The Role of Extracorporeal Photopheresis in Scleroderma is presented by Jaehyuk Choi Assistant Professor in the Department of Dermatology Director of the Extracorporeal Photopherisis Unit

1. The Role of Extracorporeal
Photopheresis in
Scleroderma
Jaehyuk Choi
Assistant Professor
Department of Dermatology
Director, Extracorporeal Photopheresis Unit
10/15/16

2. Outline of the Talk
• Brief introduction to Scleroderma Pathophysiology
• Brief introduction to ECP.
• What is it? What is it used for? How does it work?
• Lessons from other diseases
• Discussion of clinical studies in scleroderma
• Ideal candidates for ECP.
• Timing of treatments
• Goals of treatment

3. Scleroderma
• Fibrosing disease.
• Area of High Clinical
Need!
• Better insurance coverage
for off-label use of
promising therapeutics.
• As of summer, 2015, there
are no FDA-approved
agents for scleroderma.

4. Immunopathogenesis of SSc
• Clear role of immune system in Scleroderma
• Genetics show mutations in innate immune genes and adaptive immune
genes predispose to this disease.
• Immunointerventions will likely be critical for effective treatment of this disease!

5. Immunopathogenesis of SSc
• Two types of treatments.
• Inhibit T helper cells.
• Upregulate Treg cells..
https://pharmaceuticalintelligence.com/tag/shrna/

6. • Can we selectively increase Treg’s in
scleroderma?

7. Is there a role for
photopheresis?
• Photopheresis
• One of the first FDA-
approved immunotherapies
• Now utilized world-wide
over 1 million times.
• FDA indicated for
scleroderma-like
conditions.
• FDA-approved for CTCL,
GVHD, and lung/heart
transplant rejection.
• Despite promising data, not
yet FDA approved for
scleroderma.
Choi, et al. Wolverton

8. What is photopheresis?
Choi, et al. Wolverton

9. ECP-Why use for
scleroderma?
• Mechanism of Action
• Effective in analogous diseases
• Data suggests multiple benefits for patients with
scleroderma

10. Mechanisms of Action
• Mechanisms of Action
• ECP generates dendritic
cells
• ECP generates apoptotic
cells.
• ECP generates Tregs
• Apoptotic cells and Tregs
dampen inflammation.
Marshall SR (2006) Technology Insight: ECP for the treatment of GvHD—can we offer selective immune control
without generalized immunosuppression? Nat Clin Pract Oncol 3: 302–314 doi:10.1038/ncponc0511

11. Generation of Tregs
• Indirectly through the activation of antigen presenting cells
https://pharmaceuticalintelligence.com/tag/shrna/

12. Mechanisms of Action
• 8-MOP and UV light
induces apoptosis
• Passage of blood through
ECP induces antigen
presenting cells.
• Infusion of apoptosis
generates Tregs in the
graft.
• The combination of
apoptotic cells and APCs
may be tolerogenic.
Blood. 2008 Aug 15; 112(4): 1515–1521.

13. Fig 1. Time course of FEV1 and peripheral blood CD4+CD25high Treg cells in six lung transplant (Tx) recipients treated with ECP.
Following the standard protocol used at our institution,8 ECP procedure was initially performed three times weekly and thereafter
patients were treated on 2 consecutive days at 2-week intervals for 3 months. Arrows indicate start of ECP treatment.
F. Meloni, A. Cascina, S. Miserere, C. Perotti, P. Vitulo, A.M. Fietta
Peripheral CD4+CD25+ TREG Cell Counts and the Response to Extracorporeal Photopheresis in Lung Transplant
Recipients
Transplantation Proceedings, Volume 39, Issue 1, 2007, 213–217
http://dx.doi.org/10.1016/j.transproceed.2006.10.227
Triangles- FEV1
Squares- CD4+CD25high
In other diseases, when the treatment
Is effective, Treg’s increase.

14. Immunopathogenesis of SSc
• Increase in Tregs should help disease.
https://pharmaceuticalintelligence.com/tag/shrna/

15. ECP Clinical Indications
• ECP
• Originally Approved for CTCL
• Repurposed for other diseases involving clonal T cells
• Autoimmune diseases and GVHD
• Other medicare-approved indications
• GVHD
• Heart and lung transplant
• Anecdotal usage
• Lichenoid dermatoses
• Sclerodermoid dermatoses.
• Crohn’s and UC

16. Chronic cGVHD
Dermatology 2008;216:287–304
• cGVHD
• Heterogeneous disease.
• Lichenoid lesions
• Poikilodermatous lesions
• Morpheaform
• Eosinophilic fasciitis
• Morbidity to the patients
• Risks associated with
systemic immunotherapy.
• Functional deficits
• Ulcers
• Special sites- Hands
• Chest- Restrictive lung
disease.

17. Treatment for GVHD
• Treatment of GVHD Is Similar to Treatment of
Scleroderma
• Steroids
• Systemic Immunosuppression

19. What can we learn from our
GVHD experience?
• Improvements in disease
• Reductions in systemic immunosuppression
• Improvements in overall survival

20. ECP for acute GVHD
doi:10.1038/ncponc0511

21. ECP for chronic GVHD
doi:10.1038/ncponc0511

22. What is the data for ECP in
GVHD?
• Improvements in disease
• Reductions in systemic
immunosuppression
• Improvements in overall survival

23. Immunosuppression can be
effectively reduced
• Foss, et al.
• 23 patients
• Heavily pretreated.
• 2 days/2 weeks
• Improvement in 71% of
patients
• 19/23 had decrease or cessation
of immunosuppressives
• 11/23 stopped pred.
• 12/23 decreased or stopped
MMF
• 5/23 decreased or stopped
prograf.
• Dignan, et al.
• 38 patients with steroid-
refractory GVHD
• 27 completed 6 months of ECP
• 19/27 had PR or CR
• 20 had a reduction in
immunosuppressive dose.
• 17 patients had less steroids
• 5 stopped completely, 4 >75%
reduction, 4 >50% reduction,
and 4<50% reduction.

24. What is the data for ECP in
GVHD?
• Improvements in disease
• Reductions in systemic immunosuppression
• Improvements in overall
survival

25. Improvements in overall
survival***
• 59 patients
• Heavily pretreated.
• 1-2 x/week until
improvement
• Then 2 days/q2-4 weeks
This figure was published in Haematologica, Volume 91: Greinix et al, The effect of intensified
extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-
versus-host disease, pp 405 408, Copyright a 2006 Ferrata Storti Foundation.

26. ECP- Data suggests earlier utilization of
ECP is better for patients
• Why?
• Some GVHD is irreversible.
• Some immunosuppression
side effects are irreversible
• Compression fractures.
• Earlier the better
• Couriel, et al. suggests a
better response for the
patients who have de
novo diagnosis of GVHD
Type No. CR/PR
De Novo 17 13
Progressiv
e
16 7
Relapsing 30 17

27. ECP- How frequently?
Reference Regimen Patients
(n)
CR or PR
(skin)
CR or PR
(liver)
CR or PR
(oral)
Duration
of Tx
Besnier 3x/week 5 4/4 1/ - 13-30 tx’s
Smith 0.67-3/wk 18 4/10 3/13 2/7 6-48 tx’s
Child 2x/month 11 10/10 1/6 - -
Salvaneschi 3x/wk 14 10/12 6/9 8/12 1-32 mos.
Apisrnthanarax Varied 32 19/32 - - 12-98 tx’s
Kanold 3x/wk 63 31/51 24/33 - -
Messina 2x/wk 44 20/36 12/20 - -
Bisaccia 3x/wk 6 4/6 3/3 2/2 2-13 mos.
Rubegni 1x/wk 32 22/27 18/23 23/25 ~35 tx
Foss 2x/wk 25 15/25 0/6 6/13 3-24 mos.
Overall 72% 63% 74%
doi:10.1038/ncponc0511

28. ECP-How long?
• ECP
• Takes time
• Median time to response.
• Steroid discontinuation
• Median time to
discontinuation in Foss
study= 84 days
BLOOD, 1 OCTOBER 2008 VOLUME 112, NUMBER 7

29. Limitations of the clinical
studies
• Limitations:
• Small clinical studies
• Many are retrospective
• Few are randomized or placebo controlled
• Almost none are double-blinded

30. ECP in sclerosing
diseases
• Case Reports
• Uncontrolled case series
• Controlled studies

31. Date of download: 12/15/2015
Copyright © 2015 American Medical
Association. All rights reserved.
From: Extracorporeal Photochemotherapy for Generalized Deep Morphea
Arch Dermatol. 2009;145(2):127-130. doi:10.1001/archdermatol.2008.547
• 49 yo woman
• 10 years ago developed a
rash on her skin
• Over next 5 years, the
rash spread.
• She developed pruritus
and tenderness.

32. Date of download: 12/15/2015
Copyright © 2015 American Medical
Association. All rights reserved.
From: Extracorporeal Photochemotherapy for Generalized Deep Morphea
Arch Dermatol. 2009;145(2):127-130. doi:10.1001/archdermatol.2008.547
• Over the past two years,
developed arthralgias.
• Increasing limitations to
mobility.
• Inability to work a full day.
• Frequent awakening at
night with pain and
discomfort in her skin and
joints.

33. Date of download: 12/15/2015
Copyright © 2015 American Medical
Association. All rights reserved.
From: Extracorporeal Photochemotherapy for Generalized Deep Morphea
Arch Dermatol. 2009;145(2):127-130. doi:10.1001/archdermatol.2008.547
• On examination,
cobblestoning of the skin.
• Coalescing indurated
bound down, reddish
purple dyspigmented
plaques.

34. Date of download: 12/15/2015
Copyright © 2015 American Medical
Association. All rights reserved.
From: Extracorporeal Photochemotherapy for Generalized Deep Morphea
Arch Dermatol. 2009;145(2):127-130. doi:10.1001/archdermatol.2008.547
• Heavily pretreated.
• Topical and systemic
steroids.
• Azathioprine
• MMF
• Skin-directed therapy

35. Date of download: 12/15/2015
Copyright © 2015 American Medical
Association. All rights reserved.
From: Extracorporeal Photochemotherapy for Generalized Deep Morphea
Arch Dermatol. 2009;145(2):127-130. doi:10.1001/archdermatol.2008.547
• ECP
• 2 consecutive days at 2-
week intervals
• Other treatments
• Weekly physical therapy

36. Date of download: 12/15/2015
Copyright © 2015 American Medical
Association. All rights reserved.
From: Extracorporeal Photochemotherapy for Generalized Deep Morphea
Arch Dermatol. 2009;145(2):127-130. doi:10.1001/archdermatol.2008.547
The patient's abdominal skin prior to treatment. Indurated and bound-down plaques coalesced to involve most of the abdominal
skin. These lesions were tender to palpation and pruritic.
The patient's abdominal skin after 15 months of treatment. The indurated plaques had completely resolved, with marked softening
noted. A residual reticulated erythema remained.
• Improvements with ECP
monotherapy
• Softening of skin on her
abdomen and upper and
lower extremities.
• Resolution of her rash on
her skin.
• Increased range of motion
in her shoulders
• Regrowth of hair on her
legs.

37. Date of download: 12/15/2015
Copyright © 2015 American Medical
Association. All rights reserved.
From: Extracorporeal Photochemotherapy for Generalized Deep Morphea
Arch Dermatol. 2009;145(2):127-130. doi:10.1001/archdermatol.2008.547
• Improvements in range of
motion.
• By 4 months, treatments
were tapered to every
three weeks then every 4
weeks 3 months later.

39. Patient
Older woman.
History of widespread sclerotic
plaques and scars
Pretreated with light therapy
and cyclosporine, MTX,
steroids.
High degree of pain and
disability.
Picture: October 2004
• Treatment
• 2003
• -start treatment with
mycophenolate mofetil.
• 2004
• Start ECP
• start 2 days q2 weeks
• Tapering every 6 cycles.
• After 10 weeks, ulcers
healed.
• Picture: April 2005

40. Largest, modern biomarker study to
date

41. Study design
• 16 patients
• 14 female; 2 male
• Average age 46.5 years
• Mean duration of disease is 3.9 years.
• Treatments
• 2 ECP treatments every 6 weeks.
• Assessments
• Ultrasound; modified RSS

42. Efficacy

43. Efficacy

44. What is the mechanism?

45. Increased levels of Tregs

46. Increased Treg function

47. Increased Treg cytokines

48. What is the mechanism?

49. Decreased levels of Th17
cells and cytokines

50. Decreased levels of harmful,
fibrosis-inducing cytokines

51. Single-blind trial
• Single-blind comparison of ECP vs. D-
penicillamine
• 79 patients
• 2 consecutive days monthly
• Results
• 21 of 31 on ECP responded (68%)
• 8 of 25 with D-penicillamine. (32%)
• Improvements in skin severity score,
percent skin involvement, and mean
oral aperture.
• Significant improvement with ECP at 6
months.
• No improvement at 6 months with D-
penicillamine.
0
10
20
30
40
50
60
70
80
Response
Respo…

52. Larger studies
• Double-blind placebo
controlled study
• 64 patients
• 16 institutional sites.
• Recent onset of disease.
• Receive photopheresis or
sham.
• Excluded patients with renal,
pulmonary disease.
• ECP 2 days every 4 weeks
for 12 months
• Improvements in skin
score at 6 months and 12
months.

53. Improvements in Skin
• Results
• Improvements in skin score
• Statistically significant
improvement in skin scores
as compared with baseline
at 6 and 12 months.

54. Improvement in Joints
• Results
• Improvements in joints
• No statistically significant
differences in joints with
contractures in the placebo
group.
• Significant decreased
number of affected joints in
patients treated with ECP.

55. State of the field
• Photopheresis is a safe immunotherapy effective for
many immune based diseases including lung/heart
transplant rejection and treatment of sclerodermoid
GVHD.
• ECP appears to increase Tregs
• Case reports and small studies support its use in
scleroderma.
• Who is most likely to benefit?
• High skin involvement.
• Early stage disease (<2 years)
• ? Combination treatment

56. Future Directions
• FDA and many insurance companies believes the
data is not sufficient.
• Need for more studies.
• Need biomarkers

57. ECP at Northwestern
• Work closely with referring doctors and patients
• Default protocol
• 2x/week for 6 weeks and then taper.
• Tapering occurs with clinical responses.
• Reassess after 3 months
• Assess for changes in disease
• Assess for changes in doses of systemic
immunosuppression.

58. ECP unit at Northwestern
• Patient oriented:
• May adjust schedules to facilitate
• Medical staff at visits
• Address clinical issues
• Reduce the rate of cancellations.
• Decrease time from referral to visits.
• Reduce blood draws
• We will work with our referring providers to minimize phlebotomy
for patients.
• Access
• Only observed adverse effect is line sepsis
• We will try to work with you in the best interests of the patient to ensure
intravenous access.
• We would like to minimize ports or catheters.

59. ECP Unit at Northwestern
• Data driven
• Drs. Galvin, Zhou, and myself
• In conjunction with the pediatrics unit
• Will try to collect data that will be useful for future
studies.

60. ECP team
• Rube Walker
• Administrators
• Nursing Staff
• Physicians