamula P et al. Clin Gastroenterol Hepatol 2007) have shown no increased risk of flares and no serious adverse events RA: 2 studies (Milanovic et al. Tohoku J Exp Med 2013; 229:29-34 and Mori et al. Ann Rheum Dis 2013; 72:1362-8) demonstrating no increase in flares Adler et al. Rheum 2012;51: demonstrated mild & easily controlled flare of rheumatologic conditions in 8 patients during first 2 months after vaccination Slide 11 Pneumococcal Infections Invasive pneumococcal disease Pneumonia, bacteremia, meningitis Disease rates for at risk adults can be > 20x normal (CDC, unpublished data, 2011) >90 serotypes of pneumococcus 50% cases among immunocompromised adults in 2010 were caused by serotypes contained in PCV13 21% were caused by serotypes contained only in PPSV23 (CDC, unpublished data, 2011) Slide 12 Pneumococcal Vaccines PCV13: tridecavalent vaccine available since 2010 Contains antigens from 13 serotypes of pneumococcus: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F These strains cause most severe infections in children and half of those in adults Vaccine is almost 100% effective against these strains PPSV23: Protects against 23 strains Contains antigens to 12 of the 13 serotypes in PCV additional serotypes Those on immunosuppressive medications may not respond Protection occurs within 2-3 weeks

5 Slide 13 Pneumococcal Vaccines 2012 Recommendations from US Advisory Committees on Immunization Practices: Adults 65yrs One dose of PPSV23 Adults 19-64yrs with certain medical conditions or in immunosuppressed state: One doses of PPSV23 Revaccinate in 5 yrs Adults 19yrs with certain medical conditions or in immunosuppressed state, etc: One dose of PCV13 If recommending both PPSV23 & PCV13 vaccines: PCV13 vaccine first, followed by PPSV23 8 weeks later If PPSV23 already, then PCV13 1yr later Slide 14 Pneumococcal Vaccine Efficacy Dotan et al. Inflamm Bowel Dis 2012; 18(2): patients on 6-MP at 1.05±0.3 mg/kg/day Same response to PPSV23 when immunized before 6-MP Kaine et al. J Rheumatol 2007;34(2):272-9 RA patients enrolled in RCT Adalimumab vs. placebo at d1, 15, 29 PPSV23 and influenza vaccines at d8 Similar response rates & protective antibodies to PPSV23 & influenza vaccines Salinase et al. Ann Rheum Dis 2013;72(6): Modest reduction in response to PPSV23 with anti-tnf Slide 15 Pneumococcal Vaccine Efficacy Melmed et al. Am J Gastroenterol 2010;105: IBD patients on combination therapy vs. 25 IBD patients on no IM vs. 19 healthy controls Post-vaccination titers significantly suppressed in IBD patients on combination therapy No difference between IBD pts not on IM and controls

6 Slide 16 Pneumococcal Vaccine Efficacy Patients meeting geometric mean titer 1ug/100ml by serotype Patients meeting geometric mean titer 1ug/100ml and 2x increase from baseline in 3 serotypes Melmed et. al. Am J Gastroenterol. 2010;105: Slide 17 Hepatitis B Reactivation and Chemotherapy Reactivation during or after chemotherapy Mortality rate 5-40% with reactivation in chronic carriers Reactivation even with resolved ( occult ) infection (HBsAg - HBsAb + and/or HBcAb + ) Wands et al. Gastroenterol 1975; 68: /17 had markedly reduced HBsAb titer 30% had seroconversion : HBsAb + - and HBsAg - + For HSCT, 14-50% with seroconversion HBsAb + - Case reports of fatality with rituximab despite lamivudine reviewed in Yeo and Johnson. Hepatology 2006; 43: Slide 18 Hepatitis B Reactivation and Rheumatology Chung et al. J Rheumatol 2009; 36(11): out of 6 inactive hep B carriers (HBsAg+) with normal LFT s, undetectable viral load AST 457, ALT 1057, +hep B DNA after 3 rd infliximab infusion Normal LFT s & undetectable viral load after entecavir Montiel et al. Liver Int 2008; 28(5): Reactivation of latent infection with etanercept for amyloidosis

7 Slide 19 Hepatitis B Reactivation and IBD Esteve et al. Gut 2004; 53(9): Prospectively followed 80 CD pts in Spain 3 with HBsAg - cab + : no change 3 with chronic hep B infection 2 had severe reactivation after infliximab withdrawal 1 died 1 had concomitant lamivudine no change Madonia et al. Inflam Bowel Dis 2007; 13(4): Pt had 5 infusions of infliximab in for active CD Flare, HBsAg - in 2004 infliximab + steroids ALT/AST 10-12x ULN HBsAg +, anti-hbe +, anti-hbc IgM + and HBV DNA +, HbeAg - Lamivudine + infliximab cessation LFT s normal in 1 month HBV DNA - with conversion to HBsAb + Slide 20 Hepatitis B Status Check Upon first evaluation, esp before starting anti-tnf: Check HB sag, sab, cab If no immunity, offer Hep B vaccine Slide 21 Hepatitis B Vaccination: CDC Recommendations for Individuals At risk for infection by sexual exposure Sex partners of hepatitis B sag+ persons Sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., persons with more than one sex partner during the previous 6 months) Persons seeking evaluation or treatment for a sexually transmitted disease Men who have sex with men At risk for infection by percutaneous or mucosal exposure to blood Current or recent injection-drug users Household contacts of HBsAg+ persons Residents and staff of facilities for developmentally disabled persons Health-care and public safety workers with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids Persons with end-stage renal disease, including predialysis, hemodialysis, peritoneal dialysis, and home dialysis patients Others International travelers to regions with high or intermediate levels (HBsAg prevalence of >2%) of endemic HBV infection Persons with chronic liver disease Persons with HIV infection All other persons seeking protection from HBV infection

8 Slide 22 Hepatitis B Vaccination Efficacy Definition of successful vaccination controversial According to WHO, [anti-hbs] >10 IU/l at 1 3 months post vaccination = reliable marker of protection against infection Titer wanes over time UK: definition changed to [anti-hbs] >100 IU/l Altunoz ME et al. Dig Dis Sci 2012; 57: patients with IBD vs 52 healthy controls IBD patients had lower response Risk factors for lower response: Active disease Use of immunosuppressive agents Slide 23 Response to Hepatitis B Vaccination Altunoz ME et al. Dig Dis Sci. 2012; 57: AIR: adequate immune response EIR: effective immune response Slide 24 Hepatitis B Vaccination Efficacy Gisbert JP et al. Am J Gastroenterol 2012; 107: IBD patients vaccinated at 0, 1, 2 months with double dose [Anti-HBs] was >10 IU/l in 59% and >100 IU/l in 39% Response rate (anti-hbs >10 IU/l) lower among patients on anti- TNF therapy: 46% vs. 62% No difference with immunomodulators Response rate (anti-hbs >100 IU/l) after revaccination was 42%. Indicators of poor response to Hep B vaccination: age & anti-tnf use

9 Seroconversion rate (%) Slide 25 Hepatitis B Vaccination Efficacy Gisbert JP et al. Am J Gastroenterol. 2012; 107: Slide 26 Hepatitis B Vaccination Efficacy Seroconversion rate (%) overall without anti-tnf with anti-tnf 70 * anti-hbs > 10 IU/l anti-hbs > 100 IU/l Gisbert JP et al. Am J Gastroenterol. 2012; 107: Slide 27 Response to Hepatitis B Vaccination Gisbert JP et al. Am J Gastroenterol. 2012; 107:1460-6

10 Slide 28 Hepatitis B Status Check and Vaccination Upon first evaluation, esp before starting anti-tnfa: Check HB sag, sab, cab If no immunity, may offer Hep B vaccine May need accelerated schedule Months 0, 1, 2 (usually 6) May need higher dose Double dose (usually single dose) Checking antibody titer 1-3 months after last dose Controversial whether response is titer 10 or 100 IU/l If no response, consider revaccination Slide 29 Hepatitis B Status During Treatment For those with prior infection (HBsAg - HBcAb + ): Follow LFT s carefully Consider checking Hep B DNA intermittently If LFT s become abnormal with immunosuppression: Check for reactivation with HBsAg, HBsAb, HBcAb, Hep B DNA For known hep B carriers: Concurrent lamuvidine, entecavir, or tenofovir Follow LFT s and Hep B DNA carefully Slide 30 Human Papilloma Virus (HPV) Vaccine Women with IBD have higher rate of abnormal Pap smears than healthy controls (Kane et al. Am J Gastroenterol 2008;103(3):631-6) Women with past or current use of immunosuppression more likely to have an abnormal Pap smear (P < 0.001) Pap smears done with > 6 months exposure to an immunosuppressant increased risk for abnormality (OR 1.5, , p = 0.021) Vaccine targets the 4 HPV serotypes (6, 11, 16, and 18) associated with highest risk of progression to cervical dysplasia & cancer

11 Slide 31 Human Papilloma Virus (HPV) Vaccine CDC recommends vaccines for: Girls & boys at age yrs Men can get oropharyngeal, penile, and anal cancers If not yet, females 26 yrs Studies have shown decreasing benefit after 21yrs If not yet, males 21yrs Males 21-26yo may be vaccinated Vaccine also recommended for any man who has sex with men Vaccine not licensed for adults >26yo Efficacy unknown for adults >26yo Men and women with compromised immune systems 26 yrs Slide 32 HPV Vaccine: Safety Mok et al. Ann Rheum Dis 2013; 72(5): No increase in flare rate of SLE compared to non-vaccinated controls Injection site reaction most common Response rates to serotypes 6, 11, 16, 18: SLE: 82%, 89%, 95%, 76% Healthy Controls: 98%, 98%, 98%, 80% Soldevilla et al. Lupus 2012; 21: with SLE flares but 2 pts were 45yrs Slide 33 HPV Vaccine: Efficacy Jacobson et al. Inflamm Bowel Dis 2013;19(7): females 9-26yo with IBD using immunosuppressive Rx 51% on anti-tnf, 49% on immunomodulator Compared to 15 females previously vaccinated Safe Seropositivity responses: Recently vaccinated: 100% for types 6, 11 and 16 96% for type 18 Previously vaccinated: 100% for types 6, 11, and 16 40% for type 18

12 Slide 34 Varicella Zoster Incidence of HZ in adults 50yo: 7 cases/1,000 person-years Dissemination seen in up to 30% of immunocompromised pts Incidence of zoster higher in IBD patients (Gupta G et al. Clin Gastroenterol Hepatol 2006;4: ) Zoster vaccine recommended for all immunocompetent adults 60yo Has 10x the titers of varicella vaccine Vaccine may be offered for pts 50-59yo Administration of the vaccine is not recommended in patients on immunosuppressive medication; however, Lu Y and Bousvaros A. J Pediatr Gastroenterol Nutr. 2010;50(5):562-5: case series of 6 pediatric IBD patients on immunosuppressive therapy safely vaccinated against varicella with good response Slide 35 Varicella Zoster Vaccine: Safety & Efficacy Zhang J et al. JAMA 2012 Jul 4;308(1):43-9 Restrospective study on 463,541 Medicare patients with immunemediated disease (including IBD) Median followup = 2 years Use of concomitant steroids increased risk of HZ in unvaccinated patients 2x Among 551 pts on anti-tnf, no case of varicella or HZ occurred within 42 days of vaccination Of all patients, only 1 case of varicella within 42 days of vaccination (day 10 after vaccination) Pt not on any immunosuppressive therapy Adjusted hazard ratio of varicella > 42 days post-vaccination=0.61 In all subgroups of patients on different medications Slide 36 Current Recommendations for Live Viral Vaccines in Immunosuppressed Patients Avoidance of live viral vaccines MMR, varicella vaccine, HZ vaccine Within 6-12 weeks of initiating any immunosuppressive therapy Vaccines not contraindicated for household contacts Avoid exposure to any potential rash

13 Slide 37 Tetanus Vaccination Vaccine recommended as part of the childhood DTaP series Booster Td is recommended every 10 years after primary vaccination Tdap given ASAP, if not previously, for health-care workers + those with contact with infants, even if Td<10 yrs ago Efficacy: Dotan et al. Inflam Bowel Dis 2012; 18(2):261-8 No difference in response after initiation of thiopurines when immunized before thiopurine Brogan et al. J Clin Lab Immunol Oct;24(2):69-74 IBD patients less likely to have increased serum anti-tetanus and antidiptheria antibody titers post booster Effect of anti-tnf therapy on vaccine efficacy is unknown Slide 38 TB Reactivation 4-20x fold increased susceptibility to TB with anti-tnf blockers TNFa required for inflammatory cell trafficking and granuloma formation Slide 39 Latent TB: Type of Test PPD Cutoff for positive different in immunocompromised Interferon-g releasing assays: in vitro culture of patient s blood with M. tuberculosis complex specific antigen QuantiFERON-Gold: measures amount of IFN-g released upon antigen stimulation by ELISA T spot: measures the proportion of immune cells releasing IFN-g upon antigen stimulation by ELISPOT Advantages of Interferon-g releasing assays: More specific, not affected by BCG Specificity = % vs 55-95% for PPD NPV 0.88

14 Slide 40 Skin Test Criteria for Positivity Gardam et al. Lancet Infect Dis 2003; 3: Slide 41 Latent TB Prophylaxis with anti-tnf Prophylactic regimen: Isoniazid 300mg/day x9 months rifampin 600 mg/day x4 months Isoniazid 900mg + rifapentine 900mg weekly x12 weeks during observed therapy Short-course therapy with rifampin plus pyrazinamide: too high risk for hepatoxicity Duration of prophylaxis before anti-tnf initiation not well established 1-2 months 41 Slide 42 Skin Cancer: Melanoma Peyrin-Biroulet L, et al. Am J Gastroenterol 2012; 107: No increased risk in IBD patients in general: SIR 0.64 ( ) Thiopurine use: no increased risk of melanoma Anti-TNF use: no increased risk of melanoma SIR with any immunosuppressive therapy: 0.64 ( ) Long et al. Gastroenterol 2012; 143: Increased incidence of melanoma in IBD (IRR, 1.29; 95% confidence interval [CI], Therapy with biologics increased the risk of melanoma (odds ratio [OR], 1.88; 95% CI, )

15 Slide 43 Skin Cancer: Non-Melanoma Skin Cancers Long et al. Gastroenterol 2012; 143: Incidence rate of NMSC increased among patients with IBD (IRR, 1.46; 95% CI, ) Patients who had been treated with thiopurines had an increased risk of NMSC (OR, 1.85; 95% CI, ) Peyrin-Biroulet L, et al. Gastroenterol 2011; 141: (CESAME cohort) Thiopurines associated with increased risk of non-melanoma skin cancers Even with past use Slide 44 Skin Cancer: Thiopurines and NMSC Thiopurine HR 95% CI p Never Discontinued Continuing Peyrin-Biroulet L et al. Gastroenterol 2011;141: Slide 45 Skin Cancer: anti-tnf and NMSC RA IBD Long et al. Gastroenterol 2012; 143: Amari et al. Rheum 2011; 50:

16 Slide 46 Take Home Messages Review vaccination history and infectious risk at initial visit Vaccination and infection history: Chicken pox?; if no, check titers; vaccinate if no immunosuppression within 12 weeks If MMR hx not clear and born after 1956, check titer to all 3; vaccinate if no immunosuppression within 6 weeks Check hepatitis B sag, sab, cab; if not immune, offer vaccination Consider double dose Consider accelerated regimen (0, 1, 2 months) Revaccinate if no response Check for latent TB Either by PPD, T spot, or QuantiFERON-Gold Recommend HPV vaccine to all 26yo Recommend influenza vaccine Inactivated trivalent or quadrivalent Recommend PPSV23 (preceded by PCV13 by 8 weeks if <65yo) Recommend Td booster Slide 47 Take Home Messages Hep B, influenza, HPV, tetanus vaccines appear safe Avoid live attenuated viral vaccines if on immunosuppression: MMR, varicella, herpes zoster Seroprotection rate Against influenza type B and hep B lower in patients on immunosuppression/anti-tnf Against PPSV23 and influenza H1N1 vaccine lower in patients on combination Rx Skin cancer: recommend Annual dermatologic surveillance Skin protection Slide 48 Current Recommendations for Live Viral Vaccines in Immunosuppressed Patients Wasan et al. Am J Gastroenterol. 2010;

17 Slide 49 Take Home Messages Wasan et al. Am J Gastroenterol 2010; Slide 50 Varicella Zoster Vaccine: Efficacy Zhang J et al. JAMA 2012 Jul 4;308(1):43-9 Slide 51 Varicella Zoster Zhang J et al. JAMA 2012 Jul 4;308(1):43-9

18 Slide 52 HPV Vaccine: Efficacy Jacobson et al. Inflamm Bowel Dis 2013;19(7): Slide 53 Skin Cancer: Thiopurines and anti-tnf and Melanoma Thiopurine SIR 95% CI Never Discontinued Continuing Anti-TNF SIR 95% CI Never Discontinued Continuing Peyrin-Biroulet L et al. Am J Gastroenterol 2012;107:1443-3