François Lagacé, MD1; Elena Netchiporouk, MD, MSc, FRCPC1; Irina Turchin, MD, FRCPC2-4; Wayne Gulliver, MD, FRCPC5; Jan Dutz, MD, PhD, FRCPC6; Mark G. Kirchhof, MD, PhD, FRCPC7; Gizelle Popradi, MD, FRCPC8; Robert Gniadecki, MD, PhD, FRCPC9; Charles Lynde, MD, FRCPC10; Ivan V. Litvinov, MD, PhD, FRCPC1

1Division of Dermatology, McGill University, Montreal, QC, Canada
2Brunswick Dermatology Center, Fredericton, NB, Canada
3Division of Clinical Dermatology & Cutaneous Science, Dalhousie University, Halifax, NS Canada
4Probity Medical Research, Waterloo, ON, Canada
5Department of Dermatology, Discipline of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
6Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
7Division of Dermatology, University of Ottawa, Ottawa, ON, Canada
8Division of Hematology, Department of Medicine, McGill University, Montreal, QC, Canada
9Division of Dermatology, University of Alberta, Edmonton, AB, Canada
10Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflict of interest: Elena Netchiporouk has received grants, research support from Novartis, Sanofi, Sun Pharma, AbbVie, Biersdorf, Leo Pharma, Eli Lilly; speaker fees/honoraria from Bausch Health, Novartis, Sun Pharma, Eli Lilly, Sanofi Genzyme, AbbVie, Galderma, Novartis, Sanofi Genzyme, Sun Pharma, Bausch Health and Leo Pharma and consulting fees from Bausch Health, Novartis, Sun Pharma, Eli Lilly, Sanofi Genzyme, AbbVie, Galderma, Novartis, Sanofi Genzyme, Sun Pharma, Bausch Health and Leo Pharma. Irina Turchin served as advisory board member, consultant, speaker and/or investigator for AbbVie, Amgen, Arcutis, Aristea, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Kiniksa, Leo Pharma, Mallinckrodt, Novartis, Pfizer, Sanofi, UCB. Wayne Gulliver received grants/research support from AbbVie, Amgen, Eli Lilly, Novartis and Pfizer; honoraria for advisory boards/invited talks from AbbVie, Actelion, Amgen, Arylide, Bausch Health, Boehringer, Celgene, Cipher, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, PeerVoice, Pfizer, Sanofi-Genzyme, Tribute, UCB, Valeant and clinical trial (study fees) from AbbVie, Asana Biosciences, Astellas, Boehringer-Ingelheim, Celgene, Corrona/National Psoriasis Foundation, Devonian, Eli Lilly, Galapagos, Galderma, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, UCB. Gizelle Popradi has received honoraria or speaker fees from Jazz Pharma, Seattle Genetics, Abbvie, Kite Gilead, Pfizer, Taiho, Servier, Novartis, Merck, Kyowa Kirin, Abbvie, Avir Pharma, Mallinckrodt. Robert Gniadecki reports carrying out clinical trials for Bausch Health, AbbVie and Janssen and has received honoraria as consultant and/or speaker from AbbVie, Bausch Health, Eli Lilly, Janssen, Mallincrodt, Novartis, Kyowa Kirin, Sun Pharma and Sanofi. Charles Lynde was a consultant, speaker, and advisory board member for Amgen, Pfizer, AbbVie, Janssen, Novartis, Mallincrodt, and Celgene, and was an investigator for Amgen, Pfizer, AbbVie, Janssen, Lilly, Novartis, and Celgene. Ivan V. Litvinov received research grant funding from Novartis, Merck, AbbVie and Bristol Myers Squibb and honoraria from Janssen, Bausch Health, Galderma, Novartis, Pfizer, Sun Pharma, Johnson & Johnson and Actelion. Topics included in this article were based on, but not limited to, broad discussions at an advisory board meeting, which was sponsored and funded by Mallinckrodt, Inc. Consultancy fees were paid to meeting participants (EN, IT, WG, JD, MK, RG, CL and IVL). All other authors declare no existing competing interests.

Abstract:
Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used for over 35 years to treat numerous conditions. ECP was initially approved by the US FDA in 1988 for the treatment of Sézary syndrome, a leukemic form of cutaneous T-cell lymphoma (CTCL). Although CTCL remains the only FDA-approved indication, ECP has since been used off-label for numerous other conditions, including graft-versus-host disease (GvHD), systemic sclerosis, autoimmune bullous dermatoses, Crohn’s disease, and prevention of solid organ transplant rejection. In Canada, ECP is mainly used to treat CTCL, acute and chronic GvHD, and in some instances systemic sclerosis. Herein, we review the current concepts regarding ECP mechanism of action, treatment considerations and protocols, and efficacy.

Key Words:
extracorporeal photopheresis, cutaneous T-cell lymphoma, S.zary syndrome, systemic sclerosis, graft-versus-host disease, safety.


Introduction

Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used for over 35 years to treat numerous conditions (Figure 1).1,2 ECP was initially approved by the Food and Drug Administration (FDA) in the United States in 1988 for the treatment of S.zary syndrome (SS), a leukemic form of cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course, characterized by a triad of circulating neoplastic T-cells, erythroderma, and lymphadenopathy.1 Although CTCL remains the only FDA-approved indication, ECP has since been used as an off-label treatment for numerous other conditions, including graft-versus-host (GvHD) disease, systemic sclerosis (SSc), autoimmune bullous dermatoses, Crohn’s disease, and to prevent solid organ transplant rejection.1,2 In Canada, ECP is mainly used to treat CTCL, acute and chronic GvHD, and in some instances systemic sclerosis (Tables 1-2). The goal of this article is to review the current concepts regarding ECP mechanism of action, treatment considerations as well as suggested treatment protocols and efficacy in CTCL, GvHD, systemic sclerosis and other skin diseases.

Extracorporeal Photopheresis and Its Use in Clinical Dermatology in Canada - image
Figure 1. Mechanism of action of ECP. Figure adapted from Comprehensive Dermatologic Drug Therapy by Wolverton SE.1

Table 1. The use of ECP by hospital and by city in Canada in 2020.

Center (City, Province) # of Procedures (# of Patients)
Atlantic Health Sciences (Saint John, NB) 416 (18)
Foothills Centre (Calgary, AB) 407 (15)
L’Enfant-Jesus (Quebec City, QC) 426 (19)
Hospital for Sick Children (Toronto, ON) 40 (1)
University Health Network (Toronto, ON) N/A
Maisonneuve-Rosemont (Montreal, QC) 546 (25)
Royal Victoria (Montreal, QC) 294 (11)
Vancouver General Hospital (Vancouver, BC) 336 (20)
Total 2,465 (109)

Table 1. The use of ECP by hospital and by city in Canada in 2020.
Data from the University Health Network, Toronto, ON, where service is available, was not provided for this analysis. Data source: 2020 Canadian Apheresis Society.

Table 2. The use of ECP by city and by indication in Canada in 2020.

# of Procedures (# of Patients)
Indication Calgary Montreal Quebec City Saint John Vancouver Total
CTCL (MF/SS) 131 (8) 145 (5) 195 (7) 40 (2) 84 (5) 595 (27)
aGvHD 137 (3) 33 (3) 28 (2) 8 (1) 55 (3) 261 (12)
cGvHD 137 (3) 631 (27) 89 (5) 310 (13) 197 (12) 1,364 (60)
SSc 0 (0) 0 (0) 92 (3) 30 (1) 0 (0) 122 (4)
Other 2 (1) 31 (1) 22 (2) 28 (1) 0 (0) 83 (5)
Total 407 (15) 840 (36) 426 (19) 416 (18) 336 (20) 2,425 (108)

Table 2. The use of ECP by city and by indication in Canada in 2020.
Data from the University Health Network, Toronto, ON, where service is available, was not provided for this analysis. Data source: 2020 Canadian Apheresis Society.
CTCL - cutaneous T-cell lymphoma; MF - mycosis fungoides; SS - Sézary syndrome; aGvHD- acute graft vs host disease; cGvHD - chronic graft vs. host disease; SSc - systemic sclerosis

ECP involves placing a catheter to gain access to the venous circulation and collecting blood via continuous or discontinuous cycles, which is then centrifuged to create a leukocyte-rich buffy coat. The isolated leukocytes are then placed in a sterile treatment cassette, injected with liquid 8-methoxypsoralen (8-MOP) and exposed to ultraviolet A (UVA) radiation. Afterwards, the photochemically-altered white blood cells are returned to the patient’s venous circulation (Figure 1).1,2 The Therakos® ECP machine (the only available unit for this treatment) represents an automated closed system. Each treatment lasts approximately 1.5-3 hours, and the scheduling and frequency of treatments depend on the disease being treated.

The exact mechanism of action of ECP remains unknown, however, in CTCL, it is believed that the procedure leads to DNA-crosslinking and apoptosis of pathogenic T cells induced by 8-MOP with UVA exposure, the differentiation of monocytes to dendritic cell that present tumor antigens from apoptotic lymphocytes, stimulation of anti-tumor immune responses, and shifting of immunoregulatory cytokines to Th1 cytokine profile, such as interferon-gamma and tumor necrosis factor (TNF) alpha, thus restoring the Th1/Th2 balance.1-4 In particular, ECP targets mostly tumor cells since the absolute number of normal T cells remains relatively stable after the procedure.1 Given its therapeutic benefit in transplant rejection and autoimmune diseases, ECP is also believed to have unique immunomodulatory properties generating needed responses in an autoimmune setting, which are thought to be similarly mediated by DNA-crosslinking and apoptosis of autoreactive leucocytes (natural killer (NK) and T cells) and induction of T-regulatory cells after treatment, although this phenomenon was not observed in patients with SS.2 However, unlike immunosuppressive therapies, ECP is not associated with an increased risk of opportunistic infections.2 In fact, ECP is overall well-tolerated, with no reports of post-treatment Grade III or IV side effects, as per the World Health Organization classification.2 In particular, ECP is not associated with side-effects that are observed with skin systemic psoralen with UVA (PUVA) therapy, since the psoralen is not ingested orally nor applied to the skin.2 The side-effects are primarily related to fluid shifts and the need for a central catheter. Rare side-effects of ECP include nausea, photosensitivity, transient hypotension, flushing, tachycardia, congestive heart failure and thrombocytopenia.1,2 Contraindications to the use of ECP are summarized in Table 3. Currently, ECP is available in over 200 treatment centers across the world treating numerous diseases.2 The use of ECP by hospital, region and indication in Canada is summarized in Tables 1-2. Unfortunately, treatment access is limited in Canada and significant knowledge gaps are recognized (i.e., paucity of randomized clinical trials and real-world evidence) amongst physicians and patients. As a result, this treatment may be significantly underused in Canada.

Table 3. Summary of contraindications to the use of ECP

Contraindications
Absolute
  • Known sensitivity to psoralen compounds;
  • Pregnancy/lactation;
  • Aphakia;
  • Severe cardiac disease.
Relative
  • Poor venous access;
  • Thrombocytopenia;
  • Hypotension;
  • Congestive heart failure;
  • Photosensitivity;
  • Personal history of heparin-induced thrombocytopenia;
  • Low hematocrit;
  • Rapidly progressing disease.

Table 3. Summary of contraindications to the use of ECP

CTCL

CTCL represents a group of lymphoproliferative disorders where there is an accumulation of malignant T-cell clones in the skin.2 The most commonly recognized forms of CTCL are mycosis fungoides (MF) and SS. There are currently no curative treatments for CTCL, except for allo-transplantation which has been successful in select patients.2 ECP is often used as a first-line treatment for SS, as well as for patients with erythrodermic MF or advanced CTCL.1 Its use in early stages of CTCL remains controversial and impractical in Canada as many other effective treatment modalities are available (Table 4).5,6 ECP can be used as monotherapy or it can be safely given in combination with phototherapy (narrow band or broadband UVB), radiotherapy, total skin electron beam (TSEB), systemic retinoids, interferons, anti-CCR4 monoclonal antibodies, histone deacetylase inhibitors, methotrexate, and/or other treatments.1,2 One meta-analysis of 400 patients with all stages of CTCL showed a combined overall response rate (ORR) of 56% both when ECP was used as monotherapy and in combination with other therapies.2 The complete response (CR) rates were 15% and 18% for monotherapy and combination therapy, respectively.2 However, the ORR and CR were 58% and 15%, respectively, in erythrodermic patients, and 43% and 10% in patients with SS.2 The CR was defined as a complete resolution of clinical evidence of disease and for normalization of CD4/CD8 ratio for at least 1 month. The partial response (PR) was defined as greater than 25% but less than 100% decrease in lesions and no development of new lesions for at least 1 month. ORR was defined as a sum of PR and CR. Furthermore, the United Kingdom consensus statement analyzed 30 studies between 1987 to 2007 and determined that the mean ORR and CR rates were 63% (range 33-100%) and 20% (range 0-62%), respectively, with higher response rates observed in erythrodermic patients. Many factors can explain the variability in the results of these studies, such as patient selection bias, stage of the disease, ECP treatment schedule, prior treatments, and end-point definitions.2 In addition, there is a significant amount of inter-subject variability in response rates to ECP and factors that predict treatment response, as summarized in Table 5.2

Table 4. Treatment options for CTCL (MF)

Topical therapies
  • Corticosteroids
  • Bexarotene gel (United States)
  • Chlormethine gel/nitrogen mustard Tazaroten
  • Imiquimod
Ultravioletlight therapies
  • Narrow band UVB (if patches only)
  • PUVA (alone or in combination)
Systemic therapies
  • Interferon alpha
  • Oral bexarotene
  • Oral alitretinoin Mogamulizumab (anti-CCR4)
  • Brentuximab vedotin (anti-CD30 with monomethyl auristatin E)
  • Histone deacetylase inhibitors Methotrexate (low dose)
  • Alemtuzumab (low dose)
Chemotherapy
  • Pralatrexate (United States)
  • Gemcitabine (low dose)
  • Pegylated liposomal doxorubicin
  • CHOP (chemotherapy combination)
Additional treatments
  • Local radiotherapy (solitary or few tumors)
  • Total skin electron beam (generalized thick plaques and tumors)
  • Extracorporeal photopheresis (erythrodermic MF)
  • Allogenic hematopoietic stem cell transplantation

Table 4. Treatment options for CTCL (MF)5,6

Table 5. Baseline parameters and predictors of response to ECP in the treatment of cutaneous T-cell lymphoma, as per the European Dermatology Forum.

Skin
  • Erythroderma
  • Plaques <10-15% total skin surface
Blood and immune system
  • Low percentage of elevated circulating Sézary cells
  • Presence of a discrete number of Sézary cells (10-20% mononuclear cells)
  • CD4/CD8 ratio <10-15
  • Percentage of CD4+CD7- <30%
  • Percentage of CD4+CD26- <30%
  • Normal LDH levels
  • Blood stage B0 or B1
  • Lymphocyte count <20,000/μL
  • Percentage of monocytes >9%
  • Eosinophil count >300/mm3
  • No previous intense chemotherapy
  • Increased NK cell count at 6 months into ECP therapy 
  • Near-normal NK cell activity
  • CD3+CD8+ cell count >200/mm3
  • High levels of CD4+Foxp3+CD25- cells at baseline
Lymph nodes
  • Lack of bulky adenopathy
Visceral organs
  • Lack of visceral organ involvement
Other
  • Short disease duration before ECP (<2 years from diagnosis)
  • Increased peripheral blood mononuclear cell microRNA levels at 3 months into ECP monotherapy
  • Decreased soluble IL-2 receptor at 6 months into ECP 
  • Decreased neopterin at 6 months into ECP
  • Decreased beta2-microglobulin at 6 months into ECP 
  • Response at 5-6 months of ECP

Table 5. Baseline parameters and predictors of response to ECP in the treatment of cutaneous T-cell lymphoma, as per the European Dermatology Forum.
LDH - lactate dehydrogenase; NK - natural killer; CD - cluster of differentiation; ECP - extracorporeal photopheresis

Different countries have varying guidelines with respect to the use of ECP in CTCL. Most recently, the European Dermatology Forum (EDF) published new recommendations in 2020. They recommend considering ECP as first-line therapy in patients with MF clinical stages IIIA or IIIB (erythroderma), or MF/SS stages IVA1 or IVA2 (Tables 6-7). Treatments are recommended every 2 weeks for the first 3 months, then every 3-4 weeks, with a treatment period of at least 6 months or until remission is achieved, followed by a maintenance period (Table 8).2 ECP can take 3-6 months before a clinical response is appreciated, and therefore, no conclusions regarding its success should be drawn before that timeframe in erythrodermic patients.1,2

Table 6. TNMB classification of MF and SS

T (skin)
  • T1: limited patch/plaque (involving <10% of total skin surface)
  • T2: generalized patch/plaque (involving ≥10% of total skin surface)
  • T3: tumor(s)
  • T4: erythroderma
N (lymph node)
  • N0: no enlarged lymph odes
  • N1: enlarged lymph nodes, histologically uninvolved
  • N2: enlarged lymph nodes, histologically involved (nodal architecture uneffaced)
  • N3: enlarged lymph nodes, histologically involved (nodal architecture (partially) effaced)
M (viscera)
  • M0: no visceral involvement
  • M1: visceral involvement
B (blood)
  • B0: no circulating atypical (Sézary) cells (or <5% of lymphocytes)
  • B1: low blood tumor burden (≥5% of lymphocytes are Sézary cells, but not B2)
  • B2: high blood tumor burden (≥1000/mcl Sézary cells + positive clone)

Table 6. TNMB classification of MF and SS.6
TNMB - tumor-node-metastasis-blood; MF - mycosis fungoides; SS - Sézary syndrome

Table 7. Clinical staging for MF and SS.

Clinical Stage T (skin) N (lymph node) M (viscera) B (blood)
IA T1 N0 M0 B0-1
IB T2 N0 M0 B0-1
IIA T1-2 N1-2 M0 B0-1
IIB T3 N0-1 M0 B0-1
III T4 N0-2 M0 B0-1
IVA1 T1-4 N0-2 M0 B2*
IVA2 T1-4 N3* M0 B0-2
IVB T1-4 N0-3 M1* B0-2

Table 7. Clinical staging for MF and SS.6
MF - mycosis fungoides; SS - Sézary syndrome
* The required features for the three subdivisions of stage IV disease

Table 8. ECP recommendations by cutaneous disease, as per the revised guidelines by the European Dermatology Forum in 2020.

Cutaneous Disease Patient Selection Treatment Schedule Maintenance Treatment Response Assessment
CTCL (MF/SS) First-line treatment in erythrodermic stage IIIA or IIIB, or stage IVA1-IVA2 One cycle every 2 weeks at first, then every 3-4 weeks. Continue treatment for at least 6-12 months Treatment should not be stopped, but prolonged for >2 years, with treatment intervals up to 8 weeks To be conducted every 3 months. Treatment failure with ECP cannot be established before 6 months
aGvHD Second-line therapy in patients that are refractory to corticosteroids at a dose of 2 mg/kg/day 2-3 treatments per week for 4 weeks There is no evidence that maintenance therapy is beneficial. Discontinue ECP in patients with complete response Every 7 days with staging
cGvHD Second-line therapy in patients that are refractory to corticosteroids at a dose of 2 mg/kg/day or steroid intolerant or steroid dependant One cycle every 1-2 weeks for 12 weeks followed by interval prolongation depending on response Treatment intervals can be increased by 1 week every 3 months depending on response, and only after 12 weeks of treatment Disease monitoring as per the National Institutes of Health guidelines
SSc Second-line or adjuvant therapy as monotherapy or in combination with other therapy. Can be used to treat skin (but not internal organ involvement) One cycle every 4 weeks for 12 months Based on clinical response, increase intervals by 1 week every 3 months Clinically, and with validated scoring systems and photography
Atopic dermatitis

Second-line therapy if:

  • >18 months duration
  • SCORAD >45
  • refractory to all first-line therapies and one second line therapy
One cycle every 2 weeks for 12 weeks Intervals depend on the individual response; at maximal treatment response, ECP should be tapered by one treatment cycle every 6-12 weeks SCORAD assessment every 2 weeks for the first 12 weeks, then every ≥4 weeks
Pemphigus, epidermolysis bullosa acquisita, erosive oral lichen planus Recalcitrant to conventional systemic therapies One cycle every 2-4 weeks for 12 weeks, then one cycle every 4 weeks Taper by increasing intervals by 1 week every 3 months Clinically, and with validated scoring systems and photography (and with antibody titers in the case of pemphigus)
Lupus erythematosus, psoriasis, morphea, nephrogenic fibrosing dermopathy and scleromyxedema No current recommendations, more studies needed

Table 8. ECP recommendations by cutaneous disease, as per the revised guidelines by the European Dermatology Forum in 2020.2,11
SCORAD - SCORing atopic dermatitis; ECP - extracorporeal photopheresis; CTCL - cutaneous T-cell lymphoma; MF - mycosis fungoides; SS - Sézary syndrome; aGvHD - acute graft vs. host disease; cGvHD - chronic graft vs. host disease; SSc - systemic sclerosis

GvHD

GvHD can be either acute or chronic based on clinical presentation and time to disease development.1 Classic acute GvHD (aGvHD) occurs within 100 days of the transplantation with typical features, whereas chronic GvHD (cGvHD) presents after 100 days. However, persistent, recurrent or lateonset aGvHD can occur after 100 days with typical features of aGvHD. If features of both aGvHD and cGvHD are present, it is considered an overlap syndrome.7 cGvHD occurs in 30- 50% of patients receiving an allogenic transplant, involves multiple systems and most commonly presents with mucosal, skin, gastrointestinal and liver involvement.2 First-line therapy consists of systemic glucocorticosteroids with or without a calcineurin inhibitor. Second-line therapies include ruxolitinib, ECP, mycophenolate mofetil, mTOR inhibitors, methotrexate, calcineurin inhibitor. Second-line therapies include ruxolitinib, ECP, mycophenolate mofetil, mTOR inhibitors, methotrexate, imatinib, ibrutinib and rituximab.2 Notably, phase III randomized clinical trials evaluating ruxolitinib versus best available therapy for steroid refractory or dependent cGvHD demonstrated superiority of this drug when compared to ECP and other agents (ORR 50% vs. 26%, p<0.001).8 The average response rate to ECP is approximately 60% and studies have shown ORR rates ranging from 36-83%. In addition, CR in the skin, oral disease, and liver ranged from 31-93%, 21-100% and 0-84%, respectively.2 Best responses using ECP are seen in skin followed by gastrointestinal and then hepatic GvHD. The EDF recommends considering ECP as an additional secondline therapy in patients with cGvHD that is steroid-dependent, steroid-intolerant, or steroid-resistant, as well as for those with recurrent infections or with a high-risk of relapse (Table 8). Also, steroid-dependent patients (i.e., inability to reduce corticosteroid dose to <0.5 mg/kg/day without recurrence of Grade II or worse cGvHD) could benefit from ECP.

Similarly, systemic glucocorticoids are currently used as firstline therapy for aGvHD.2 However, response rates are <50%.2 In 2019, the US FDA approved ruxolitinib for steroid-refractory aGVHD in adult and pediatric patients ≥12 years of age. This approval was based on an open-label, single-arm, multicenter study of ruxolitinib that enrolled 49 patients with steroidrefractory aGVHD Grades II-IV occurring after allogeneic hematopoietic stem cell transplantation.9 Clinical trials have shown the superiority of ruxolitinib therapy when compared to ECP and other treatments (ORR 62% vs. 39%, p<0.001).10 In these patients, ECP may serve as an additional second-line treatment with ORR of 65-100% in the skin, 0-100% in the liver, and 40-100% in the gastrointestinal tract.2 As such, the EDF recommends adjunct ECP, as second-line therapy, in patients not responding to appropriate doses of systemic corticosteroids (Table 8). Interestingly, it is also showing promising results as a prophylaxis therapy to prevent cGvHD.1 This treatment option may be considered by dermatologists consulting on these patients in acute setting in the hospital especially at times when the diagnosis is uncertain, as ECP is recognized as not being an immunosuppressive therapy.

SSc

SSc is a multisystemic connective tissue disease characterized by collagen deposits in the skin and other visceral organs.1,11 Although there are currently no FDA-approved treatments for cutaneous involvement in SSc, limited studies have investigated the use of ECP and have shown promising results.11 For example, one multicenter trial showed that ECP was well-tolerated and improved disease severity, the mean percentage of skin involvement (-7.7% from baseline after 10 months, p=0.01) and the mean oral aperture measurements (+2.1 mm from baseline after 10 months, p=0.02).11,12 Other studies have shown that ECP leads to improvement in dermal edema and skin elasticity, normalization of collagen synthesis, and improvement of extracutaneous symptoms, and that ECP-treated patients with SSc have a favorable long-term survival.1,13 Further, one study found that, in most patients, ECP leads to a reduced usage of corticosteroids and other immunosuppressive agents, which have numerous adverse effects.14 The EDF currently recommends ECP as second-line or adjuvant therapy for SSc, either as monotherapy or in combination with other treatments (Table 8).11

Other Cutaneous Conditions

ECP has been studied in numerous other cutaneous diseases, including atopic dermatitis (AD), immunobullous diseases, eosinophilic fasciitis and others. Although there are many other treatment options for AD, including emollients, topical therapies, phototherapy/photochemotherapy, immunosuppressive medications, targeted therapies15 and monoclonal antibodies, several small open-label trials have shown that ECP is beneficial in patients with severe AD, including erythrodermic AD, that are not responding to standard therapy. Although previous guidelines have not recommended routinely treating AD with ECP given the lack of consistent findings and the multiple other treatment options available, the EDF’s revised guidelines recommend its use as second-line therapy in patients that meet specific criteria (Table 8).11 However, as new effective treatments are emerging for the treatment of AD, ECP should only be reserved for exceptional patients. Studies have also shown promising results for the use of ECP in pemphigus. One study of 11 patients with severe treatment-resistant pemphigus vulgaris or foliaceus showed an OR rate of 91% and CR rate of 73%.11 As such, the EDF recommends ECP in patients with pemphigus vulgaris or foliaceus that is recalcitrant to conventional first- and second-line therapies.11 Further, the EDF recommends considering ECP for severe epidermolysis bullosa acquisita (EBA) and erosive oral lichen planus that is refractory to conventional topical and/or systemic therapies.11 Low level evidence suggests a possible role for ECP in the treatment of lupus erythematosus, however, further controlled clinical trials are needed to assess its efficacy. For this reason, no official recommendations for the use of ECP in lupus erythematosus have been published to date.11 Studies have also investigated the use of ECP in other cutaneous diseases, including psoriasis, nephrogenic fibrosing dermopathy, morphea and scleromyxedema, however, the results have been inconclusive.11

Pediatric Population

Many studies support the use of ECP in a pediatric population. It has been used as an off-label treatment for various conditions, including aGvHD and cGvHD.11 In this patient population, the ECP protocol is adapted and can vary depending on the patient’s weight. Importantly, very few side effects are reported in this population, which further supports the favorable safety profile of ECP.11

Conclusion

In conclusion, ECP has been used on- and off-label for decades to treat numerous diseases, including SS, CTCL, GvHD, and SSc, among others. Results from multiple studies have shown promising response rates, and ECP has an overall excellent safety profile with very few adverse events reported.2,11 Unlike many other immunomodulatory therapies, an increased risk of infection has not been observed with ECP, which can be a significant cause of morbidity and mortality for patients on other immunosuppressive therapies.11 Although ECP is still being studied for multiple diseases, in Canada clinicians should restrict its use to the diseases that have been extensively studied, as per the EDF guidelines.

References



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Funding: The genesis of the paper was initiated at a meeting organized by a pharmaceutical company (Mallinckrodt Inc.) and EN, IT, WG, JD, MK, RG, CL and IVL were provided honoraria to attend that meeting. No funding bodies or other organizations had any role in data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgment: We thank RBC Consultants for editorial support, facilitating the preparation of tables, and coordinating the review of the manuscript.