immunological factors for endometriosis: the clinical...
TRANSCRIPT
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ImmunologicalFactorsforEndometriosis:TheClinicalImplications
Christian Becker University of Oxford
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Consultancy: ObsEva(IDDM)
Researchgrants: Bayer
RocheDiagnostics
MDNALifesciences
Conflict of interest
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Nisolle M & Donnez J, Fertil Steril 1997
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Reference npatients AFSStage Progression Stable Regression
Thomas,1987 17 I-II 8 0 9
Telimaa,1987 12 I 3 8 1
Mahmood,1990 11 I-III 7 1 3
Overton,1994 15 I-II 4 3 8
Sutton,1994 24 I-III 7 10 7
Harrison,2000 43 I-IV 4 12 27
Abbott,2004 18 II-IV 8 6 4
TOTAL 140 41(29%) 40(29%) 59(42%)
Modified from Evers JLH, Hum Repord 2013
Natural course of disease
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Clinicalimplicationsofimmunefactorsinendometriosis
Pathogenesis Biomarkers
Symptoms Treatments
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➔ Screening
➔ Patientstratification
➔ Indicatoroftreatmentresponse
➔ Courseofdisease
➔ Riskofrecurrence
Applications for biomarkers
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May et al., Hum Reprod Update 2010
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Working Group D. Adamson, R. Anchan, G. Buck-Louis, K. Chwalisz, T. D’Hooghe,
A. Fassbender, T. Faustmann, L. Giudice, M. Laufer, G. Montgomery, N. Rahmioglu, P. Rogers, P. Stratton, S. Tworoger, P. Vigano, A. Vitonis
EPHect Study
Extended Working Group
Harvard Stacey Missmer
University of Oxford Krina Zondervan Christian Becker
Lone Hummelshoj
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FertilSteril,2014
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Endometriosis Centres currently using WERF EPHect tools
http://endometriosisfoundation.org/ephect/
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Clinicalimplicationsofimmunefactorsinendometriosis
Pathogenesis Biomarkers
Symptoms Treatments
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Patients
Pain Infertility
Fatigue
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Berkley KJ et al., Science 2004 Tokushige et al., Hum Reprod 2006
Peripheral nerve fibres
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De-regulation of peripheral autonomic nerve system in endometriosis
IncreaseofsensorynervefibresLossofsympatheticnervefibres
(Arnold J et al, Brain Behavious and Immunity 2013)
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Morotti M et al, Hum Reprod Update 2014
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Tracey I & Mantyh PW, Neuron 2007
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Clinicalimplicationsofimmunefactorsinendometriosis
Pathogenesis Biomarkers
Symptoms Treatments
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Wong et al., 2009
Pain improvement with COCP
FavorsPlacebo FavorsCOPC
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Becker CM et al., Fertil Steril 2017
Response to medical therapy - Symptom recurrence after treatment cessation -
No reduction in symptoms
Pain symptom remaining at end of treatment
Recurrence of symptoms after treatment cessation
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Jacobson et al., 2010
Pain improvement after laparoscopy
FavorsNoSurgery FavorsSurgery
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No reduction in pain symptoms
Persistence of pain symptoms remaining after
surgery
Recurrent symptoms
Recurrent surgery
Change in VAS score from
baseline (cm)
AEs (AEs/ women)
Diagnostic surgery
77.4% ND ND 77.4% +0.3 0/31
Lesion excision11.8%
(3.6–22.2%)25.0%
(4.4–41.7%)15.8%
(0.0–42.0%)22.6
(5.8–56.9%)–3.6 124/1527
Lesion ablation 11.4% ND ND ND –2.4 0/79
Endometrioma drainage only
ND ND54.8
(52.9–75.0%)51.5%
(22.9–80.0%)ND 0/32
Pelvic denervation
6.7% (5.8–15.0%)
34.3% (8.6–48.1%)
28.7% (10.0–36.0%)
12.5% –2.2 27/182
Hysterectomy with ovarian preservation
ND ND ND 19.1% ND ND
Hysterectomy without ovarian preservation
ND ND ND 8.0% ND ND
DIE0.0%
(0.0–4.4%)2.3%
(2.2–4.4%)7.0%
4.1% (1.3–27.6%)
–6.2 63/779
Response to surgical therapy - Main outcome measures -
Singh S et al., submitted
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Recurrence rate of endometriosis after surgical treatment
5 years 40 - 50%
2 years 21.5%
Guo SW, Hum Reprod Update 2009
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Current/future immune targets to endometriosis
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TNF-α in endometriosis
• Pro-inflammatory cytokine
• Produced by activated macrophages and endometriosis lesions
• Induces IL-8 production by peritoneal mesothelial cells
• Up-regulated in peritoneal fluid of endometriosis patients
• Levels correlated with stage of disease
• Possible Mechanisms: Stromal cell adhesion and proliferation ECM degradation and invasion Inhibition of embryo development in rodents
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Monoclonal antibodies (Infliximab)
Baboons (c5N)
Inhibition of endometriosis
↓
Human study
Soluble TNF-α receptors (r-hTBP-1)
Rodents
Inhibition of implants
Baboons
Inhibition of development and growth of endometriosis
↓
No human study
TNF receptor fusion protein (Etanercept)
↓
No human study
Nopainstudiesinanimals
Blockage of TNF-α In vivo studies
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21 women with rectovaginal endometriosis
Infliximab (n= 13) Placebo (n = 7)
40 weeks ↓
4 weeks observation ↓
12 weeks treatment ↓
Surgery ↓
24 weeks follow-up
Start of Menses
2 weeks
6 weeks
Koninckx PR et al, Hum Reprod 2008
Blockage of TNF - α RCT study outline
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• Single centre, randomized, double-blind, placebo- controlled pilot study
• NCT 00604864 (Phase II trial)
• Primary outcome: Change in pelvic pain including use of analgesics (Biberoglu/ Behrman, VAS)
• Secondary outcomes: Volume change of rectovaginal nodules (clinically/TVU)
Appearance of nodules (surgery)
Extent of disease (surgery)
Koninckx PR et al, Hum Reprod 2008
Blockage of TNF - α (RCT) Study outcomes
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Koninckx PR et al, Hum Reprod 2008
Blockage of TNF - α (RCT) Study results
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Koninckx PR et al, Hum Reprod 2008
Blockage of TNF - α (RCT) Study conclusions
Pain severity decreased by 30% in both groups
No effect of Infliximab in any of the outcome measures
Surgery improved pain scores to < 20% in both groups
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Pentoxifylline
Methylxanthine inhibiting phosphodiesterase
Usually used to improve blood flow
May induce sperm motility
Has anti-inflammatory effects Inhibits TNF production in vitro
Reduces action of TNF and IL-1 on neutrophils
Inhibits phagocytosis and production of ROS from macrophages and neutrophils
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Pentoxifylline in endometriosis Cochrane review - Background
Lu D et al., Cochrane Database Syst Rev, 2012
Four studies with total 334 patients included
Intervention: Pentoxifylline 800 mg qd after laparoscopy
Comparator: Placebo (3 studies)
Study length: 3-12 months
Outcomes: Pain relief (VAS; 1 study)
Clinical pregnancy rates (3 studies)
Recurrent rate (1 study)
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Lu D et al., Cochrane Database Syst Rev, 2012
Primary outcome: Pain reduction
Secondary outcome: Clinical pregnancy
Secondary outcome: Recurrence rate
Pentoxifylline in endometriosis Cochrane review - Results
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Pentoxifylline in endometriosis Cochrane review - Conclusions
Lu D et al., Cochrane Database Syst Rev, 2012
Overall poor study quality: - no LBR recorded
- no non-pain related endometriosis-associated symptoms recorded
- no adverse events recorded
- no intention-to-treat approach
- allocation concealment in two studies recorded
- double blinding in three studies
- different stages of endometriosis included in different studies
Not enough evidence to support the use of pentoxifylline in endometriosis for subfertility or relief in pain outcomes
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PPAR-γ in endometriosis
• Peroxisome proliferator-activated receptor γ
• Nuclear receptors usually activated by free fatty acids , eicosanoids
• Activation of PPAR-γ: Inhibits macrophage activation and cytokine
production of monocytes Antiangiogenic
Inhibits endometrial cell proliferation
Antiestrogenic properties
• PPAR-γ is expressed in endometriotic stromal cells
• Correlation between PPAR-γ expression and pain scores
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PPAR-γ in endometriosis
Baboon model Surgically induced endometriosis 1 month treatment
Controls n = 6
Pioglitazone n = 6
Lebovic D et al., Endocrinology 2010
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PPAR-γ in endometriosis
Baboon model
Lebovic D et al., Endocrinology 2010
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• Single centre study, placebo controlled study
• NCT 01184144 (Phase 2)
• Primary outcome: Difference in soluble pro-inflammatory markers in peritoneal fluid
• Status: Withdrawn
→ Other studies have been withdrawn due to cardiovascular risk (rosiglitazone)
PPAR-γ ligand pioglitazone Human study
Source: clinicaltrials.gov
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Ancién P et al., Fertil Steril, 2002
Rationale: Enhancement of cytotoxic activity of macrophages and NK cells Reduction in experimental endometriosis in rodents
Study: Single centre, open-label RCT
Intervention: Conservative open surgery +/- intraperitoneal IFα-2b or placebo +/- postoperative GnRHa or Indomethacin
Second-look laparoscopy after 9-12 months
Primary outcome: Recurrence of endometriosis at 2nd look laparoscopy
Secondary outcomes: CA125 levels Lymphocyte populations Immunoglobulin levels
Interferon α-2b
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Ancién P et al., Fertil Steril, 2002
Interferon α-2b Study profile
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Ancién P et al., Fertil Steril, 2002
Interferon α-2b Results
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Interferon α-2b Conclusions
Ancién P et al., Fertil Steril, 2002
Intraperitoneal IF α-2b after conservative surgery increases recurrence rates of ovarian endometriosis
No change in lymphocyte or IG levels
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Rationale: Triggers NK cells activation by T cells Activates growth and expansion of T lymphocytes Causes cytolysis of aberrant ectopic cell in vitro Reduction in experimental endometriosis in rodents
Study: Single centre, double-blinded RCT
Intervention: 3 months GnRHa + 1x transvaginal drainage of endometrioma +/- intra-cystic injection of 1x 600,000 IU rIL-2 or placebo
Primary outcomes: Changes in pain scores (VAS) Endometrioma size change CA125 levels
Secondary outcome: Time to pregnancy
Interleukin – 2 Background
Ancién P et al., Gynaecol Obstet Invest, 2003
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Ancién P et al., Gynaecol Obstet Invest, 2003
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Interleukin – 2 Conclusions
Recurrence of endometriomas similar in both groups
rIL-2 group: Prolonged period until recurrence
Lower VAS scores
Fewer cases with increased CA125
Fewer surgeries necessary (n.s.)
Very small study
Ancién P et al., Gynaecol Obstet Invest, 2003
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V-Endo
• Open-label, one arm immunotherapy for 2 months, phase 1
• NCT 03340324
• Primary outcome: Change in pelvic pain (VAS) over 2 months
• Secondary outcomes: Quality of life changes Effect on liver and kidney parameters and FBC
• V-Endo is a tableted immunotherapeutic derived from hydrolyzed, heat-inactivated, pooled blood from women with endometriosis
• Location: Mongolia
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IRAK
IL-1 receptor-associated kinases
Regulating expression of inflammatory genes in immune cells
Critical for elimination of bacteria, viruses, cancer cells
IRAK-4 is the central member
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IRAK-4 Inhibitors
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Boher RN et al, AACR 2017
IRAK-4 Inhibitor in cancer
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Boher RN et al, AACR 2017
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Current/future immune targets to endometriosis
Clinicaltrials.gov ↓
Endometriosis (n = 306)
Not yet recruiting (12) Recruiting (57) Enrolling by invitation (6) Active, not recruiting (17)
Suspended (4) Terminated (13) Withdrawn (12)
Completed (140)
With Results (13)
Without Results (127)
Unknown(45)
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Future prospects
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Lesion Colour
Lesion Location
Pain Quality Infertility
Genetics
Molecular Markers
Co- Morbidities History
?
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Source:ManchesterPrecisionMedicineInstitute
Stratified and precision medicine
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TNF-α
Esposito E & Cuzzocrea S, Trends Pharmacol Sci, 2011
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Ancién P et al., Gynaecol Obstet Invest, 2003
Interleukin – 2 Results
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EvaluationofM1andM2MacrophagesinEndometrioticTissueofWomenAffectedbyEndometriosisatDifferentStages.NCT03136978
OpenLabelImmunotherapyofEndometriosisNCT03340324
DoesImmunotherapyHaveaRoleintheManagementofEndometriosis?NCT03464799
Endometriosis:ImmunomodulationNCT01184144
EffectofRosiglitazoneonPeritonealCytokinesinWomenWithEndometriosisNCT00121953
EffectofAntiTNFaUponDeepEndometriosisAssociatedPain(Infliximab)NCT00604864
PGL5001ProofofConceptStudyinInflammatoryEndometriosis(JADE)NCT01630252
StudytoInvestigatetheEfficacyofaNon-hormonalDrugAgainstEndometriosisAssociatedPelvicPainNCT00185341
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PentoxifyllineandEndometriosis(LETS1)NCT00632697
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Attributes of ideal biomarkers
Cheap
Robust
Reliable Replicable
Validated
Relevant
Sensitive Specific
Accessible
Simple