Immunological Factors for Endometriosis: The Clinical Implications - Christian Becker University of Oxford - SEUD
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Immunological Factors for Endometriosis: The
Clinical Implications
Christian Becker
University of Oxford
Conflict of interest
Consultancy: ObsEva (IDDM)
Research grants: Bayer
Roche Diagnostics
MDNA Lifesciences
Nisolle M & Donnez J, Fertil Steril 1997
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Natural course of disease
Reference n patients AFS Stage 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
Clinical implications of immune factors in
endometriosis
Pathogenesis Biomarkers
Symptoms Treatments
Applications for biomarkers ➔ Screening ➔ Patient stratification ➔ Indicator of treatment response ➔ Course of disease ➔ Risk of recurrence
May et al., Hum Reprod Update 2010
EPHect Study
Lone Hummelshoj
Harvard University of Oxford
Stacey Missmer Krina Zondervan
Christian Becker
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
Extended Working GroupFertil Steril, 2014
Endometriosis Centres currently using
WERF EPHect tools
http://endometriosisfoundation.org/ephect/Clinical implications of immune factors in
endometriosis
Pathogenesis Biomarkers
Symptoms TreatmentsPatients
Pain Infertility
FatiguePeripheral nerve fibres Berkley KJ et al., Science 2004 Tokushige et al., Hum Reprod 2006
De-regulation of peripheral autonomic
nerve system in endometriosis
Increase of sensory nerve fibres
Loss of sympathetic nerve fibres
(Arnold J et al, Brain Behavious and Immunity 2013)Morotti M et al, Hum Reprod Update 2014
Tracey I & Mantyh PW, Neuron 2007
Clinical implications of immune factors in
endometriosis
Pathogenesis Biomarkers
Symptoms TreatmentsPain improvement with COCP
Favors Placebo Favors COPC
Wong et al., 2009Response 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
Becker CM et al., Fertil Steril 2017Pain improvement after laparoscopy
Favors No Surgery Favors Surgery
Jacobson et al., 2010Response to surgical therapy
- Main outcome measures -
Persistence of
Change in VAS
No reduction in pain symptoms Recurrent Recurrent AEs
score from
pain symptoms remaining after symptoms surgery (AEs/ women)
baseline (cm)
surgery
Diagnostic
77.4% ND ND 77.4% +0.3 0/31
surgery
11.8% 25.0% 15.8% 22.6
Lesion excision –3.6 124/1527
(3.6–22.2%) (4.4–41.7%) (0.0–42.0%) (5.8–56.9%)
Lesion ablation 11.4% ND ND ND –2.4 0/79
Endometrioma 54.8 51.5%
ND ND ND 0/32
drainage only (52.9–75.0%) (22.9–80.0%)
Pelvic 6.7% 34.3% 28.7%
12.5% –2.2 27/182
denervation (5.8–15.0%) (8.6–48.1%) (10.0–36.0%)
Hysterectomy
with ovarian ND ND ND 19.1% ND ND
preservation
Hysterectomy
without ovarian ND ND ND 8.0% ND ND
preservation
0.0% 2.3% 4.1%
DIE 7.0% –6.2 63/779
(0.0–4.4%) (2.2–4.4%) (1.3–27.6%)
Singh S et al., submittedRecurrence rate of endometriosis
after surgical treatment
2 years 21.5%
5 years 40 - 50%
Guo SW, Hum Reprod Update 2009Current/future immune targets to
endometriosisTNF-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 rodentsBlockage of TNF-α
In vivo studies
TNF receptor fusion protein Soluble TNF-α receptors Monoclonal antibodies
(Etanercept) (r-hTBP-1) (Infliximab)
Rodents Baboons (c5N)
Inhibition of implants Inhibition of endometriosis
↓ Baboons ↓
No human study Inhibition of development Human study
and growth of endometriosis
↓
No human study
No pain studies in animalsBlockage of TNF - α
RCT study outline
21 women with rectovaginal endometriosis
Infliximab (n= 13) Placebo (n = 7)
40 weeks
↓
4 weeks observation Start of Menses
↓
12 weeks treatment 2 weeks
↓
Surgery 6 weeks
↓
24 weeks follow-up
Koninckx PR et al, Hum Reprod 2008Blockage of TNF - α (RCT)
Study outcomes
• 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 2008Blockage of TNF - α (RCT)
Study results
Koninckx PR et al, Hum Reprod 2008Blockage 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
Koninckx PR et al, Hum Reprod 2008Pentoxifylline
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
neutrophilsPentoxifylline in endometriosis
Cochrane review - Background
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)
Lu D et al., Cochrane Database Syst Rev, 2012Pentoxifylline in endometriosis
Cochrane review - Results
Primary outcome:
Pain reduction
Secondary outcome:
Clinical pregnancy
Secondary outcome:
Recurrence rate
Lu D et al., Cochrane Database Syst Rev, 2012Pentoxifylline in endometriosis
Cochrane review - Conclusions
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
Lu D et al., Cochrane Database Syst Rev, 2012PPAR-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 scoresPPAR-γ in endometriosis
Baboon model Surgically induced endometriosis 1 month treatment
Controls
n=6
Pioglitazone
n=6
Lebovic D et al., Endocrinology 2010PPAR-γ in endometriosis
Baboon model
Lebovic D et al., Endocrinology 2010PPAR-γ ligand pioglitazone
Human study
• 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)
Source: clinicaltrials.govInterferon α-2b
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
Ancién P et al., Fertil Steril, 2002Interferon α-2b
Study profile
Ancién P et al., Fertil Steril, 2002Interferon α-2b
Results
Ancién P et al., Fertil Steril, 2002Interferon α-2b
Conclusions
Intraperitoneal IF α-2b after conservative surgery increases
recurrence rates of ovarian endometriosis
No change in lymphocyte or IG levels
Ancién P et al., Fertil Steril, 2002Interleukin – 2
Background
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
Ancién P et al., Gynaecol Obstet Invest, 2003Ancién P et al., Gynaecol Obstet Invest, 2003
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, 2003V-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: MongoliaIRAK 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
IRAK-4 Inhibitors
IRAK-4 Inhibitor in cancer
Boher RN et al, AACR 2017Boher RN et al, AACR 2017
Current/future immune targets to
endometriosis
Clinicaltrials.gov
↓
Endometriosis (n = 306)
Not yet recruiting (12) Suspended (4) Completed (140)
Recruiting (57) Terminated (13)
Enrolling by invitation (6) Withdrawn (12)
Active, not recruiting (17)
With Without
Results (13) Results (127)
Unknown (45)Future prospects
Lesion
? Genetics
Colour
Pain Lesion
Infertility
Quality Location
Molecular Co-
History
Markers MorbiditiesStratified and precision medicine
Source: Manchester Precision Medicine Institutehttp://www.wrh.ox.ac.uk/research/endometriosis christian.becker@wrh.ox.ac.uk krina.zondervan@wrh.ox.ac.uk
TNF-α Esposito E & Cuzzocrea S, Trends Pharmacol Sci, 2011
Interleukin – 2
Results
Ancién P et al., Gynaecol Obstet Invest, 2003Evaluation of M1 and M2 Macrophages in Endometriotic Tissue of Women Affected by Endometriosis at Different Stages. NCT03136978 Open Label Immunotherapy of Endometriosis NCT03340324 Does Immunotherapy Have a Role in the Management of Endometriosis? NCT03464799 Endometriosis: Immunomodulation NCT01184144 Effect of Rosiglitazone on Peritoneal Cytokines in Women With Endometriosis NCT00121953 Effect of Anti TNFa Upon Deep Endometriosis Associated Pain (Infliximab) NCT00604864 PGL5001 Proof of Concept Study in Inflammatory Endometriosis (JADE) NCT01630252 Study to Investigate the Efficacy of a Non-hormonal Drug Against Endometriosis Associated Pelvic Pain NCT00185341
Pentoxifylline and Endometriosis (LETS1) NCT00632697
Attributes of ideal biomarkers Accessible Cheap Relevant Reliable Replicable Robust Sensitive Specific Simple Validated
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