The Role of Extracorporeal

Photopheresis in Scleroderma

Jaehyuk ChoiAssistant Professor

Department of DermatologyDirector, Extracorporeal Photopheresis Unit

10/15/16

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

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.

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!

Immunopathogenesis of SSc• Two types of treatments.

• Inhibit T helper cells.• Upregulate Treg cells..

https://pharmaceuticalintelligence.com/tag/shrna/

• Can we selectively increase Treg’s in scleroderma?

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

What is photopheresis?

Choi, et al. Wolverton

ECP-Why use for scleroderma?

• Mechanism of Action• Effective in analogous diseases• Data suggests multiple benefits for patients

with scleroderma

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

Generation of Tregs• Indirectly through the activation of antigen presenting cells

https://pharmaceuticalintelligence.com/tag/shrna/

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.

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- FEV1Squares- CD4+CD25high

In other diseases, when the treatmentIs effective, Treg’s increase.

Immunopathogenesis of SSc• Increase in Tregs should help disease.

https://pharmaceuticalintelligence.com/tag/shrna/

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

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.

Treatment for GVHD

• Treatment of GVHD Is Similar to Treatment of Scleroderma• Steroids• Systemic Immunosuppression

What can we learn from our GVHD experience?

• Improvements in disease• Reductions in systemic immunosuppression• Improvements in overall survival

ECP for acute GVHD

doi:10.1038/ncponc0511

ECP for chronic GVHD

doi:10.1038/ncponc0511

What is the data for ECP in GVHD?

• Improvements in disease

• Reductions in systemic immunosuppression

• Improvements in overall survival

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.

What is the data for ECP in GVHD?

• Improvements in disease• Reductions in systemic immunosuppression

• Improvements in overall survival

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.

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/PRDe Novo 17 13Progressive

16 7

Relapsing 30 17

ECP- How frequently?Reference Regimen Patient

s (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’sKanold 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 txFoss 2x/wk 25 15/25 0/6 6/13 3-24

mos.Overall 72% 63% 74%

doi:10.1038/ncponc0511

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

Limitations of the clinical studies

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

ECP in sclerosing diseases

• Case Reports• Uncontrolled case series• Controlled studies

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.

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.

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.

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

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

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.

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.

PatientOlder woman.History of widespread sclerotic plaques and scarsPretreated 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

Largest, modern biomarker study to date

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

Efficacy

Efficacy

What is the mechanism?

Increased levels of Tregs

Increased Treg function

Increased Treg cytokines

What is the mechanism?

Decreased levels of Th17 cells and cytokines

Decreased levels of harmful, fibrosis-inducing cytokines

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.

D-Penicil-lamine

ECP0

20406080

Response

Respo...

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.

Improvements in Skin • Results

• Improvements in skin score

• Statistically significant improvement in skin scores as compared with baseline at 6 and 12 months.

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.

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

Future Directions

• FDA and many insurance companies believes the data is not sufficient.

• Need for more studies.• Need biomarkers

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.

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.

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.

ECP team• Rube Walker

• Administrators• Nursing Staff• Physicians