¹Faculté de médecine, Université de Montréal, Montréal, Québec
²Division of Dermatology, McGill University, Montreal, Quebec

Conflicts of Interest: 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. Other authors declare no competing financial interests.

Introduction

Human Papillomavirus (HPV) is the most common sexually transmitted disease. Its lifetime
prevalence is >75% and this rate continues to increase.¹ This virus infects keratinocytes and is primarily transmitted by skin-to-skin contact.²

Chronic HPV infection, especially from low-risk strains such as 6, 11, 42, 43, and 44, plays an important role in the pathogenesis of cutaneous warts.³ For example, HPV strains 6 and 11 are responsible for 90% of anogenital warts (condyloma acuminate).⁴ Warts can also be found in the mouth, throat, penis/vagina and elsewhere on the skin.⁵

While many HPV infections are asymptomatic⁶, some can result in malignancies. A classic example of this in the skin is represented by carcinoma cuniculatum, a rare form of squamous cell carcinoma (SCC) that often presents on feet in the setting of a longstanding exophytic plantar wart, several decades after the initial infection.⁷ High-risks strains with the potential to lead to cancer or squamous intraepithelial lesions include 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and 70.³ The Canadian Cancer Society lists HPV as the fifth most preventable cause of cancer.⁸ However, this ranking likely underestimates the role of HPV in carcinogenesis since cutaneous SCCs, where HPV is recognized as a co-carcinogen, are not included in cancer statistics. Cutaneous SCCs and Basal Cell Carcinomas (BCCs), together called keratinocyte carcinomas, are the most common cancers with an estimated ~5.4 million new cases diagnosed every year in the United States alone.⁹

Notably, a high proportion of HPV-associated cancers are diagnosed in males.¹⁰ Since males are under-vaccinated and are increasingly disproportionately affected by certain HPV-associated cancers, namely oropharyngeal and penile cancers, current vaccination efforts should be refocused on male patients.^6,11-13 Effective vaccination protocols can help promote both physical health as well as mental health since male patients with HPV often encounter numerous psychosocial impacts secondary to their infection, namely depression, reduction in quality of life and sexual dysfunction.⁶

Male HPV Vaccination Statistics and Guidelines

HPV vaccination programs and guidelines have changed several times in the past decade, causing important gaps in vaccination rates between males vs. females. In 2007, the first Canadian vaccination program for school-aged females was implemented, and by 2010 all Canadian provinces had established vaccination programs for females.⁶ In Alberta, before the start of the vaccination program for school-aged males, 98.3% of vaccinated individuals were females.¹⁴ The first Canadian public vaccination program for males was launched in 2012, while national coverage for the vaccine was only established in 2017.⁶ In Ontario, even after the sex-neutral school vaccination programs were created, there was still a gap in HPV vaccination rates between males and females.⁶ Hence, most males remain unvaccinated for HPV, especially the middle age population, which is at risk of developing the aforementioned cancers in the future. One narrative review investigating reasons for suboptimal vaccination in males found that lack of information, the misconception that the virus only affects females, vaccine hesitancy, lack of recommendations from healthcare providers, costs and logistics all acted as barriers to vaccination.¹⁵

According to the National Advisory Committee on Immunization (NACI) of Canada, the HPV vaccine was previously only recommended for males ages 9 through 26 years to prevent anogenital warts and other HPV-associated cancers.¹⁶ However, now there is no age limit on receiving a quadrivalent or nonavalent HPV vaccine. While the vaccine before was not routinely recommended for males ages 27 to 45 years, the guidelines state that the vaccine may be administered to this age group if there is an ongoing risk of HPV exposure,⁶ for example, healthcare providers treating warts.¹⁷ Recent reports, however, strongly argued that this vaccine should be given to middle aged males.¹⁸ On the other hand, there is currently insufficient research to encourage HPV vaccination in males over 45 years of age.

Natural Immunity Post HPV Exposure in Males and Cancer Risks

There are important differences between males and females regarding their immune response to HPV. A study has shown that males are 4 to 10 times less likely to seroconvert after an HPV infection, regardless of the infected anatomic site.¹⁹ In fact, within 36 months after HPV DNA was detected as a result of an oral, anal or genital HPV infection (strains 6, 11, 16, 18), only 7.7% of men developed detectable serum HPV antibodies.¹⁹ In the same study, the seroconversion rate following a genital HPV 16 infection was only 4.1% in males compared to 60% in females.¹⁹ Further, the HPV in Men (HIM) study showed that healthy males do not have a reduced risk of subsequent HPV oral infection from natural HPV L1 antibodies (immunoglobulin G antibodies to the L1 capsid protein in serum) following an HPV infection, as it was previously thought.²⁰ Thus, these antibodies are not protective against future HPV infection and, unlike females, males are at risk of reinfection with the same HPV strain.²⁰ On the other hand, females’ existing antibodies confer partial immunity.¹⁹ As such, males acquire HPV infections at a steady rate.²¹ The prevalence of male genital HPV infections, which do not decrease with age (Figure 1), highlights the suboptimal natural immunity against HPV in males.

Importantly, in recent years the number of oropharyngeal SCC cancers has surpassed the number of cervical cancers caused by HPV. In fact, most of the oropharyngeal SCC cancer patients are males (Figure 2).²² Cervical cancer rates are declining, whereas oropharyngeal cancer rates in Canadian males are on the rise (Figure 3).¹² Anal cancer rates are also on the rise, while the incidence rates of penile and oral cancers, unfortunately, remain unchanged (Figure 3).^11-13

Some males are at a particularly higher risk for HPV-associated cancers. Males who have sex with males (MSM), especially MSM who have Human immunodeficiency virus (HIV), have higher rates of anal carcinoma.²³ Males who are solid organ transplant recipients also have higher rates of penile and anal cancer.²³ Additionally, there is currently no approved HPV DNA test for males in Canada.²⁴ In contrast, females who get a Pap test can be co-tested for HPV using a sample of cervical cells taken at the same visit.²⁵

Recommendations for Vaccinations Should Focus on Males and Health Care Professionals at Risk of HPV Exposure

Side Effects of Spironolactone

Taking into consideration the above important points, we recommend that all males at risk of exposure to HPV between the ages of 9 and 45 receive the vaccine. Sufficient data exists to update the current guidelines, which only recommend vaccination for males between the ages of 9 and 27.⁶ The recommended vaccine is HPV9 (GARDASIL^®9) a nonavalent vaccine that prevents HPV infections caused by strains 6, 11, 16, 18, 31, 33, 45, 52 and 58²⁶ and received in 2022 Health Canada approval for the prevention of oropharyngeal cancer and other head & neck cancers (along with the prevention of cervical, vulvar, vaginal and anal intraepithelial neoplasia) caused by HPV.²⁷ The nonavalent vaccine is preferred to the quadrivalent vaccine since it protects against a wider range of high-risk strains.²⁸

The effectiveness of the vaccine in males aged 27 to 45 is inferred from the efficiency data in females of the same age and by the immunogenicity data from the Mid-Adult-Aged Men (MAM) Trial.²⁹ The MAM Trial evaluating response to the quadrivalent vaccine showed a 100% seroconversion rate 6 months after vaccination in 150 males between the ages of 27 and 45.²⁸ Another study reported 95% seroconversion rate 28 weeks following the quadrivalent vaccine administered in males with HIV between the ages of 22 and 61.³⁰

The vaccine is also proven to be safe. In fact, a study demonstrating the safety profile of the quadrivalent HPV vaccine in adult men 27 to 45 years of age with HIV-1 found no grade 4 (life-threatening) or 5 (death) adverse events.²⁹ Most adverse events were of either mild or moderate intensity.²⁹ Given these promising results, the vaccine should be strongly recommended to unvaccinated males aged 27 to 45.

HPV Vaccination for Healthcare Professionals

HPV vaccination is also recommended to all physicians, nurses and residents in obstetrics and gynecology, oncology, dermatology and any staff that treat patients with warts.³¹ HPV DNA was found in the vapour of 62% and 57% of plantar warts treated with ablative laser and electrocautery, respectively.³² Normal non-lesioned skin was shown to contain in >60% of cases pathogenic HPV strains.³³ Hence, use of cautery on normal skin can too produce plume with HPV particles. This poses an occupational risk for dermatologists and other health care providers,¹⁷ which is why the vaccine is highly recommended in this group. In addition, reports indicate that (1) using local exhaust ventilation, (2) general room ventilation and (3) full personal protective equipment including a fit tested particulate respirator of at least N95 grade can decrease operator from HPV inhalation exposure.³⁴ Another study mentions that even though protective equipment, mainly gloves, can get contaminated with HPV, transmissions to medical professional is less likely to occur if the equipment is disposed of properly.³⁵

Conclusion

While the incidence of cervical cancer is decreasing in females, the incidence of oropharyngeal and other HPV-driven cancers is increasing at an alarming rate, especially in males. As such, vaccination efforts should be aimed at addressing this important public health concern. Males are significantly under-vaccinated compared to females and acquire HPV infections at a steady rate, with a very low rate of seroconversion following infection. Therefore, we advocate to provide routine vaccination against HPV in all males between the ages of 27 and 45, and continue to actively vaccinate males ages 9 to 26. Vaccines are effective, as shown by the high rate of post-vaccination seroconversion, which is an important factor in preventing oropharyngeal SCCs and other HPV-related cancers. Finally, it is crucial to routinely promote the HPV vaccination for all patients and healthcare professionals at risk of exposure to HPV, the same way we promote sun safety for all.

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.

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

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

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

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)

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

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

Table 7. Clinical staging for MF and SS.

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

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.

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.

Purchase Article PDF for $1.99