When can I stop taking my medications? Maria T. Abreu, MD University of Miami Miller School of Medicine Miami, Florida

Transcription

1 When can I stop taking my medications? Maria T. Abreu, MD University of Miami Miller School of Medicine Miami, Florida

2 Post-op low risk patient Uc de-escalation Discuss combo therapy Which one worked

3 IBD Management Journey Induction of remission Maintenance of remission Maintenance of remission off steroids and / or mucosal healing (histology)

4 Knowing Which Therapy Combinations Work Best Experimental Therapies Biologics 5-ASAs Immunomodulators Steroids

5 The Mildest Moderate Patient Symptoms Mild (bothered but functions at a normal capacity) Moderate (affects daily life) Severe (close to or needing hospitalization) Severity of Inflammation Superficial ulcerations Deep ulcerations / inflammatory stricture Fibrotic stricture Internal perforating disease (+/- abscess) Perianal perforating Location Limited ileal disease Extensive small bowel involvement Extensive colonic involvement Rectal disease

6 What Do I Want to Know When I See a Patient? I also want to know what has been tried Was an immunomodulator used for long enough? Was the dose correct or optimized of the medication? Did they really have a side-effect that cannot be worked around? A mild patient can be moderate if they do not respond to medications

7 Assessing Disease Severity Talk to patient Look at laboratory parameters: anemia, ESR, CRP, fecal markers Colonoscopy if not done recently Sometimes do magnetic resonance enterography instead, especially if I need to know more about extent of small bowel disease

8 What Do We Know: Guiding Principles for CD Management Combination therapy is better than monotherapy?subset that monotherapy is okay Early therapy is better than late therapy Well timed surgery is okay

9 Biologics in IBD Infliximab cover Gastro 1995; NEJM 1997 (ca2) Adalimumab for Crohn s disease (2002) Certolizumab Pegol for Crohn s disease (2008) Adalimumab for UC (2012) Infliximab approved for Crohn s disease 1998 Infliximab for ulcerative colitis (2005) Natalizumab for Crohn s disease (2008) Golimumab for UC (2013)

10 The First-line Biologic Agents for the Treatment of CD or UC Infliximab Adalimumab Golimumab Certolizumab Pegol VL VH PEG No Fc CH 1 IgG 1 Chimeric monoclonal antibody (75% human IgG 1 isotype) Mouse Human PEG, polyethylene glycol. IgG 1 Human recombinant antibody (100% human IgG 1 isotype) PEG Humanized Fab fragment (95% human IgG 1 isotype)

11 What do we know: Guiding principles for IBD management Combination therapy is better than monotherapy?subset that monotherapy is okay Early therapy is better than late therapy Well timed surgery is okay

12 SONIC Moderate-to-severe CD in patients with no prior exposure to biologic agents or immunomodulators Excluded intermediate TPMT activity Average disease duration 2.3 years AZA 2.5mg/kg IFX 5mg/kg IFX + AZA 1 endpoint: Induction + maintenance of steroid-free remission 2 endpoint: Mucosal healing

13 SONIC Clinical Remission Without Corticosteroids at Week 26 Primary Endpoint p<0.001 p=0.009 p= /170 75/169 96/169 Colombel, J.F., et al., N Engl J Med. 362(15): p

14 SONIC Mucosal Healing at Week 26 p<0.001 p=0.023 p= /109 28/93 47/107 Colombel, J.F., et al., N Engl J Med. 362(15): p

15 UC SUCCESS study Patients (%) * Panaccione R et al. Gastroenterology Feb;146(2): e3. *P<.05 compared to IFX; #P<.05 compared to AZA

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17 Azathioprine (AZA) AZA 6-MP TPMT 6-MMP 6TG XO Rac 1 6TG-MP 6TG-DP Co-stimulation 6TGTP CD28 - c l T-cell CD3 Tiede I et al. J Clin Invest. 2003; 111: Neurath M et al. Clin Gastroenterol Hepatol. 2005;3:

18 What are Advantages of Immunomodulators? Inexpensive Long-term benefit without loss of response over time Can stop and start without loss of efficacy Old school all side effects known

19 Impact of Combination Therapy (biologic + thiopurine or methotrexate) Synergy Reduced immunogenicity Reduced drug clearance

20 SONIC: IFX Trough Levels at Week 30* are Higher with Concomitant AZA (N=97) (N=109) * Patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis Sandborn, W. et al. NEJM, 2010

21 Trough Concentration of Infliximab is Higher With Concurrent Methotrexate Infliximab plus Feagan B et al. DDW Abs no. 682C.

22 Crohn s Disease Duration Remission at 1 year (%) 80 SUTD REACH 2 CHARM 6 subanalysis CHARM SONIC 3 4 ACCENT I Disease duration (years) Durations shown are median values 1. D Haens G, et al. Lancet 2008;371: Hyams J, et al. Gastroenterology 2007;132(3): Colombel JF, et al. N Engl J Med 2010;362; Colombel JF, et al. Gastroenterology 2007;132: Hanauer S, et al. Lancet 2002;359: Schreiber S, et al. Gastroenterol 2007;132(4 Suppl 2):A-147.

23 Who Needs Combination Therapy? When Can We Use Sequential Monotherapy? Immunomodulators: Thiopurines MTX Anti-TNFs Biologics (immunogenic) Mechanistic synergy Higher levels of biologic Moderate-to-severe disease Steroid-refractory disease Severe prognostic markers

24 Who Needs Combination Therapy? When Can We Use Sequential Monotherapy? Immunomodulators: Thiopurines MTX Anti-TNFs Biologics (immunogenic) Steroid-dependent disease (applies to both CD/UC) Steroid-refractory disease Mild course/ prognostic markers Hi-risk for complications from combo therapy?

25 Why are we discussing stopping medications? Medications not working Steroids always want to stop these Side-effects of medications Co-morbidities (i.e. other medical conditions) Fear of side-effects

26 It is a subgroup of patients at higher risk for infections and lymphomas Older Average age = 63 (systematic review); 67 (Mayo) Multiple co-morbidities Concomitant steroids and/or narcotics Young healthy patients are not in the clear, but probably much less at risk Young men and hepatosplenic T cell lymphoma Siegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006; Toruner, Gastro 2008

27 Treatment and Risk for Lymphoma Causality bias (ie, incipient lymphoma present at time of initiating therapy) 26 cases of lymphoma following treatment with etanercept or infliximab in postmarketing surveillance 81% NHL vs 19% Hodgkin, multiple subtypes Median interval between initiating therapy and lymphoma = 8 weeks 27

28 Risk of Lymphoma Associated with Immunomodulators 19,486 IBD patients 30.1% currently receiving thiopurines 14.4% discontinued thiopurines 55.5% never exposed to thiopurines Exposure Rate per 10,000 pt- years Receiving thiopurines vs. never exposed HR 5.28 ( ) 95% CI Current use DisconRnued Never exposed Beaugerie et al, Lancet 2009;7:374.

29 Cesame Trial 19,486 parents with IBD in a naronwide French cohort from 5/04-6/05 Multivariate Hazard Ratio for Lymphoproliferative Disorder From Thiopurine Use = 5.28 ( ) Beaugerie L et al. Lancet. 2009;374:

30 Risk of NH Lymphoma with anti-tnf + IM treatment for Crohn s Disease Meta-analysis Results 8905 patients representing 20,602 pt-years of exposure 13 Non-Hodgkin s lymphomas à 6.1 per 10,000 pt- years Mean age 52, 62% male 10/13 exposed to IM* (really a study of combo Rx) NHL rate per 10,000 SIR 95% CI SEER all ages IM alone Anti-TNF + IM vs SEER Anti-TNF+ IM vs IM alone Siegel et al, CGH 2009;7:874. *not reported in 2

31 Risk of Lymphoma Returns to Normal After Stopping Thiopurines " 36,891 VA patients with UC with a median follow up of 6.7 years and a median age of 60 years at inclusion Thiopurine Use " 4,734 patients using thiopurines; median duration of exposure: 0.97 years " 142 confirmed lymphoma cases Incidence Rate (per 1,000 person- years) Unexposed 0.6 During 2.3 AGer stopping 0.3 Khan N, et al. Gastroenterology Nov;145(5): e3. doi: /j.gastro Epub 2013 Jul 25.!

32 Risk of Developing NH Lymphoma PaRent receiving anr- TNF + Immunomodulator Therapy for 1 year Risk without IM combinaron monotherapy medicaron therapy Siegel et al, CGH 2009;7:874.

33 Scenarios for stopping medications Doing well on thiopurine (AZA/6-MP) alone Doing well on anti-tnf + thiopurine (or methotrexate) Which one worked? Was one started first and then second added because first one not working?

34 AZATHIOPRINE WITHDRAWAL IN PATIENTS WITH CROHN'S DISEASE (CD) MAINTAINED ON PROLONGED REMISSION UNDER TREATMENT IS ASSOCIATED WITH A HIGH RISK OF RELAPSE Xavier Treton Sr., Yoram Bouhnik, Jean Yves Mary, Jean Frederic Colombel, Bernard Duclos, Jean Claude Soule, Robert Modigliani, Marc Lemann Clin Gastroenterol Hepatol Jan;7(1):80-5.

35 AZA/6-MP Withdrawal Study Design and Results 83 CD parents remission x >42 mos (pred <10mg) AZA, n=40 Placebo, n=43 3/40 relapsed 7.9 +/- 4.4% 18 mo follow- up 9/43 relapsed /- 6.3% Treton, X. et al. Clin Gastroenterol Hepatol Jan;7(1):80-5.

36 AZA/6-MP Withdrawal Study Probability of relapse months 36 months 54 months

37 AZA/6-MP Withdrawal Study Conclusions More relapses with AZA withdrawal Factors associated with relapses: Younger age C-reactive protein >20 Neutrophil >4000 Low HgB level Most patients restarted on AZA achieve remission again Approximately 80% of patients on placebo do not flare

38 Patient Population for Model Development 796 well-characterized pediatric CD patients Enrolled from 21 centers from North America Demographic, clinical, genetic, and immune response data were prospectively collected Treatment data collected Steroids, immunomodulators (IMs), anti tumor necrosis factor (anti-tnf) agents Timing in relationship to a disease complication Model concordance index (Harrell s C = 0.81) Siegel CA et al. Inflamm Bowel Dis. 2011;17:30.

39 Control Panel and Output 16-year-old girl, small bowel and perianal disease, QSS group = 4 Risk of ComplicaRon 100 No treatment Early IM treatment Year From Present Siegel CA et al. Inflamm Bowel Dis. 2011;17:30.

40 IMID: Impact of Concomitant Immunosuppression on the Outcome of Maintenance Infliximab Therapy " Randomization! (n = 80)! Continued IMM (n = 40)! Week 104! Discontinued IMM (n = 40)! Patients treated with AZA, 6-MP, or MTX plus IFX 5 mg/kg, and in clinical remission for 6 months! Percentage of patients requiring a change in IFX dosing or who discontinued IFX! AZA = azathioprine; 6-MP = 6-mercaptopurine; MTX = methotrexate; IFX = infliximab; IMM = immunomodulator therapy with AZA, 6-MP, or MTX. Van Assche G, et al. Gastroenterology Jun;134(7):1861-8!

41 Concomitant Immunosuppression Does Not Impact the Outcome of Maintenance IFX Therapy Percentage of Patients! Results of the IMID Trial " Change in IFX Dosing! Continuous IMM! Discontinued IMM! Discontinued IFX! 24/40! 22/40! 11/40! 9/40! IFX = infliximab; IMM = immunosuppression with azathioprine, 6-mercaptoprine, or methotrexate. Most patients (17/20) stopped treatment due loss of response or intolerance. Van Assche G, et al. Gastroenterology Jun;134(7):1861-8!

42 Why Don t Patients Respond to Anti-TNFs? Dose not high enough Dose of anti-tnf proportional to extent and severity of inflammation Tissue versus serum levels of drug Different mechanism driving inflammation Could be different cytokines Could be epithelial dysfunction Microbial dysbiosis

43 Monoclonal antibody-based therapies (like vedolizumab) Trough levels, peak levels Functional assay: % receptor occupancy Downstream biologic effect Small molecule inhibitors (like tofacitinib) Drug levels Monitoring Therapeutic Levels for Novel Biologics Functional assays cytokine inhibition

44 %of subjects/0.5 units of acrvity TPMT Phenotypic Distribution TPMT L TPMT L TPMT L TPMT H TPMT H TPMT H Erythrocyte TPMT acrvity (U/ml) Weinshilboum RM, Sladek SL. Am J Hum Genet. 1980;32:

45 Patients with Low TPMT Activity Have Early Leukopenia Median (Range) Time to Bone Marrow Toxicity TPMT H /TPMT H (N=30) TPMT H /TPMT L (N=7) 3 months (0.5 87) 4 months (1 18) TPMT L /TPMT L (N=4) Colombel JF et al. Gastroenterology. 2000;118: month (1 1.5) Months

46 Analysis of TPMT Activity to Guide Dosing of AZA/6-MP TPMTH/TPMTH or >23.6u/ml mg/kg/d (6-MP) mg/kg/d (AZA) TPMTH/TPMTL or >6.7<23.6u/ml 50% normal starting dose TPMTL/TPMTL or <6.7u/ml Alternate therapies should be considered vs 10mg/m2 qod

47 Is there anything I can monitor to guide efficacy?

48 AZA Response at 4 months (%) TPMT and Therapeutic Response TPMT level <15.3 U/mL: 6.2 times more likely to respond to AZA therapy. P<.001 TPMT enzyme activity U/ml Cuffari C et al. Clin Gastr Hepatol. 2004;2:

49 Clinical Remission Without Corticosteroids at Week 26 Primary Endpoint ProporRon of PaRents (%) P<.001 P=.009 P= /170 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA SONIC Sandborn WJ et al. Presented at: American College of Gastroenterology; October 7, 2008; Orlando, FL. Abstract.

50 Association Between Clinical Response and 6-TGN in Pediatric Patients with 6- TG QuarRles Frequency of response (pmol/ 8x108 RBC) (%) % % n=44 n=42 n=43 n= ,203 IBD TherapeuRc Efficacy Frequency of 6- TG level >235 (pmol/8x10 8 RBC) (%) Response Failure Dubinsky MC et al. Gastroenterology. 2000;118:

51 Meta-Analysis: 6-TGN levels and Clinical Remission Author & Year Patients (Remission) 6TGN Threshold Proportion Above Threshold in Remission Proportion Below Threshold in Remission Odds Ratio 95% Confidence Interval Dubinsky (30) Gupta (47) Belaiche (19) Cuffari (47) Goldenberg (15) Achkar (24) Pooled Estimate % CI % CI Osterman MT et al. Gastroenterology. 2006:130;

52 Metabolite-Adjusted vs Weight-Based Dosing of Azathioprine in CD Objective: Double-blind, randomized controlled trial comparing the efficacy and safety of AZA standard dosing (SD) vs. individualized dosing (ID) by 6- thioguanine nucleotides (6-TGN) in inducing and maintaining remission in steroid-treated CD SD: AZA 2.5 mg/kg/d ID: 1.0 mg/kg/d in intermediate thiopurine S-methyltransferase (TPMT) or 2.5 mg/kg/d if normal TPMT; starting at wk 5, dose adjusted to target 6-TGN of pmol/8x108 RBC, or to a maximal dose of 4 mg/kg/d Dassopoulos T et al. Gastroenterology 2009;136(Suppl 1):A-519. Steroids were tapered

53 Metabolite-Adjusted vs Weight-Based Dosing of Azathioprine in CD (Cont d) Individualized dosing Standard dosing p value ITT CR at wk 16 40% (10/25) 16% (4/25) 0.11 Per protocol CR at wk 16 60% (9/15) 25% (3/12) 0.12 Mean dose from baseline through wk 16 in PP patients 2.0 mg/kg/d 2.2 mg/kg/d 0.49 Mean 6-TGN at wk pmol/8x10 8 RBC 230 pmol/8x10 8 RBC 0.86 There were no differences in frequencies of severe myelosuppression and severe hepatotoxicity Only 4 patients (2 per group) were in remission at week 52 Dassopoulos T et al. Gastroenterology 2009;136(Suppl 1):A-519.

54 Relationship Between 6-MP Dose and 6-TGN Levels in Patients with IBD Dose of 6- MP mg/kg Weak correlation between 6-TGN levels and the absolute dose or weight-based dose Morales A et al. Inflamm Bowel Dis. 2007;13:

55 Trough serum infliximab predicts clinical outcome for infliximab treatment in ulcerative colitis > TGN 24 level at study entry 0 Seow, C. et al Gut 2010;59:49 54

56 Biochemical Explanations for 6-MP/AZA Failure Drug Failure 6-TGN MMPN <5700 5% 6% Lack of Adherence 6-TGN <<230 6-MMPN <<5700 Inadequate Dose 6-TGN <230 6-MMPN <5700 N=110 74% Seidman EG. Rev Gastroenterol Disord. 2003;3(suppl 1):S30-S38. Roblin X et al. Am J Gastroenterol. 2008; 103: % Predominant TPMT 6-TGN <230 6-MMPN >5700 ~74% of treatment failures are due to under dosing Nearly 9 /10 IBD parents may tolerate standard dosing

57 How to aspects to 6-MP and AZA On everyone I am going to start aza/6-mp, tpmt enzyme activity 2.5 mg/kg of aza, usu divide the dose in 2 (75 bid) Really weird things, happen in 1 st 3 weeks: pancreatitis, fever 103/ myalgias If nauseous, take with food, h/a s take at nite Labs: cbc, cmp after 3 weeks; ideally I d like to get 6-mp metabolite levels at the same time For a small change in dose; recheck labs in 1-2 months but for big changes, I check again in 3 weeks Once u ve picked a dose; then labs every 3 months

58 Leukopenia: neutropenia Wbc 4 start worrying lower the dose; consider rechecking the 6mp metabolite level Alt/ast start worrying >2x UNL; may need to decrease dose of aza SAM-E

59 AZA Xanthine Oxidase Inhibition for Preferential 6-MMP Metabolism XO 6- MP X 6- thiouric acid HPRT 6- TGNs TPMT 6- MMP

60 Allopurinol Therapy for Preferential 6-MMP Metabolizers Pre-allopurinol Post-allopurinol Allopurinol 100 mg added; 6-MP/AZA dose reduced to 25% to 50% of baseline Sparrow MP et al. Aliment Pharmacol Ther. 2005;22:

61 Clinical efficacy of Allopurinol in CD Decrease in partial Harvey-Bradshaw Index Partial Harvey-Bradshaw index Sparrow M et al. Clin Gastroenterol Hepatol Feb;5: P=.001

62 Factors in Deciding on Biologics +/- Immunomodulators Earlier use of biologics rather than immunomodulators in young men and old men A woman starting an anti-tnf and wanting to get pregnant soon certolizumab Heavy/large patients or lots of inflammation I start with infliximab Post-op recurrence I tend to use an anti-tnf if high risk for recurrence

63 When Do We Use Immunomodulators? Steroid-dependent disease This includes budesonide-dependent (Uceris and Entocort) Combined with biologics Decrease clearance of biologics (decrease antibodies against biologics) After biologics don t work

64 Can we ever stop biologics? Usually continue indefinitely but may be subset of patients on immunomodulators that can stop

65 STORI Maintaining Remission on Antimetabolites After Stopping Infliximab in Crohn s Disease: A Prospective Cohort Study Kaplan-Meier Curve of Relapse n=52 relapses/115 patients Median follow-up 28+/- 2 months Median time to relapse: 16.4 months Louis E, et al. Gastroenterology Jan;142(1):63-70

66 Predictive Model for Time-to-Relapse Kaplan Meier time-to-relapse curves according to multivariate models and scores generated through Cox model using multiple imputations method Proportion without relapse Months since infliximab withdrawal Deleterious factors were: No previous surgery Steroid use within 12-6 months before infliximab withdrawal Male gender Haemoglobin 14.5 g/dl Louis E, et al. Gastroenterology Jan;142(1):63-70 leukocyte count > /l hscrp 5 mg/l faecal calprotectin 300 µg/g CDEIS >0 infliximab trough 2 mg/l No. of deleterious factors < >6

67 Stopping medications Deep remission on combo therapy keep one most likely to have induced remission or least likely to be causing side-effects (if there are side effects) Deep remission on monotherapy If UC, can 5-ASAs hold it? Tricky until cure Post-op remission (CD) Low risk for recurrence Assess in 6 months with colonoscopy and annually

68 What should doctors do to minimize risk Routine laboratory monitoring Age and risk: older men and younger men and thiopurines Vaccinate patients: Seasonal flu HPV (young women) Pneumococcal vaccine Avoid live vaccines if already on immunomodulators: Varicella MMR Skin exams yearly Develop a simple checklist