How Should the Risk of Malignant and Infectious Complications Influence My Treatment Choice...

How Should the Risk of Malignant and Infectious Complications

Influence My Treatment Choice

Meenakshi Bewtra, MD, MPH, PhDUniversity of Pennsylvania

Division of GastroenterologyCenter for Clinical Epidemiology &

Biostatistics

CCEB

Outline:• Risks of immunosuppressant therapy*• Benefits of immunosuppressant therapy*• Putting it all together• Conclusion

• Immunosuppressant therapy: thiopurine analogs, biologics, calcineurin inhibitors, methotrexate

RISKS ESTIMATE

Serious/Opportunistic Infections

Lymphoma

Hepatosplenic T-Cell Lymphoma (HSTCL)

Progressive Multifocal Leukoencepholapthy (PML)

Risks in Immunosuppressant Therapy

STUDY REPORTED INFECTION RISK

Grijalva CG et al, JAMA 2011 10 / 100-person-years

Colombel JF et al, NEJM 2010 (SONIC)

4-5% at 54 weeks (mono and combination therapy)

Toruner M et al, Gastro 2008 3.3-4.4 times increased odds (mono)14.5 times increased (combination

therapy)

Peyrin-Biroulet L et al, CGH 2008 no increased risk

Colombel JF et al, Gastro 2004 2.8%/year

Feagan et al, NEJM 2013 (GEMINI 1)Sands et al, Gastro 2014 (GEMINI 3)

9-13%/year


RISKS ESTIMATE


3% per year (monotherapy)5% per year (combination therapy)

Lymphoma




MEDICATION REPORTED LYMPHOMA RISK

THIOPURINES Kandiel, Gut 2005 (meta-analysis) Beaugerie, Lancet 2009 (CESAME)

SIR 4.06 (2.01-7.28)SIR 6.5 (3.5-11.2)

ANTI-TNFs Siegel CA, CGH 2009 (meta-analysis) Anderson NN, JAMA 2014

SIR 3.23 (1.5-6.9)RR 1.07 (0.85-1.36)

THIOPURINES + ANTI-TNFs Herrinton Am J Gastro 2011 Beaugerie, Lancet 2009 (CESAME):

SIR 6.6 (4.4-8.8)SIR 10.2 (1.2-36.9)


RISKS ESTIMATE



Lymphoma 4x increased risks (monotherapy)8x increased risk (combination therapy)




STUDY REPORTED HSTCL RISK

Herrinton L et al, Pharmacoepi Drug Safety 2012 Baseline population risk IBD population risk

0.3 per million-person-years48 per million-person-years

Beaugerie, Lancet 2009 (CESAME): 0 per 16,659 person-years


RISKS ESTIMATE




Hepatosplenic T-Cell Lymphoma (HSTCL) 160 times increased risk



STUDY REPORTED PML RISK

Singh S et al, IBD 2012:JC Ab negative, +/- prior immunosuppressant therapy

1:7,099 – 1:28,397

Bloomgren G et al. NEJM 2012JC Ab negative; +/- prior immunosuppressant therapy

1:7094


RISKS ESTIMATE




Hepatosplenic T-Cell Lymphoma (HSTCL) 160 times increased risk


1 out of every 7000(infinitely increased compared to general

population)


RISKS ESTIMATE


30/1000 annual incidence (monotherapy)50/1000 annual incidence (combo therapy)

Lymphoma 0.8/1000 annual incidence (monotherapy)1.6/1000 annual incidence (combo therapy)

Hepatosplenic T-Cell Lymphoma (HSTCL) 0.0034/1000 annual incidence


0.14/1000 (not annual incidence)


Outline:

• Risks of immunosuppressant therapy• Benefits of immunosuppressant therapy• Putting it all together• Conclusion

Untreated IBD:

Medication Efficacy: Mesalamine• Mild-Moderate UC

– Response: 50-70%– Remission: 15-40%

• Remission rates vary by definition of remission– Complete resolution (stool freq, bleeding, endo, pt

& physician assessment): 22%– UCDAI ≤ 1, rectal bleeding/stool freq = 0; ≥ 1pt

decrease in baseline endo score: 28%– Mayo score ≤ 2: 40%

Hanauer SB et al. Ann Intern Med 1996;124-204 Hanauer SB et al. Am J Gastro 1993;88:1188Hanauer SB et al. Am J Gastro 2005;100:2478 Levine et al. Am J Gastro 2002;97:1398Sninsky CA et al. Ann intern Med 1991;115-350 Sandborn WJ et al. Gastro 2009;Epub ahead of print

6 weeks

Risk of medication cessation:• Azathioprine

Trenton X et al. Clin Gastroenterol Hepatol 2009;7:80-5

Risk of medication cessation:

• InfliximabIntra-abdominal surgeries CD-related hospitalizations

Rutgeerts P et al. Gastroenterology 2004;126(2):402

Monotherapy vs. Combination Therapy

Colombel JF et al. NEJM 2010;362(15):1383

Monotherapy vs. Combination Therapy

Scott FI et al. CGH 2014

Risk of medication cessation:• Cessation of anti-TNF therapy when on

combination therapy

Louis E et al. Gastroenterology 2012;142(1):63-70

Elective colectomy in UC:Mortality HR (95% CI) for Elective Colectomy

Compared to Medical Therapymatched patients; adjusted for comorbidities

Overall 0.67 (0.52-0.87)Age ≥ 50 0.62 (0.47-0.82)

Bewtra M et al. Ann Int Med 2015 Aug 18;163(4):262-70

In UC….

54 weeks0

5

10

15

20

25

30

35

40

17

35 34

Placebo IFX 5mg/kgIFX 10mg/kg

Patie

nts

(%)

ACT 1

0

5

10

15

20

25

30

8.7

20.5

10

24

Placebo Vedo q8 wks Vedo q4 wks

54 weeksPa

tient

s (%

)

GEMINI 1

52 weeks in Week 6 Responders (47%)

47% x 21% = 10%

Corticosteroids:• Fluid retention• CHF• Metabolic abnormalities• Hypertension• Muscle weakness• Loss of muscle mass• Osteoporosis• Compression fractures (spine)• Aspectic necrosis

(femoral/humeral head)• Pathologic fractures• Tendon rupture• Hyperglycemia• cataracts

• Gastric ulcers• Pancreatitis• Impaired wound healing• Bruising• Pseudotumor cerebri• Emotional disturbances• Menstrual irregularities• Cushingoid features• Growth suppression

(children)• Secondary adrenocortical

/pituitary unresponsiveness• Diabetes mellitus• Glaucoma• Weight gain

are bad

STUDY REPORTED INFECTION RISK

Lichtenstein et al Clin Gastro Hep 2006

Serious InfectionsAdj OR 2.2 (1.5-3.3), p=0.001

Toruner et al. Gastro 2008 Opportunistic InfectionsOR 3.3 (1.8-6.1), p<0.001

Aberra et al. Gastro 2003 Post-operative infections: elective surgeryAny infection: OR 3.7 (1.2-11.0)

Major infection: OR 5.5 (1.1-27.3)

Corticosteroids: Infection risk

STUDY MORTALITY RISK

Lichtenstein et al. Clin Gastro Hep 2006 (TREAT registry)

OR 2.1 (1.1–3.8) p=.016

Lewis et al. Am J Gastro 2008 (GPRD Database)

CD: HR 2.48 (1.85-3.31)UC: HR 2.81 (2.26-3.50)

Corticosteroids: risk of mortality

STUDY MORTALITY RISK

Lewis et al. Am J Gastro 2008 (GPRD Database)

CD: HR 2.44 (1.84-3.25)UC: HR 1.67 (1.34-2.09)

Untreated/Active IBD: risk of mortality

Outline:


How do these risks stack up?

Adapted from: Lewis JD et al, Am J Gastro 2008 Lichtenstein G et al. CGH 2006Kandiel A et al. Gut 2005 Siegel C. et al. CGH 2006 Herrinton L et al Pharm Drug Safe 2012Trenton X et al. CGH 2009 Rutgeerts P et al. Gastro 2004 Singh S et al, IBD 2012Toruner M et al, Gastro 2008 Grijalva CG et al, JAMA 2011 Bloomgren G et al NEJM 2012

Immunosuppressant therapy

Corticosteroids /Active Disease

Number needed to treat to cause one additionallymphoma per year with therapy

4357 (age 20-29; AZA)355 (age > 65; AZA)

2380 (infliximab)714 (combo therapy)

Number needed to treat to cause one additional HSTCL per year with therapy

20,964

Number needed to cause one additional relapse per year by stopping therapy

3

Number needed to cause one additional hospitalization per year with episodic therapy

7

Number needed to cause one additional abdominal surgery per year with episodic therapy

14

Number needed to treat to cause one additional death 146 (steroids)

Number needed not to treat to cause one additional death 21 (active disease)

Number needed to treat to cause one additional PML per year with therapy

7,000

Number needed to treat to cause one additional seriousinfection per year with therapy

483 (monotherapy)276 (combo therapy)

483 (steroids)

Why do we fear medications?

• How one perceives risk:– Epidemiologist: risk is a measured property of a

group of people– Physician/patient: risk is a specific property of ME

• Perception becomes reality:– Reject statistical reasoning in favor of anecdotal

reasoning– Accept common risks we “know” in favor of

uncommon risks we “fear”

Outline:


Conclusions:

• There are documented risks with immunosuppressant therapy– The absolute risks are low

• The absolute risks of active/untreated disease and/or corticosteroid therapy are high

Thank you

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How Should the Risk of Malignant and Infectious Complications Influence My Treatment Choice...

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