IBD Medical Treatments 2018

Transcription

1 Specialty Medicine with Commitment, Care and Compassion IBD Medical Treatments 2018 Swapna B. Reddy, M.D. TOC GI South October 6, /10/2018 CCF Best Practices in IBD Management 1

2 Goals of Treatment Patient feels better Achieving clinical remission Improving outcomes Prevent further flare ups Prevent need for surgeries due to IBD complications 10/10/2018 CCF Best Practices in IBD Management 2

3 How do we treat patients Individualize treatment based on disease severity, phenotype, possibly genotype in the future, response to treatment and achievement of goals Patient's return to normal, functional bowel habits, eating, lack of abdominal pain Drug level testing to help guide dosing or treatment plan 10/10/2018 CCF Best Practices in IBD Management 3

4 Agenda Brief Review of Pathogenesis of IBD Local Anti-inflammatory therapy Complementary therapy Steroids/Immunomodulator Agents Biologic Agents 10/10/2018 CCF Best Practices in IBD Management 4

5 Specialty Medicine with Commitment, Care and Compassion Pathogenesis 10/10/2018 CCF Best Practices in IBD Management 5

6 IBD: Multi-factorial Genetic Environmental Diet Immunologic Microbial 10/10/2018 6

7 Specialty Medicine with Commitment, Care and Compassion Local Anti-inflammatory Therapy 10/10/2018 CCF Best Practices in IBD Management 7

8 Local Anti-inflammatory Therapy Aminosalicylates Antibiotics 10/10/2018 8

9 Aminosalicylates Contain 5-aminosalicyclic acid (5-ASA) Sulfasalazine 5-ASA bonded to sulfapyridine Mesalamine 5-ASA Asacol, Delzicol Pentasa Apriso Lialda Rowasa enema, Canasa suppository Balsalazide Olsalazine Baseline BMP, UA and 3-6 months after starting treatment repeat and may consider repeating thereafter annually 10/10/2018 9

10 Aminosalicylates: Possible AEs Sulfasalazine DRESS (drug reaction with eosinophilia, systemic symptoms) Rash GI upset; nausea, dyspepsia Reversible oligospermia Leukopenia, thrombocytopenia, hemolytic anemia Abnormal LFTs Mesalamine GI upset; nausea, dyspepsia Stevens-Johnson syndrome Interstitial nephritis Abnormal LFTs Lupus like syndrome Pancreatitis Headache Photosensitivity STOP THE MEDICATION 10/10/

11 Antibiotics-Treatment of Complications Indication Antibiotics Evidence Crohn's anorectal disease Metronidazole +/- Ciprofloxacin Crohn's related complication: abscess/infect ion Fulminant, severe UC with signs of toxicity Fluoroquinolones or cephalosporins + metronidazole ACOG Guidelines 2009 ACOG Guidelines 2009 De Groof EJ et al; Dig Dis 2014 Broad spectrum antibiotics ACOG Guidelines /10/

12 Aminosalicylates in CD Agent Comparative agent End point Efficacy Caveat Sulfasalazine Placebo Induction of CR + trend, nonsignfiicant Sulfasalzine Corticosteroid Induction of CR AE s Inferior lower Olsalazine Placebo Inferior CD High dose mesalamine High dose mesalamine We cannot rely on aminosalicylates to treat Crohn s disease Placebo Corticosteroid, budesonide Induction of clinical response or remission Induction of clinical response or remission Not superior inferior Crohn s colitis only CD CD CD 10/10/2018 Lim et al CDSR

13 Aminosalicylates in UC Aminosalicylates can be effective in mild to moderate UC Agent Comparative agent End point Sulfasalzine 5-ASA Induction of UC Maintenance of UC 5-ASA Placebo Induction of UC Maintenance of UC Efficacy 58% failed to enter CR vs. 54% 5-ASA 41% relapse sulfasalazine vs. 48% 5-ASA 71% 5-ASA failed to enter CR vs. 83% placebo 41% relapse on 5ASA, 58% relapse on placebo *These are all severity levels of UC patients in these studies, hence high rate of failure to induce CR and prevent relapse 10/10/2018 Wang et al CDSR

14 Steroids/Immunomodulators 10/10/

15 Corticosteroids Immunomodulators 10/10/

16 Corticosteroids Prednisone No grapefruit juice: increases bioavailability of budesonide, 54% CR in UC, 30% partial remission, 16% no response 1 -Budesonide increasing possible side effects Entocort: Ileum, AC (delayed release)-crohn's Uceris: Colon (extended release)-9 mg daily pill or rectal foam 2 mg bid x 2 weeks and 2 mg daily for 4 weeks or rectal enema 2 mg daily x 4 weeks at bedtime CR in UC 18% vs. placebo 6% 10/10/ Faubion et al; WJG

17 Corticosteroids: AEs Osteoporosis Increased risk when taking > 7.5 mg prednisone x 3 months cumulatively Hyperglycemia Hypertension Mood lability Insomnia Glaucoma Fluid retention Acne Skin thinning Adrenal suppression PUD/Esophagitis Muscle wasting Wound healing impairment Aseptic necrosis-hips Increased risks of infection Short term medication to quickly induce remission WHILE working on better long term therapy. "Band-Aid' Decrease to lowest effective dose and taper once patient is on long term therapy 10/10/ Faubion et al; WJG

18 Immunomodulators Thiopurines Methotrexate Cyclosporine 10/10/

19 Thiopurines Disease Steroid free remission Adverse Effects Moderate to severe UC Induction of remission: ineffective Maintenance of remission:21% lower risk of relapse compared to placebo Moderate to severe CD Week 26: 57% infliximab + azathoprine 44% infliximab alone 30% azathioprine alone Nausea/Vomiting Fatigue Increased risk of infection Rash Pancreatitis Bone marrow suppression Hepatotoxicity Lymphoma (3/10k- >>6/10k) Skin cancer 10/10/

20 Thiopurine Pearls Azathioprine ( mg/kg/day: UC & CD), Mercaptopurine ( mg/kg/day: CD, off label for UC-50 mg/day initial and then mg/kg/day) May take up to 3 months to get full effect Reduce dose of thiopurine (by 1/3-1/4th) when given with allopurinol May affect warfarin on INR effect Check CBC, LFTs 1-2 weeks after starting medication, then q3-6 months thereafter if labs are normal Check TPMT genotype (don't give to homozygous deficiency, heterozygotes: reduce by 1/3-2/3 dose) or phenotype to dose accurately Azathioprine --> 6MP --> 6TG and 6-TU or 6-MMP (by TPMT). High 6- MMP levels predict hepatotoxicity. Need to adjust dosing based on TPMT Enzyme a ctivity. 10/10/

21 Methotrexate CD Effective mono-therapy for steroid free CR at week 16; TX 25 mg IM weekly CD: 39% CR vs. 19% placebo Fegan et al; NEJM 1995 UC Not effective mono-therapy Carbonel et al;gastro 2016 Possible AEs N/V, Diarrhea, headache, fatigue Rash Pulmonary fibrosis Hepatotoxicity, Check baseline CXR, LFTs, CBC and consider monitoring annually 10/10/

22 Cyclosporine Used for severe, hospitalized UC patients Need inpatient nurses and facility that is familiar in running frequent drug levels and also monitoring for AE's. 10/10/

23 Biologics 10/10/2018 Legacy Meridian Park Hospital 23

24 Biologics Anti-TNF Medications Adalimumab = Humira Inflixima= Remicade Golimumab = Simponi Certolizumab = Cimzia Α4β7 Integrin Antagonist Vedolizumab Natalizumab IL12-23 Inhibitors Ustekinumab 10/10/

25 Biologics Highly specific Cost of production is high Risk of immunogenicity Lab monitoring: Prior to induction: Hep A, B, TB testing (PPD or Quantiferon TB gold) Annually: CMP, CBC AEs for all biologics : increased risk of infections, latent TB or HBV reactivaction, lymphoma 3--> 6/10k, skin cancers, BM suppression, lupus like syndrome, optic neuritis, sarcoidosis, interstitial lung disease, hepatotoxicity, ALT elevation, hypertension, pruritits, nausea, headache. Infusion reaction, injection reaction, Increased mortality in NYHA II/III CHF, paradoxical psoriasis, other rashesneutrophilic dermatoses 10/10/

26 Infliximab Chimeric IgG1Ab Dosage: 5 mg/kg week 0, 2, 6 for induction, then q8 weeks thereafter. Consider 10 mg/kg in certain patients (Severe UC or Crohn's colitis, hospitalized, low albumin) 10/10/

27 Adaliumumab Fully human IgG1 Ab Dosage (SQ): 160 mg week 0, 80 mg week 2 for induction, then 40 mg every 2 weeks thereafter 10/10/

28 Golimumab Human IgG1 TNFα Antagonist Ab Dosage (SQ): 200 mg week 0, 100 mg week 2 for induction, then 100 mg every 4 weeks 10/10/

29 Certolizmumab pegol Pegylated humanized Ab fragment Dosage 400 mg SQ every 4 weeks and if there is a lack of response, give every 2 weeks Does not cross placenta 10/10/

30 Vedolizumab = Entyvio Humanized igg1 monoclonal ab against integrinα4β7 Blocks T-Cell migration into the gut; CD4+CD45O+ T cells. Targets adhesion molecules that block endotheliallymphocyte trafficking Dosage: 300 mg week 0, week 2, week 6 for induction, then 300 mg every 8 weeks thereafter AEs: -nasopharyngitis -rash -no known increased risk of PML 10/10/2018 GEMINI I trial; Feagan et al CGH

31 Vedolizumab = Entyvio in UC patients V V V V 10/10/2018 GEMINI I trial; Feagan et al CGH

32 Vedolizumab = Entyvio in CD patients V V 10/10/2018 Sandborn et al NEJM

33 Vedolizumab = Entyvio 10/10/2018 GEMINI trial; Loftus et al JCC

34 IL 12/23 in CD Ustekinumab = Stelara FDA Approved for moderate-severe CD treatment (2016) Monoclonal Ab against p40 subunit of IL 12/23 Dosage: IV Induction dose: 260 mg (<55 kg), 390 mg (55-85 kg), 520 mg (>85 kg), then maintenance 90 mg SQ q8 weeks 10/10/

35 Biologics in UC Infliximab, adalimumab, golimumab,, vedolizumab have evidence for induction and maintenance of UC and mucosal healing Infliximab for acute severe UC or Crohn's colitis (hospitalized) 10/10/2018 Cote-Daigneault et al; UEG

36 Ulcerative Colitis Tofacitinib = Xeljanz Janus Kinase (JAK) and tyrosine kinase 2 (TYK2) inhibitor Oral medication Moderate-Severe UC 5 or 10 mg twice daily. Increased dose, increased possible AEs. 10/10/

37 Tofacitinib DON'T USE WITH AZATHIOPRINE Stop Xeljanz IF a serious infection develops and resume once infection is controlled Test for latent TB before and during Xeljanz treatment. Treat latent TB. Test for viral hepatitis Caution in patients with chronic lung disease (increase susceptibility to infection) Increased risk of invasive fungal infections: cryptococcosis and pneumocytosis Most common, serious infections were pneumonia, cellulitis, HZV, UTI, Diverticulitis, Appendicits Increased risks of serious infections in patients taking 10 mg bid > 5 mg bid Lymphoma, other malignancies (non melanoma skin cancers), EBV-post transplant lymphoproliferative disorder (renal transplant patients) 10/10/

38 Tofacitinib May cause neutropenia, don't give to patients ANC <1000 May cause anemia, don't give to patients with Hb < 9. Interrupt treatment in patients with hb < 8 or drop in Hb > 2 g/dl on Xeljanz treatment. Get baseline Hb and after 4-8 weeks of treatment and q3 months thereafter EFFICACY: 31% mucosal healing (induction) 37-45% mucosal healing (maintenance) 18% CR induction 34-40% CR maintenance 10/10/

39 Complementary Therapies: Diet, Vitamin D, Curcumin 10/10/2018 Legacy Meridian Park Hospital 39

40 Vitamin D Low vitamin D correlates with increased inflammatory response and failure to anti-tnf regimens 1 Screen patients and normalize levels High dose Vit D3 10,000 IU daily better than 1,000 IU daily with lower rates of clinical relapse and improvements in depression 2 10/10/ Arsenescu et al ACG 2014 Abstract Narula et al; 2015 AIBD meeting 4 0

41 Curcumin Curcumin 3 grams daily with mesalamine vs. mesalmine alone in RCT, MC, placebo controlled (active mild-moderate UC) -54% in curcumin group achieved CR at week 4 vs. 0 of the control group -Endoscopic remission observed in 38% vs. 0 of the control group. 10/10/ Lang et al CGH

42 UC Algorithm UC Mild Moderate Severe Aminosalicylates Corticosteroids Thiopurines+/- Biologics Biologics +/- Immunomodulators Cyclosporine with bridge to Immunomodulator Surgery 10/10/

43 CD Algorithm CD Mild Moderate Severe Limited Crohn's colitis: Aminosalicylates Small bowel involvement:thiopurines or methotrexate Corticosteroids Thiopurines+/- Biologics Biologics +/- Immunomodulators Cyclosporine with bridge to Immunomodulator Surgery 10/10/