Prevention of Complications from IBD Therapies

Transcription

1 Prevention of Complications from IBD Therapies July 23, 2011 Millie D. Long MD, MPH Inflammatory Bowel Diseases Center University of North Carolina-Chapel Hill Outline: Complications of IBD Therapies Osteoporosis Malignancy Cervical cancer / dysplasia Non-melanoma skin cancer Infections TB Zoster Influenza Pneumonia 1

2 Outline: Complications of IBD Therapies Osteoporosis Malignancy Cervical cancer / dysplasia Non-melanoma skin cancer Infections TB Zoster Influenza Pneumonia Osteoporosis 2

3 Osteoporosis Associated with bone fragility and fractures Fractures of the hip and spine are associated with significant morbidity including hospitalizations, major surgery and even death Risk Factors in general population Female, thin frame, postmenopausal Family history Smoking and alcohol use Corticosteroid use National Osteoporosis Foundation Osteoporosis Associated with bone fragility and fractures Fractures of the hip and spine are associated with significant morbidity including hospitalizations, major surgery and even death Risk Factors in general population Female, thin frame, postmenopausal Family history Smoking and alcohol use Corticosteroid use National Osteoporosis Foundation 3

4 Osteoporosis in IBD Prevalence of osteoporosis in IBD is 15% Strongly affected by age No gender predilection Risk factors Corticosteroid use is the variable most strongly associated with osteoporosis Risk of fractures Relative risk of fractures is 40% greater than that of the general population Increases with age Gastro 2003;124: Corticosteroid Use Prevalence at tertiary-care GI clinic: 12.9% Long MD, et al. Dig Dis Sci; 2010 Aug;55(8):

5 US Guidelines: Prevention and Management All patients should receive education on the importance of lifestyle changes Weight bearing exercise Quitting smoking Preventive measures should be used for anyone on >5 mg prednisone/day for three months DEXA scan for those initiating corticosteroids Calcium (1500 mg) /Vitamin D (800 IU) and bisphosphonates h as needed d for treatmentt t Corticosteroid dosing in IBD should be kept to a minimum Gastro 2003;124: Adler RA, Hochberg MC. Arch Int Med Nov 24;163(21): American College of Rheumatology UK Guidelines: Prevention and Management Lifestyle (exercise, diet, quit smoking, ETOH in moderation) Calcium and Vitamin D, particularly when on steroids Steroid sparing therapy (6mp/AZA, biologic) If age >65 bisphosponates at start of steroids If age <65 and high risk w/ >3 months steroids, DEXA and consider bisphosphonate if T score <1.5 DEXA if active IBD, weight loss >10%, BMI <20, Age >70 If osteoporosis / fragility fracture Oral bisphosphonate first line Check blood testosterone for men, replace if low Lewis NR, et al. British Society of Gastro Guidelines 2007:

6 Bisphosphonates in young women In animal studies bisphosphonates cross the placenta Accumulate in the fetal skeleton Decrease fetal weight Reduce bone growth Can result in protracted deliveries and neonatal deaths In humans, approximately half of the absorbed dose of alendronate is bound to bone, from which the drug is released with an elimination half life of over 10 years It is possible that alendronate stored in the bone will be mobilized during pregnancy and taken up by fetal bones McKenna M, et al. Aliment Pharmacol Ther 29, Bisphosphonates in young women Case series of 51 cases of exposure to bisphosphonates before or during pregnancy; none with any skeletal abnormality or other congenital abnormality in the infants Separate small (n=10) case series from Italy showed 20% anomalies among pregnant women with BP exposure Long term consequences remain unclear, caution should be used in fertile women McKenna M, et al. Aliment Pharmacol Ther 29, Losada I, et al. Autoimmun Rev 2010 Jun;9(8):

7 Malignancy Relative Risk of Malignancy: CD Kappelman MD, et al. Abstract 180. Gastro, DDW

8 Relative Risk of Malignancy: UC Kappelman MD, et al. Abstract 180. Gastro, DDW Cervical Cancer 8

9 Cervical Cancer In 2010 it is estimated that there were 12,200 new cases of cervical cancer, with 4200 deaths in the United States Largely preventable disease via screening: Pap smear It is estimated that 50% of women who receive diagnoses of cervical cancer have never been screened SEER Statistics, available at: ACOG practice bulletin: clinical management guidelines no. 44, July 2003 Cervical Dysplasia in IBD Studies have shown a higher incidence of abnormal Pap smear in women with IBD compared to healthy controls 42.5% in IBD vs 7% of controls, p= Increased risk associated with immunosuppression (OR 1.5, , p= 0.021) A population-based study from Canada with no increased risk of abnormal Pap in IBD There was increased risk in patients on a combination of corticosteroids and immunosuppressants Kane S, et al. Am J Gastroenterol 2008; 103: Singh H, et al. Gastro 2009; 136:

10 Cervical Testing in IBD Large US study of administrative claims data assessing cervical testing in women with IBD Patients with IBD have suboptimal rates of cervical testing Factors associated with reduced rates of cervical testing include: Lack of PCP Immunosuppression Lower socioeconomic status Long MD, et al. Clin Gastroenterol Hepatol Jun; 7 (6): Cervical Testing in IBD Proportion of women with IBD who obtain Pap smear over 36 month interval* Long MD, et al. Clin Gastroenterol Hepatol Jun; 7 (6):

11 Prevention of Cervical Dysplasia: Screening ACOG 2010 Guidelines Women should have their first screening Pap smear at age 21 Women in their 20 s should have a Pap smear every two years (assuming prior Pap smears have been normal) Women age 30 and older who have had three consecutive normal Pap smears should have a Pap smear every three years Prevention of Cervical Dysplasia: Screening ACOG 2010 Guidelines, continued Women who have had a hysterectomy for noncancerous reasons do not need a Pap smear unless they have a cervix These guidelines need to be followed regardless of whether a woman has had the HPV vaccine 11

12 Prevention: HPV Vaccine Inactive IM vaccine 3 dose series, at time 0,2,6 months Recommended age is females age years Catch-up vaccination is recommended for females aged years who have not been previously vaccinated Vaccinated females should have cervical cancer screening as recommended MMWR. Recommendation statement. Prevention: HPV Vaccine in IBD Open label study assessing the response to HPV vaccination in women with IBD on immunosuppression Total of 34 women with IBD age 9-26 Patients with IBD on immunomodulators or anti- TNF medications have a similar appropriate response to vaccination when compared to a cohort of healthy controls Lu Y, et al. Gastro: 140; 5, Suppl 1, S-158-S

13 Skin Cancer Skin Cancer (non-melanoma) 1 in 5 Americans develops skin cancer, which accounts for 1/3 of all cancers in the US Categorized into squamous and basal cell carcinoma Environmental risk factors for NMSC Ultraviolet light Chemical exposures Host risk factors Human papilloma virus Genetic susceptibilities Immunosuppression Robinson JK. JAMA 2005; 294: Leiter U, Garbe C. Adv Exp Med Biol 2008;624:

14 Incidence of Skin Cancer in IBD Those IRR with IBD 95% are CI >60% more likely IBD CD UC versus to develop controls skin cancer cer,000 nual Skin Canc dence per 100, Ann Incid CD UC IBD Control CD or UC Long MD, et al. Clin Gastro Hepatol. 2010;8: Risks of Immunosuppression in IBD Recent ( 90 days) and persistent ( 365 days) medication use and skin cancer in patients with CD or UC* Crohn s disease Ulcerative Colitis Recent (n=1935) Persistent (n=1141) Recent (n=1775) Persistent (n=1123) Thiopurine class OR 3.87 ( ) OR 4.25 ( ) OR 3.09 ( ) OR 4.34 ( ) Methotrexate OR 1.58 OR 2.69 N/A N/A ( ) ( ) Any biologic OR 2.07 ( ) OR 2.18 ( ) N/A N/A *Adjusted for other classes of medications and Medicaid insurance Long MD, et al. Clin Gastro Hepatol. 2010;8:

15 Combined Immunosuppression in CD Association of Combined Persistent Immunosuppressive Medication Use and Skin Cancer Cases Controls OR (95% CI) p value n=228 n=913 None 154 (68%) 817 (89%) 1.0 (reference) Any immunomodulator 56 (25%) 73 (8%) 4.45 ( ) <0.01 Any biologic 7 (3%) 13 (1%) 3.23 ( ) 0.02 Combined 11 (5%) 10 (1%) 6.75 ( ) <0.01 Long MD, et al. Clin Gastro Hepatol. 2010;8: Thiopurines and IBD Prospective observational cohort study (CESAME) of patients with IBD Comparison cohort of general population Linkage to French cancer registries for outcome Ongoing thiopurine use HR 5.9; 95% CI Past thiopurine exposure HR 3.9; 95% CI Peyrin-Biroulet L, et al; CESAME study group. Gastroenterology Jun

16 Skin Cancer Prevention in IBD Primary prevention via sun avoidance, sun protection or minimization of modifiable risk factors for skin cancer Sun protective clothing with a UPF of 30 Broad-spectrum sunscreens (UVA and UVB) with a SPF of 30 or greater Reapplication of sunscreen every 2 hours Long MD, et al. Inflamm Bowel Dis Jun;17(6): Skin Cancer Prevention in IBD Secondary prevention No current recommendation for annual skin examination in IBD (or in the general population) Annual skin examinations are recommended in posttransplant patients on immunosuppression Any skin lesion suspicious for malignancy in a patient with IBD on immunosuppression should be evaluated by a trained dermatologist Long MD, et al. Inflamm Bowel Dis Jun;17(6):

17 Infections: TB Tuberculosis Globally 9 million with active M. tuberculosis (TB) each year 2 billion are thought to be latently infected (LTBI) with TB People with LTBI have increased risk for TB Approximately 11 million U.S. residents (4.2% of the U.S. population aged >1 year) have LTBI Rates of LTBI and active TB vary based on the presence of risk factors U.S. residents with no risk factors are considered to be at low risk with a prevalence of infection of 1%. Mazurek M, et al. MMWR Recomm Rep 2010; (59) World Health Organization Report 2009, available online. 17

18 Risk Factors for TB Close contacts of persons with active TB Foreign-born persons or visitors of endemic areas Residents of congregate settings Correctional facilities, long-term care facilities, and homeless shelters Health-care workers Populations with increased incidence Low income, ETOH/drug abuse, children exposed to adults with increased risk, etc CDC Updated Guidelines. MMWR 2010; 59(No. RR-5);1-25. Reactivation with anti-tnf therapy Risk of serious infection is doubled with anti-tnf Risk is 95/ 100,000 person-years for active TB Much higher than risk of other opportunistic infections Effective screening tools for LTBI are available, specificity may limited with immunosuppression. TST or interferon gamma release assay (IGRA) IGRA may be more specific w/ BCG vaccination Treatment of LTBI prior to initiation of anti-tnf decreases the incidence of active TB by > 80% Bongartz T, et al. JAMA 2006; 295: Dixon WG,et al. Ann Rheum Dis 2010; 69: Zabana Y, et al. Inflamm Bowel Dis 2008; 14: Menzles D, et al. Ann Intern Med 2007; 146:

19 Prevention: TB Test for latent TB prior to initiation of anti-tnf Mechanisms in US can include TST, IGRA, CXR In UK: clinical H&P, CXR and TST if approp If positive test for latent TB Per UK guidelines, chemoprophylaxis should be complete prior to anti-tnf initiation if possible In US, anti-tnf can be initiated after 1 month of chemoprophylaxis, total of 9 months of INH Once on anti-tnf, BTS recommends q 3 month CXR If active TB, 6 mos therapy, anti-tnf after 2 mos British Thoracic Society Guidelines. Thorax 2005;60: Infections: Herpes Zoster 19

20 Herpes Zoster Herpes zoster (HZ) is caused by reactivation of latent varicella zoster virus (VZV) There are an estimated 1 million cases of HZ annually, this incidence is increasing In the US, lifetime risk approaching 1 in 3 About 10% 18% of persons with HZ develop post-herpetic neuralgia (PHN), a disabling pain syndrome that can last months or even years with no consistently effective treatments Leung J, et al. Clin Infect Dis Feb;52(3): Herpes Zoster in IBD Incidence of zoster is higher in patients with CD and UC compared with matched controls UC incidence id rate ratio, 1.21; 95% CI CD incidence rate ratio, 1.61; 95% CI, Medications associated with zoster Corticosteroids (adjusted OR 1.5; 95% CI, ) Azathioprine/6-mp (adjusted OR 3.1; 95% CI, ) Study based in Great Britain, prior to introduction of anti-tnf agents Gupta et al. Clin Gastroenterol Hepatol Dec;4(12):

21 Prevention of Zoster Vaccine Single SC dose Live vaccine Age >60 years Not indicated: to treat acute zoster, to prevent persons with acute zoster from developing PHN, to treat ongoing PHN, or with immunosuppression Prophylaxis in those with development of zoster on anti-tnf therapy Consider suppressive antiviral therapy, no data as to optimal duration or dosing MMWR. Recommendation statement. Infections: Influenza 21

22 Influenza Rates of infection are highest among children Rates of serious illness and death are highest Among persons age >65 Those with chronic medical conditions (such as IBD) Pregnant women MMWR. Recommendation statement. Prevention of Influenza: Vaccine Currently 2 options, inactivated vaccine or live, attenuated vaccine Live vaccine contraindicated t d with immunosuppressioni Patients with IBD on immunosuppression respond appropriately to influenza vaccine No evidence of flares associated with vaccination MMWR. Recommendation statement. Dotan I, et al. Inflamm Bowel Dis Mar 15. Lu, Y. Am J Gastro Feb;104(2):

23 Infections: Pneumonia Pneumonia Community acquired pneumonia (CAP) is the most common infectious cause of death Hospitalization rates for CAP have increased, as have comorbidities among these patients Treatment costs of CAP were estimated at $12.2 billion during the late 1990s, with additional costs in lost productivity Overall mortality among those hospitalized for pneumonia in 2005 was 4.7% Ruhnke et al. Medical Care: 48; 12, Dec 2010:

24 Pneumonia in IBD In trials of various medications used to treat IBD, one of the most common complications is bacterial pneumonia In mortality studies of IBD patients, infectious complications are among the most common causes of death in patients with IBD In RA, increased risk of mortality from pneumonia Prednisone use increased the risk of pneumonia hospitalization (hazard ratio [HR] 1.7 [95% CI ]) Pneumonia among most common complications in patients treated with anti-tnf Little is known about the specific incidence of pneumonia in IBD, although it is thought to be increased Furst DE, et al. Semin Arthritis Rheum Wolfe F, et al. Arthritis Rheum 2006;54: Prevention of Pneumonia: Vaccine Vaccination does not prevent pneumonia, but rather prevents invasive pneumococcal disease Bacteremia, meningitis iti Risk for IPD is greatest among persons who have congenital or acquired immunodeficiency, abnormal innate immune response, HIV or asplenia Vaccine given IM x 1 Consider repeat dose at least 5 years after initial dose MMWR. Recommendation statement. 24

25 Pneumococcal Vaccination in IBD In one academic IBD clinic, the prevalence of pneumococcal vaccination was 9% (13/169) Immunogenicity to pneumococcal vaccine in IBD patients IBD patients on no immunosuppression were similar to controls IBD patients on combination immunosuppression (anti-tnf and immunomodulator) mounted a lower immune response Melmed GY, et al. Am J Gastroenterol 2006; 101: Melmed GY, et al. Gastroenterology. 2008; 134: Abstract S1 A68 Prevention: Immunizations 25

26 Immunization Guidelines in IBD* Standard recommended immunization scheduled for adults should be adhered to At diagnosis, all adults should have review of immunization history, with catch up vaccination given as needed Live vaccines should be avoided in patients on immunosuppression Sands BE, et al. Inflamm Bowel Dis (10) 5, *Prior to several newly licensed vaccines Immunization Guidelines in IBD Patients with chronic immunologic illnesses seem to respond well to vaccines Patients do not experience worsened disease activity as a result of immunization Killed or inactivated vaccines do NOT present a risk of infection to patients on immunomodulators or biologics Sands BE, et al. Inflamm Bowel Dis (10) 5, *Prior to several newly licensed vaccines 26

27 Live Vaccines: Contraindicated with Immunosuppression Anthrax vaccine Intranasal influenza Measles-Mumps-Rubella M ll (MMR) Polio live oral vaccine (OPV) Smallpox vaccine Tuberculosis BCG vaccine Typhoid live oral vaccine Varicella Zoster Yellow fever Melmed GY. Inflamm Bowel Dis. 15 (9), 2009 Live Vaccines: Contraindicated with Immunosuppression Anthrax vaccine Intranasal influenza Measles-Mumps-Rubella M ll (MMR) Polio live oral vaccine (OPV) Smallpox vaccine Tuberculosis BCG vaccine Typhoid live oral vaccine Varicella Zoster Yellow fever Melmed GY. Inflamm Bowel Dis. 15 (9),

28 Summary: Immunization in IBD Recommend Special Considerations Immunization review to HPV vaccine determine catch-up For women up to age 26 vaccinations needed without prior vaccination Influenza vaccine Varicella vaccine Pneumococcal vaccine Prior to immunosuppression Standard age appropriate Zoster vaccine adult immunizations >60 years old Prior to immunosuppression Hepatitis A and B vaccine If not already given Summary Recommendations 28

29 Summary: Prevention in IBD Prevention of osteoporosis Calcium (1500 mg) and Vitamin D (800 IU) replacement Possible role of bisphosphonates DEXA when >3 month history of corticosteroids Prevention of cervical dysplasia Pap smears at recommended intervals by ACOG Co-management with a primary care physician HPV vaccination Summary: Prevention in IBD Prevention of non-melanoma skin cancer Known increased risk, particularly on combined immunosuppression Patient and physician awareness Sun protective clothing, broad spectrum sunscreen Avoid tanning beds Referral to dermatologist for suspicious skin lesions Prevention of infections TST or IGRA +/- CXR prior to anti-tnf medications Appropriate vaccinations, preferably prior to immunosuppression Avoid live vaccines with immunosuppression 29

30 Questions? 30