New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and...
Transcript of New IBD Therapies - nesgna.org IBD Therapies 031216_final.pdf · New IBD Therapies Promise and...
New IBD Therapies Promise and Pitfalls
Frederick L. Makrauer, MD Center for Crohn’s and Colitis
Brigham and Women’s Hospital March 12, 2016
Conflicts of Interest and Disclosures
• None
Treatments we will discuss
• Antibiotics, prebiotics, probiotics
• Corticosteroids
• Azulfidine, 5-ASA’s
• Immunomodulators (AZT/6-MP, cyclosporine, tacrolimus)
• CAM (complementary and alternative therapy)
Today -
• anti- TNF’s (IFX, adlimumab, certolimumab, golimumab)
• anti-adhesion molecules (natalizumab, vedolizumab)
• Cytokine inhibitors (ustekinumab)
• Step-Up vs Step Down Rx
• Combination, Cessation and Resumption of Therapy
• Experimental therapies: fecal transplant, nutrients
I. Patient Susan S. 2004
• 68 y teacher, L-sided UC x 2002, Mayo Score 0
• FHx: F- CRC, M-UC
• PMHx: Colonic adenoma 2003
• 5ASA 2.5 g/d, AZA 50 mg (metabolites good)
• Colonoscopy - L-sided mild scarring, inactive
• Is there anything else we should do?
The Challenges to Proper IBD Rx
• Worldwide - increasing incidence/prevalence
• U.S. - UC 1:400, Crohn’s 1:500
• Proper study endpoint – ‘deep remission’
• No drug > 70 % effective
• Toxicity
• Insurance coverage
Good IBD Care is Patient - Centered
Individualized Rx Decisions
• Clinical Factors (‘phenotype’ and ‘activity’)
• Fertility, Pregnancy, Delivery and Lactation
• Genetic Factors (‘genotype’)
• Past Rxs & Response
• Drug Metabolism (assay)
• Insurance Coverage
• Goal of Therapy (patient vs provider) Siegel, 2014
Monitoring The Patient
• Symptoms (activity indices)
• Labs: calprotectin, drug levels and antibodies
• Imaging (monitor radiation exposure)
• IBD Conference
• Support (patient & family)
Supportive Care
• Oral/perineal hygiene and comfort • Anti-diarrheals • Pain control • Nutrition • Counseling, support, advocacy (CCFA)
Gerson and Triadafilopoulos 2000
IBD in Pregnancy and Delivery
• A dedicated Ob/Gyn Service is recommended
• Sweden 1209 UC and 787 CD, with 10,773 controls
• DVT in UC OR 3.78
• Antepartum hemorrhage in CD OR 1.66
• Emergency C section in UC OR 1.39; in CD OR 1.50
Broms G et al. 2012
Pregnancy Outcomes on Anti-TNF Therapy
Case-control study following 124 pregnant women over 133 pregnancies on anti-TNF therapy
Seirafi et. al. APT. 2014; 40(4): 363-373
II. Susan S. 2006
• Rapid onset of cramps, diarrhea and urgency
• What questions need to be answered?
Complications of Therapy
• Infection (disease activity, narcotic, CS, IFX)
• Hematologic
• Cancer – skin (melanoma), cervical, lymphoma
• Bone marrow, liver/pancreas, skin, hair, nerve, heart
• TREAT Registry
Why does IBD happen?
• Genetics + innate immunity + environment
• Genes - NOD2, ATG16L1, Arg381Gln, and > 150 others
• Innate Immunity - inappropriate response to invader
• Environment - Microbiome ‘dysbiosis’ (diet, antibio., hygiene)
Abreu 2015, Serban, 2015
An Imbalanced Host-Microbiome Interaction
Kahng, 2009
Gene Impact on Disease expression Only in 7.5 – 13.6 % patients
• NOD2/CARD15 – complicated CD course • ATG16L1, JAK2 – stenosis CD • IRGM, TNFS15 – need for surgery CD • IL23R, CDPRDM1 – fistulizing CD • TLR4 – pancolitis UC, colitis CD • IKBL – severity of UC Serban, 2015 from ncp.sagepub.com @ H.U.
Foods alter the activity of IBD
• Ant-inflam: fresh fruit & veggie’s, SCFA, S. boulardii, VSL-3, curcumin
• Eg., curcumin - UC mild to moderate
• Inflam: fat, refined sugars, alcohol. Gluten?
• Eg., emulsifiers, carrageenan, metals
The’westernized’ diet’s impact on the microbiome
from breast milk to Burger King
• Herbivore to carnivore • Shift to hostile bacterial populations • Less fruit fiber, more refined CHO, fat, sulfur • Less intra-luminal SCFA*, and more H2S • N-6 FA’s > N-3 = more inflammation!
* short-chain fatty acids = n-3 PUFA (poly-unsaturated fatty acid)
TNF II-1b IL-12/IL-18 IFN
Pro-inflammatory
Anti-inflammatory
IL-10 TGF IL-4/IL-13 IL-1Ra PGE2
Loss of Tolerance
Tolerance
Chronic inflammation vs mediator balance in IBD
Crohn’s disease
Crohn’s - Esophagus
Crohn’s - Rectum
1 o’clock: incision site with a silk seton in place; drainage of pus. 3 o’clock: sinus tract with fistula opening
Crohn’s - Perineum
Crohn’s - Perianal Abscess
Ulcerative Colitis
Ulcerative Colitis Endoscopic Spectrum of Severity
Normal
Moderate
Mild
Severe
U.C. - Colonic Wall Thickening
Be sure it is IBD
• Infection • Mesenteric Ischemia • IBS (‘Irritable Pouch’) • Medication (NSAID, Cellcept, etc.) • Diverticulitis • Endometriosis • Radiation therapy • Lymphoma, leukemia, GVHD, cancer • Microscopic colitis • Diversion colitis
III. Susan S. – 10/2009
• Flared with urgency, bleeding on prednisone + + imuran + 5-ASA
• Should we check any additional studies?
• Are there other treatment options?
Treatments We Will Discuss
• Antibiotics, prebiotics, probiotics
• Corticosteroids
• Azulfidine, 5-ASA’s
• Immunomodulators (AZT/6-MP, cyclosporine, tacrolimus)
• CAM (complementary and alternative therapy)
Today -
• anti- TNF’s (IFX, adlimumab, certolimumab, golimumab)
• anti-adhesion molecules (natalizumab, vedolizumab)
• Cytokine inhibitors (ustekinumab)
• Step-Up vs Step Down Rx
• Combination, Cessation and Resumption of Therapy
• Experimental therapies: fecal transplant, nutrition
Targeted Drug Therapy
Korzenik 2006; Sands 2002
Currently Approved Biologics For IBD
Initial cA2 (Infliximab) NEJM (1997)
Infliximab approved for Crohn’s disease (1998)
Infliximab approved for ulcerative colitis (2005)
Adalimumab approved for Crohn’s disease (2007)
Certolizumab Pegol approved for Crohn’s disease (2008)
Natalizumab approved for Crohn’s disease (2008)
Adalimumab approved for ulcerative colitis (2012)
CD
UC Golimumab approved for ulcerative colitis (2013)
Vedolizumab approved for ulcerative colitis (2014)
Vedolizumab approved for Crohn’s disease (2014)
TNF Alpha
First described in 1975
Synthesized by activated macrophages and T cells as a transmembrane precursor protein
Binds to one of two receptors-TNFR1 and TNFR2
Stimulation of release of inflammatory cytokines (IL-1beta, IL-6, IL-8, and GM-CSF)
Upregulation of endothelial adhesion molecules (ICAM-1, VCAM-1, E-selectin) and chemokines
35 35
anti-TNF’s
• Infliximab – CD and UC
• Adalimumab – CD and UC
• Certlizumab - CD
• Golimumab - UC
Anti-TNF Therapy in Crohn’s Disease
Infliximab, adalimumab, and certolizumab are approved for use in CD
Indications for Early Treatment:
Complex fistula
Deep ulceration on endoscopy
Young age
Steroid dependence/resistance
High risk anatomy
Severe disease activity (wt loss, low albumin, Hgb)
37
Clinical Response and Remission with Infliximab
Targan SR, et al. N Engl J Med. 1997.
4%
16%
48%
81%
0
20
40
60
80
100
4-week Clinical
Response
4-week Clinical
Remission
Placebo (n=25)
REMICADE 5 mg/kg
(n=27)
P<0.001
P<0.001
% P
atie
nts
38
Long-term endoscopic remission 5 year follow up data
Regueiro M, et al. Clin Gastro Hep. 2014.
Infliximab Prevents CD Recurrence After Ileal Resection
Regueiro M, et al. Gastroenterology. 2009. 40
CD: Primary Non-Responder
Individuals who fail induction within 12 weeks
Approximately 35-40% of patients in anti-TNF clinical trials are primary non-responders
For primary non-responders
Add an antimetabolite (6MP/AZA/methotrexate) for patients not previously on these agents
Switch to second anti-TNF Switch to natalizumab/vedolizumab Surgery may be an option to consider in patients with
limited disease
Lichtenstein G, et al. Am J Gastroenterol. 2009. Yanai H et al. Am J Gastroenterol. 2011.
41
SONIC: Mucosal Healing at Week 26 secondary endpoint
42 Colombel JF, et al. NEJM. 2010.
SONIC: IFX Trough Levels Wk 30 Higher with Concomitant AZA M
ed
ian
Se
rum
Tro
ug
h
Le
ve
ls (
mg
/ml)
1.6
3.5
0
2
4
6
8
10
IFX + placebo IFX + AZA
(N=97) (N=109)
Sandborn W, et al. NEJM. 2010. 43
CD: Secondary Non-Responder
Improve after initial induction but lose response
Between 10-15% lose response annually
For secondary non-responders
Measure drug levels and antibodies Escalate the dose Switch to another anti-TNF Switch to natalizumab/vedolizumab Work up for infections or other pathological
processes
44
Afif W, et al. Am J Gastroenterol. 2010; Brandse, J et al. Clin Gastro and Hep 2016
Clinical Utility of Measuring Anti-TNF Trough and Antibody Levels
45
Anti-TNF Therapy in Ulcerative Colitis
Indications:
Moderate to severe UC
Steroid-dependent UC
Refractory pouchitis
Maintenance of disease in remission
Infliximab, adalimumab, and golimumab are approved for use in UC
46
Rates of Sustained Clinical Remission in ACT 1 and 2
ACT 2 ACT 1
Remission at Week 8 and 30 Week 8 and 30 Week 8, 30, and 54
Remission
P<0.001
P=0.001
P=0.002
P=0.002
P<0.001
P<0.001
Sustained Clinical Remission
Pa
tie
nts
(%
)
Pati
en
ts (
%)
Placebo Infliximab 5 mg/kg Infliximab 10 mg/kg
8.3 6.6
23.1 19.8 26.2
20.5
0
20
40
60
80
100
2.4
14.9 22.5
0
20
40
60
80
100
Rutgeerts P, et al. NEJM. 2005. 47
UC: Non-Responder
• Enhanced clearance with
– High BMI – Male – Lack of concomitant immunosuppression – Low albumin – Severe Inflammation
• Loss of proteins, lytes, minerals via ulcerated mucosa
48
ULTRA 1 and ULTRA 2
49 Sandborn WJ, et al. Gastroenterology. 2012.
IV. Susan S. -11/2009
• Hair loss!
• Mayo Score 0, colonic mucosa healed.
• What might be causing her hair loss?
• What should we do next?
Anti-TNF Adverse Effects
Neutropenia
Infections
Demyelinating disease
Heart failure
Cutaneous reactions, including psoriasis
Malignancy
Induction of autoimmunity
53
Anti-TNF Opportunistic Infections
Toruner M, et al. Gastroenterology. 2008 54
Most Frequently Reported Organisms: Herpes Zoster Candida albicans Herpes simplex Cytomegalovirus Epstein-Barr virus Histoplasma capsulatum
Association of Immunosuppressive Medication Combinations with Opportunistic Infection
Number of Immunosuppressive Medication Combinations
OR (95% CI)
None 1.0 (reference)
1 2.9 (1.5 to 5.3)
2 or 3 14.5 (4.9 to 43)
55 Toruner M, et al. Gastroenterology. 2008.
Italian study of patients over 65 with IBD receiving infliximab or adalimumab
Two control groups: < 65 with anti-TNF and > 65 with IBD but no biologics
Outcome of interest: serious infection, neoplasm or death
Advanced Age and Anti-TNF Side Effects
Age/Years Infection (%) Neoplasm (%) Death (%)
> 65 11 3 10
< 65 Control (anti-TNF)
2.6 0 1
> 65 Control (no biologics)
0.5 2 2
Cottone M, et al. Clin Gastroenterol and Hepatol. 2011. 56
Skin Cancer Among Patients with IBD
Long MD, et al. Gastroenterology. 2012. 57
Hepatosplenic T-Cell Lymphoma
• Rare and usually fatal lymphoma, that primarily affects men <35 years old
• As of 2013, 37 reported cases of HSTCL among patients with IBD
• In a systematic review of the first 36 cases, no cases were associated with anti-TNF therapy alone
– 20 occurred with combination therapy with infliximab and a thiopurine
– 16 occurred with thiopurine monotherapy
Kotylar DS, et al. Clin Gastro Hep. 2011. Selvaraj, et al. Systematic Reviews. 2013. 58
Stopping Anti-TNF Alpha Therapy
One study1 : 115 CD patients in remission IFX & AZA > 1 yr, remission for 6 mo
IFX stopped; followed for 1 yr; 39% relapsed
Similar study2 : 84% CD relapsed in 5 yr
In Crohn’s, relapse after stopping IFX > 6MP/AZA
1. Louis E et al. Gastroenterology. 2009. 2. Schnitzler F et al. Gut. 2009. 59
Summary anti-TNF Points
• Anti-TNF - CD perianal fistulas, post-op prevention
• Combo therapy (IFX + IM) better for CD and UC
• Lymphoma: Imm only 4/103pt-yr; Imm + IFX 6/103pt-yr
• Combination therapy = higher IFX levels
60
Leucocyte Adhesion Molecule Inhibitors
• Natalizumab - CD, anti-alpha 4 integrin (gut and CNS)
• Vedolizumab – CD + UC, anti-alpha4B7 integrin (gut only)
• FDA-approved after failure of AZT, CS, anti-TNF’s
• Future: Etrolizumab UC anti beta7 integrin (gut only)
• AJM300 anti-alpha-4 integrin antibody.
Natalizumab
Humanized IgG4 monoclonal antibody that blocks the adhesion and subsequent migration of leukocytes into the gut
Antibody is directed towards alpha 4 integrin
α4β1 and α4β7 antibody
Natalizumab is approved for the treatment of moderate to severe CD.
62
Progressive Multifocal Leukoencephalopathy
63 Wenning W, 2009
Natalizumab-Associated PML
Factors Associated with Increased Risk
Positive status – anti-JC virus antibodies
Increased duration of natalizumab treatment: greatest risk occurred after 2 years of therapy (25-48 months in this study)
Prior use of immunosuppressants
Bloomgren G, et al. NEJM. May 2012. 64
• Vedolizumab - humanized, monoclonal α4β7 antibody
– blocks lymphocyte trafficking to gut, but not CNS
• The α4β7 integrin is variably expressed on circulating B and T lymphocytes
– interacts with addressin-cell adhesion
molecule 19 (MAdCAM-1) on intestinal vasculature
Vedolizumab
65
Vedolizumab for Crohn’s GEMINI 2
Maintenance phase Sandborn W, 2013. 66
New ‘Orphan’Biologics
Ulcerative Colitis Tofacitinib – JAK inhibitor (rheumatoid arthritis)
Crohn’s Disease Ustekinumab - ab to p40 unit IL’s -12, -23 (psoriasis) Wils, 2016 retrospective, 122 pts 2011-14, 20 centers, steroid-free.
- @ 3 mo 65% responders; with immunosuppressive OR 5.43
- @ 12 mo 68% responders.
67
Janus Kinase (JAK) Inhibitors Tofacitinib
• Oral inhibitor of JAK kinases 1-3
• Reduced cytokine production
• FDA-approved only for rheumatoid arthritis
• UC (off-label)
• Elevates of LDL
Sandborn W, et al. ,2012. 69
Tofacitinib
IL-12 & IL-23 Receptor Inhibitors Ustekinumab
• Blocks IL-12 & IL-23 rec on T lymph, Ag-presenting cells • FDA-approved only for psoriatic arthritis. • CD (off label) after failure of anti-TNF agents • 6 wk (6 mg/kg iv), U 39.7 % vs placebo 23.5 % (p = .005) • 22 wk (90 mg sc q 8wks) - clinical response U 41.7 % vs placebo 27.4 % p < 0.03
- mucosal healing - equal - clinical remission U 69.4 % vs placebo 42.5 % p < 0.001
• Serious infection: @ induction 6/7; @ maintenance 4/11 • Cancer - basal cell 1
V. Susan S. – 04/2013
• 2010-2013 flares respond to 5 ASA boosts
• But, multiple skin ca’s, hematuria and,
• Low bone density, increased glucose
• Urology – transitional cell ca of renal pelvis
• What are our treatment options?
Oral Therapies Present and future
A. Non-targeted (today) i. induction: CS, 5-ASA, CSA, tacrolimus
ii. maintenance: thiopurines, MTX, 5-ASA, tacrolimus
B. Targeted (breakthrough agents)
i. Anti-TNF’s, anti-integrins, IL 12/23 inhibitors (Stelara off label)
ii. Synthetic
1. jakinibs: reduce inflammatory CK production (Tofacitinib off label)
2. anti-integrins: block circ lymphocyte entry into mucosa (AJM300)
3. sphingosine-1-phos (S1P): blocks nodal lymphocytes (Ozanimod)
4. anti-sense nucleotide: normalizes TGF B1 signaling (Mongersen)
The ‘Promise’
• Bio-engineered E. coli Nissl (IL-10) - anti-inflammatory
• n-3 PUFA, curcumin
• Fecal Transplant - under investigation
• Oral Therapies
• Pre-Rx tissue ‘signatures’ - ‘personalized care’
The ‘Pitfalls’
• Is it really an IBD flare? (infection, IBS)
• Underestimating disease activity
• Under-treating (bottom-up, mono Rx)
• Non-responders
• Drug toxicity
Good IBD Care is Collaborative
Acknowledgements
• Our patients
• Our professional organizations: SGNA, CCFA
• Our Colleagues: Crohn’s & Colitis Center
• Our Trainees: Edward L. Barnes, Rachel W. Winter
• Our Teachers: Dr. Peter A. Banks.
Bibliography
• Genetics and Environmental Interactions Shape the Intestinal Microbiome to Promote Inflammatory bowel Disease Versus Mucosal Homeostasis Gastroenterology 2010;139:1816-19
• Inflammatory Bowel Disease: Role of Diet, Microbiota, Lifestyle Translational Research 2012;160:29-44
• Combinatorial Effects of Diet and Genetics on IBD Pathogenesis Inflamm Bowel Dis 2015; 21: 912-922
• Mechanism of Probiotic Action: Implications for Therapeutic Applications in IBD Inflamm Bowel Dis 2008;14:1585-96
• Guidelines for Management of Growth Failure in Childhood IBD Inflamm Bowel Dis 2008;14:839-849
• DNA-driven Nutritional Therapy of IBD Nutrition 2009;25:885-91