Extracorporeal Photopheresis in Dermatological Diseases

Extracorporeal photopheresis (ECP) is an apheresis procedure that is conventionally used as a first-line treatment for cutaneous and leukemic subtypes of T-cell lymphoma, such as Sezary’s syndrome and mycosis fungoides. Over the past three decades, its immunotherapeutic properties have been tested on a variety of autoimmune conditions, including many dermatologic diseases. There is ample evidence of ECP’s ability to modify leukocytes and alter cytokine production for certain dermatologic diseases that have been refractory to first-line treatments, such as atopic dermatitis. However, the evidence on the efficacy of ECP for the treatment of these dermatologic diseases is unclear and/or lacks sufficient evidence. The purpose of this paper is to review the literature on the utilization and clinical efficacy of ECP in the treatment of several [autoimmune] dermatologic diseases and discuss its applications, guidelines, recommendations, and future implementation for dermatologic diseases.


Introduction 1.Photopheresis
Extracorporeal photopheresis is a nonsurgical procedure that was first introduced in 1988 as a way to treat cutaneous T-cell lymphoma (CTCL) [1].However, over the past three decades, ECP has been utilized as a therapeutical treatment for a variety of diseases, along with hematopoietic stem cell transplantation and graft vs. host disease.During an ECP procedure, plasma is extracted via a cubital vein or a permanent catheter and flows into the photopheresis device.The photopheresis device utilizes centrifugation to separate the leukocytes or "buffy coat" from the rest of the plasma.The rest of the plasma is returned to the patient while the separated leukocytes are then treated with 8-methoxypsoralen (8-MOP), also called psoralen, a compound used to increase the amount of UV light that is absorbed in the patient's leukocytes, commonly found in lemons and figs [2].Once the white blood cells are chemically treated, they are then exposed to ultraviolet light (UVA), ranging from 329 to 400 nm, which activates the 8-MOP, which forms cross-links in the DNA, inducing cell injury and apoptosis [3].These treated leukocytes are then reintroduced back into the patient, where the patient's immune system targets the damaged leukocytes for apoptosis [4].

ECP Mechanism of Action
There is some debate as to whether or not the amount of apoptotic material reintroduced to the patient's blood will outcompete the patient's immune system's ability to clear the apoptotic debris from their system.The massive amount of uncleared apoptotic debris can then go on to wreak havoc on the immune system by inducing pathways such as cell necrosis, auto-antibodies to the uncleared apoptotic material, and an increase in other inflammatory factors, which could potentially result in autoimmune disorders such as systemic lupus erythematosus (SLE).However, scientists such as Renzo et al. have found that rarely do patients with a massive amount of apoptotic debris in a patient's system go on to develop clinical autoimmune diseases [5,6].Additionally, there are no reports that show that ECP procedures can lead to the onset of autoimmune diseases.

Atopic Dermatitis
Atopic dermatitis (AD) is a chronic eczematous disease that affects an estimated 16.5 million U.S. adults, with about 40% diagnosed with a moderate to severe course of the disease [9].Patients usually present with erythematous papules localized to the face, trunk, extremities, and flexor surfaces.Patients can also present with dry, scaly patches on their extremities as well as lichenization, which presents as thick and leathery patches of skin due to chronic itching.Although the mechanism of action behind atopic dermatitis is not completely understood, it is universally understood as a multifactorial disease, with genetic and environmental factors playing a role in the onset and persistence of this disease.A possible genetic cause that might play a role in the onset of AD in a subset of patients includes a genetic defect in the FLG gene, which is responsible for the production of filaggrin protein, which normally serves as a part of the skin protection barrier that maintains hydration to the skin [10].This causes an impairment in the permeability of the epidermis, allowing antigens to diffuse into the lower layers of the epidermis and dermis, activating Th2 cells, which produce IL-4 and IL-13, ultimately leading to an inflammatory response [10].Many first-line treatments, such as calcineurin inhibitors and corticosteroids, have been utilized in order to treat this debilitating condition; however, several moderate to severe AD patients are recalcitrant to these therapies, especially if AD is chronic and widespread.
ECP, for the treatment of AD, has been explored as early as 1994 [11].A summary of each of the ECP treatments for AD is depicted in Table 2.  Prinz et al. observed that patients showed a noticeable decrease in skin lesions and an improvement in pruritic symptoms and erythema [11].Additionally, the laboratory results showed a decrease in IgE in all three patients with stable IgG, IgA, and IgM levels, suggesting that ECP may interfere with the pathogenic mechanisms behind AD [11].Over the next three decades, many prospective, retrospective, and case reports that followed have all validated the previous finding that ECP has been proven effective in the treatment of severe AD (n = 167).Many of the studies followed the EDF recommendation for initial treatment scheduling and administered ECP in 2-week intervals for 12 weeks and decreased the ECP treatments thereafter.Prospective trials that proved ECP efficacious include Wolf et al., who conducted ECP treatments over a 20-week period on 10 AD patients that had a SCORAD of >45 and were refractory to first-line therapies.The results show that there was a significant decrease in the mean of the SCORAD of all patients by week 20 [18].Additionally, a recent study conducted by Gambichler et al. found measured blood parameters at 3-month intervals up to 1 year of treatment in 60 AD patients treated with ECP.Leukocytes and lymphocytes were found to remain decreased after one year of ECP treatment [23].Additionally, there was a significant decrease in eosinophils and eosinophil cationic protein levels, along with IgE and lactate dehydrogenase levels [23].
Accumulation of the positive findings has led to the EDF labeling ECP as a second-line treatment for refractory and severe AD.The EDF states that the initial treatment dosage is recommended to be one cycle every 2 weeks for 12 weeks.Maintenance schedules should be tailored to the patient; however, the goal is to taper the ECP treatment to one cycle every 6-12 weeks [8].Clinical assessment includes a biweekly SCORAD assessment for the first 12 weeks and then at monthly or longer intervals.In contrast, AFSA has acknowledged that ECP could be a beneficial treatment based on the previously published high-quality literature; however, there is not enough evidence for AFSA to confidently label ECP as a first-or second-line treatment for AD.Therefore, more studies on the efficacy of ECP on refractory AD patients should be conducted in order to verify the observations of previously published literature.

Cutaneous Lupus Erythematosus
Cutaneous lupus erythematosus (CLE) is a subtype of lupus erythematosus (LE) that solely affects the skin.This autoimmune disease has ten subtypes, including acute cutaneous lupus, subacute cutaneous lupus, and discoid lupus [24].Acute cutaneous lupus is the typical "butterfly rash" that is seen in systemic lupus erythematosus (SLE), which usually involves autoimmune destruction of other organs.Subacute cutaneous lupus is solely limited to the skin and is characterized by red/pink polycyclic annular patches or plaques seen in sun-exposed areas.Discoid lupus is normally limited to the face and is described as red macules/plaques that evolve into atrophy, scarring, and pigment changes and rarely have mucosal involvement [24].Evidence of the use of ECP for the treatment of LE is depicted in Table 3.A case series conducted by Knobler et al. utilized 10 patients diagnosed with SLE and treated the patients with two ECP treatments every 4 weeks for 6 months, followed by one treatment every 8 weeks for 6 months.Only 8 out of the 10 patients could complete the study, as one dropped out for personal reasons, and another patient passed away during the study [25].The results of the study showed that at 4-6 months, seven out of the eight patients showed significant improvement in their skin manifestations, such as discoid rash, alopecia, and photosensitivity, with an improvement in their arthralgias.These patients were able to decrease their dose of immunosuppressants and steroids.It was also noted that there were no notable changes in the serology measurements during or after this trial [25].The remaining evidence of ECP on LE treatment is limited to case reports with chronic CLE patients (n = 3), subacute cutaneous lupus (n = 4), discoid lupus erythematosus (n = 2), and SLE accompanied with urticarial vasculitis (n = 1) [27][28][29][30][31][32].All the case studies reported positive effects on ECP, including complete remission in several patients, with partial remission in others, regardless of photosensitivity.
Despite the evidence that shows that cutaneous lupus erythematosus can be treated successfully with ECP, the ASFA has not published guidelines on the use of ECP for cutaneous lupus erythematosus, most likely due to the lack of external validity.However, the EDF guidelines state that the preliminary results prove to be an effective and safe option for lupus erythematosus.

Dermatomyositis
Dermatomyositis (DM) is a rare idiopathic disease that affects about 200,000 individuals in the United States [33].DM is characterized by inflammatory myopathy and cutaneous skin findings.Cutaneous skin findings include pruritic, red, or violet-colored skin, most commonly found on sun-exposed areas, such as the face, eyelids, elbows, knees, chest, and back.
Evidence of the use of ECP for the treatment of DM is limited to case reports.One case reported that ECP successfully treated an 18-year-old female diagnosed with juvenile DM and was recalcitrant to methotrexate therapy [34,35].Another case report modifies the ECP procedure by using autologous cryopreserved mononuclear cells in order to reduce apheresis sessions for patients who are treated at distant care facilities.The results of the study proved cryo-ECP to be safe while effectively reducing the number of apheresis sessions [35].In the ASFA recommendations published in 2016, dermatomyositis was initially labeled in the IV category with a 2C grade of recommendations, meaning "very weak references" [36].Due to the continuous lack of evidence, the newest ASFA recommendations published in 2019 retired the DM fact sheet from its guidelines.

Eosinophilic Fasciitis
Eosinophilic fasciitis (EF) is a type of rare sclerodermiform syndrome caused by a thickening and inflammation of the muscular fascia and subcutaneous tissue due to eosinophilic infiltrates.Currently, the cause of this disease is unknown, and the current treatment for this disease includes a combination of methotrexate with systemic glucocorticoids [37].
Evidence on the efficacy of ECP for the treatment of EF is limited to case reports (n = 6) [38][39][40].Minciullo et al. administered ECP treatments on two patients who developed eosinophilic fasciitis after undergoing an allogeneic bone marrow transplantation [40].Both patients reported a significant improvement in their symptoms after 7 and 11 months, with one patient experiencing a normalization of their eosinophil counts [40].Romano et al. treated three patients with EF that had contraindications or were refractory to first-line treatments [39].After one year of therapy, two patients experienced a significant clinical improvement in their clinical parameters, while one patient experienced a moderate improvement.All three patients reported an increase in their quality of life and were able to decrease the dose of their immunosuppressants [39].Partarrieu-Mejias et al. reported a successful ECP treatment for a patient who was diagnosed with steroid-resistant EF [38].
Although the literature shows promising results on the usage of ECP for the treatment of EF, the lack of evidence hinders its recognition by the ASFA and EDF as a safe and effective treatment.Therefore, further studies on this topic are recommended.

Lichen Planus
Lichen planus (LP) is an idiopathic disease that usually affects middle-aged adults, causing inflammation of the skin and mucous membranes.Symptoms are often remembered by the "six P's": pruritic, purple, polygonal, planar, papules, and plaques" [41].The mucous membranes that are commonly affected include oral membranes that are normally characterized by lacy, white, thread-like lesions known as Wickham's striae.Other presentations of oral lichen planus include plaque-like, papular, erosive, bullous, and ulcerative lesions [42].The pathogenesis behind this disease has been linked to cytotoxic T-cells that target the skin and mucous membranes, inducing apoptosis of the epithelial basal cells [43].High-potency topical steroids and retinoic acid are the first-line treatments in treating all forms of this condition, including mucosal, urogenital, and cutaneous erosive lichen planus [44].However, these therapies have shown to be ineffective against severe subtypes of LP, such as chronic erosive LP.
There are several studies of varying study designs that show promising results that ECP has a positive effect on severe lichen planus, especially in patients suffering from oral erosive lichen planus.The results are summarized in Table 4.  Recent studies include a retrospective study of 11 patients suffering from oral erosive lichen planus that were calcitrant to at least two treatments [54].Two sessions of ECP were administered for two consecutive days every two weeks at the beginning of the treatment, followed by a tapering off of the treatments, depending on the patient's therapeutic response and tolerance.The response assessment was measured by complete clinical remission, characterized by the complete healing of erosions and partial remission, and characterized by the regression of functional symptoms but persistence in the same number of erosions that were seen pre-ECP treatment.The results showed that 6 out of 11 patients achieved complete remission at a mean of 5.5 months, and the remaining patients obtained partial remission.Although a relapse was observed in longer time lapses between ECP sessions and after the discontinuation of ECP treatment, the symptoms disappeared once the ECP treatments resumed [54].The most recent case study validates the earliest case report as well as the two decades of case reports that followed, proving that ECP can be used to treat many severe subtypes of lichen planus [53].Molochkova et al. reported a patient who was diagnosed with LP pigmentosus that was refractory to topical and intralesional corticosteroids.The patient received four sessions of ECP along with IM chloropyramine and loratadine, and after the fourth treatment, the lesions were noted to have faded, and a decrease in pruritis was also observed [53].
Despite the positive evidence, the ASFA has yet to recognize ECP as an effective treatment for LP.EDF has stated that ECP can be used for oral erosive LP when all conventional therapies, including systemic and topical therapies, have failed.The recommended treatment scheduling includes two successive treatments every 2 weeks for the first 12 weeks, followed by two successive treatments every 4 weeks for an additional 12 weeks.Maintenance dosages should be tailored to the patient and their clinical response.A response assessment is recommended to be based on the disappearance of the lesions.

Lichen Sclerosis
Lichen sclerosis (LS) is a rare, idiopathic, autoimmune pruritic disease that is most commonly seen in pre-pubertal and post-menopausal women [55].LS is known to cause white, hypopigmented, thin patches on the skin that are most commonly present in the genital area.First-line treatment includes topical steroid ointments.
Evidence of the ECP procedure on LS lesions is limited to three case reports (n = 3).ECP proved successful in all three patients with severe refractory LS [56][57][58].One of these patients had severe extragenital LS that covered the flexor surfaces of the legs, arms, and ankle joints, along with the upper aspects of the arms, legs, and neck [58].The patient was not only refractory to topical steroids and phototherapy with psoralen + UVA but also presented with severe joint restriction due to LS patches that impaired her ability to walk and plantarflex.A total of 14 ECP cycles were conducted that consisted of two consecutive ECP sessions every 2 weeks for 3 months, followed by one ECP session a month.By the fourteenth cycle, her joint mobility was noted to significantly improve, reaching almost normal joint mobility values.Additionally, the patient was able to walk after the LS patches appeared to remain stable after a 6-month follow-up.The remaining LS cases showed that refractory LS could show remission in as little as four and seven ECP treatments with no adverse side effects [56,57].
Although the results of this case study prove promising, the lack of evidence discourages the ASFA and the EDF from grading the efficacy and usage of this disease in its guidelines.Therefore, more research on the efficacy of ECP on LS should be explored.

Morphea (Localized Scleroderma)
Scleroderma, also known as systemic sclerosis (SS), is an idiopathic autoimmune disease that appears more commonly in women and causes vasculopathy and fibrosis of the dermis.SS can be local or diffuse and may affect visceral organs such as the heart, lungs, and digestive tract.Systemic scleroderma includes diffuse systemic sclerosis and limited cutaneous systemic, which presents with CREST syndromes such as calcinosis and telangiectasis.All forms of systemic scleroderma usually include organ involvement, whereas localized scleroderma, such as morphea and linear scleroderma, are solely confined to the skin.Since the ASFA recommends ECP as a treatment for SS without organ involvement, the review will be focused on the localized scleroderma form of SS.Localized scleroderma (LoS) has an incidence of 3/100,000 individuals each year and can present as linear, round, or oval-shaped plaques that usually appear on the trunk and proximal extremities [59,60].Although the pathophysiology is complex, it is hypothesized that the inflammation in LoS triggers the connective tissue cells to produce an excessive amount of collagen, leading to fibrosis of the skin [61].
There is mixed evidence regarding the efficacy of ECP on localized scleroderma, which is summarized in Table 5.

Cribier et al. conducted an open clinical trial
where seven patients with SS and two patients with severe localized scleroderma received ECP treatments for six months without any simultaneous treatments [62].A physical assessment after six months showed that the cutaneous manifestations of the SS increased in severity in 4/7 of the patients, with the remaining patients observing no change to their indurations.Visceral involvement did not improve after ECP treatment, and it was concluded that ECP was not effective as a treatment for those with SS.In regards to the localized scleroderma patients, one patient had to terminate their treatment halfway through the study due to the lack of vascular access, and their 6-month assessment was not recorded, while the other patient experienced a decrease in the multitude of their plaques and the visibility of their lesions decreased at 16 months of ECP treatment [62].In a recent prospective study, twelve patients diagnosed with severe localized scleroderma refractory to treatment received an ECP session every two weeks for six months [65].The response assessment to treatment included a physical assessment as well as a high-frequency ultrasound session.The results showed that the majority of patients (7/12) saw a decrease in skin thickening/hardening of their plaques, while two patients experienced a halt in their uncontrolled disease progression.One patient did experience a continuation of their localized scleroderma despite treatment, but all patients did not experience any adverse side effects.
Although studies such as Cribier et al. suggest that ECP is ineligible to treat SS, there is an ample amount of evidence that tips the scales in favor of ECP as a treatment for cutaneous manifestations of systemic sclerosis due to its positive effects on the overall improvement or halt in the progression of the skin manifestations of this disease [68][69][70].Therefore, it has been recognized by the EDF as a second-line treatment for the cutaneous manifestations of SS.However, although the AFSA recognizes the potential benefits of ECP on SS, they require more evidence in order to state that ECP would be an effective secondor first-line treatment for the disease.Additionally, it is yet to be clarified as to whether or not that acknowledgment extends to localized scleroderma, as LoS and SS are found to be two distinct clinical entities that share similar histopathologic and serology findings [71].

Necrobiotic Xanthoma
Necrobiotic xanthoma (NX) is a rare chronic granulomatous disorder that manifests as nodules and yellowish plaques on the skin that are most commonly found in the peri-orbital region [72].Although the pathophysiology is not well understood, it is associated with monoclonal gammopathy, cholesterol build-up, and hypocomplementemia [73].
There is only one case report to date that explores the possibility of ECP treatment on refractory necrobiotic xanthogranulomas, which reports a positive and beneficial outcome of the use of ECP for refractory NX [74].However, due to the lack of evidence, NX is not recorded in the EDF or ASFA as a condition that can be treated with ECP.Therefore, further research is suggested to explore the usage of ECP on refractory NX.

Nephrogenic Systemic Fibrosis
Nephrogenic systemic fibrosis (NSF) is a rare idiopathic disease that is commonly found in people who have been diagnosed with advanced kidney failure after exposure to gadolinium, a chemical used in magnetic resonance imaging (MRI).This condition causes thickening and fibrosis of the skin, cutaneous tissues, and sometimes skeletal muscle and can cause swelling, pain, and joint contractures [75].
Evidence for photopheresis as an efficacious treatment for NSF is limited to case series and reports, but all the published literature observed positive effects utilizing ECP (n = 16) [76][77][78][79][80][81][82].One case series reported that all three of the patients treated with ECP found an improvement in their joint mobility and softening of skin indurations in as little as 4 cycles of treatment, with one patient developing complete remission after 16 cycles of therapy [76].The most recent case study published to date explored the usage of ECP on a NSF patient refractory to sodium thiosulfate, who presented with severe and progressive skin fibrosis that restricted his joint mobility on all four limbs [82].Therapeutic dosages were utilized according to ASFA's guidelines for therapeutic dosages for ECP for the treatment of several diseases (two consecutive treatments (one cycle) per week for four weeks).The maintenance therapeutic dosage after a 3-month pause in treatments included one cycle every 2 weeks for 12 weeks and then one cycle monthly.The results show that the patient exhibited a significant improvement in skin lesions and joint mobility after four cycles of ECP.Before ECP therapy, the patient was wheelchair-bound, and after four cycles of therapy, the patient was able to walk approximately 150 ft without any assistance.The patient's skin lesions and joint mobility were steadily improving until about 14 months of therapy when the benefits seemed to plateau [82].
Due to the sparse amount of studies that prove photopheresis as a beneficial treatment for NSF, the ASFA and EDF recognize ECP as a potential treatment for NSF but under weak evidence, as stated in Table 1.

Pityriasis Rubra Pilaris
Pityriasis rubra pilaris (PRP) is a rare inflammatory and idiopathic papulosquamous disease that is characterized by well-demarcated and distinct orange-hued patches and plaques [83].These scaly patches are most commonly seen on extensor joint surfaces and extremities that vary in size and severity of scaling.Although the pathogenesis is unknown, several hypotheses include a dysfunction in vitamin A metabolism and inflammatory and/or autoimmune triggers [83].
Only three case reports are noted to date that explore the use of ECP for the treatment of PRP (n = 4) [84][85][86].All of these cases included patients with severe PRP that was refractory to many of the first-line treatments, such as cyclosporin, topical calcineurin inhibitors, corticosteroids, and PUVA therapy.The earliest case report documented a successful treatment of two calcitrant PRP patients, with one patient on a combination of acitretin and ECP and the other on cyclosporin with ECP [86].Another case report administered one ECP cycle monthly to a patient with refractory ECP and found that after the third ECP session, a physical examination of the skin parameters, such as erythroderma, scaling, itching, and papules, was significantly improved.After the sixth cycle, the application of topical steroids was reduced, and the patient could stop using calcineurin inhibitors.The patient continues to be in partial remission with maintenance with ECP [84].In contrast, one case report documented a decrease in PRP erythema in the lower limbs but a lack of improvement in her excruciating pruritis when exposed to ECP therapy [85].
There are no guidelines or recommendations to date on the usage of ECP on PRP.Therefore, further exploration is highly encouraged in order to determine the efficacy of ECP in the treatment of PRP.

Psoriasis
Psoriasis (PS) is a chronic, immune-mediated disease that affects over 60 million people worldwide [87].PS presents itself in many subtypes on the skin, with the most common cutaneous presentation being plaque psoriasis, characterized as raised skin plaques, mostly on extensor surfaces, the lower back, and the scalp [88].Although the cause of PS is unknown, psoriasis etiology is found to have a strong genetic component, as it is highly associated with a heritability of 60-90% [89].Environmental triggers have been observed to induce or exacerbate psoriasis, and T-cells such as TH17 have been found to be upregulated in the onset of psoriasis and disease progression.Current first-line treatments for PS include but are not limited to corticosteroids, calcineurin inhibitors, retinoids, and phototherapy.
Prospective, retrospective, and case reports provided mixed evidence on the ability of ECP to successfully treat cutaneous PS (Table 6).Wolfe et al. report a de novo development of psoriatic plaques in two patients with cutaneous T-cell lymphoma exposed to interferon-alpha treatment and ECP [95].However, it has been hypothesized that the incidence is most likely due to the interferon-alpha treatment and not due to ECP.In another prospective study, five patients diagnosed with PS along with psoriatic arthritis were treated with ECP, and all patients showed an improvement in their psoriatic arthritis clinical parameters but no improvement in their skin lesions [92].In contrast, Vonderheid et al. conducted a prospective trial on four patients with chronic refractory psoriasis who were administered ECP treatments within a range of 6-13 months, and the results showed a partial clearing of skin lesions with an improvement in erythema, induration, and scaling of the lesions [90].PS flare-ups did still occur when exposed to minor exacerbations after ECP treatment.The immunologic parameters measured a decrease in IL-2 production by peripheral lymphocytes, suggesting that ECP has an anti-inflammatory effect either through the inhibition of IL-2 cytokine production and/or apoptosis of T-cell lymphocytes [90].The remaining studies in the literature on the treatment of PS with ECP have been positive and in favor of ECP treatment, showing an improvement in the clinical parameters, such as scale, thickness, redness, and magnitude, along with a significant improvement in joint mobility in patients with accompanying psoriatic arthritis [93,97,99].
The ASFA recognizes PS as a grade III, meaning that they recognize the potential benefits of ECP in the treatment of PS; however, external validity and data to support these claims are relatively weak.Similarly, the EDF does not report any recommendations for ECP in the treatment of PS due to "inconclusive evidence".

Pemphigus Diseases
Pemphigus diseases are rare autoimmune diseases that affect men and women approximately equally.Pemphigus is characterized as flaccid blisters on the skin and mucous membranes due to the immune system attacking the intra-epidermal layer of cells in the stratum spinosum layer of the skin, leading to acantholysis and fluid accumulation [100].Pathogenesis occurs due to the Th2 and B-cell interaction, leading to the production of IgG auto-antibodies against desmoglein-a desmosomal protein that holds keratinocytes in the epidermis together [101].The two most common types of pemphigus diseases are pemphigus vulgaris and pemphigus foliaceus.Pemphigus vulgaris (PV) is characterized by blisters on the skin and mucous membranes with auto-antibodies against the desmoglein 1 and/or 3 proteins.In contrast, pemphigus foliaceus (PF) is characterized by blisters on the skin without any mucosal involvement, and only desmoglein 1 is targeted by the immune system [102].
The majority of the ECP studies and case reports on pemphigus disease treatment pertains to PV (n = 14) [103][104][105][106][107][108][109][110].A recent retrospective study on the efficacy of ECP was conducted on eight patients who were diagnosed with drug-resistant PV and who were refractory to first-line treatments, such as corticosteroids and adjuvant therapies, such as colchine [104].ECP was added to the patient's systemic therapy and administered for one cycle every 2-4 weeks, and the clinical assessment was recorded every 3 months.The results showed complete remission in all but one of the patients after 2-4 cycles of treatment.All patients were able to decrease their doses of prednisone, with two patients able to completely stop their immunosuppressive therapies.In another retrospective study, drug-resistant PV, as well as PF, was observed to be successfully treated with a monthly cycle of ECP in addition to systemic therapies [103].All PV patients (n = 3) achieved complete remission, while one PF patient achieved partial remission; however, all patients were able to decrease their corticosteroid dosage [103].Although the majority of the studies validate the hypothesis that ECP is beneficial for the treatment of bullous diseases, one recent case report states that high-intensity ECP failed to treat a patient with refractory PV after 5 months of treatment.Immunophenotyping showed no change in the auto-antibody desmoglein titers, and the patient continued to experience oral lesions that interfered with his oral intake [110].
To date, there are only two case reports and one retrospective study conducted by Wollina et al., mentioned above, that reports on the efficacy of ECP on PF (n = 3) [103].In both cases, a clinical assessment of PF showed blister improvement, and the immunotherapy dosage was able to be lowered after ECP treatment [27,111].
The ASFA has recognized the previous literature and labeled pemphigus vulgaris as a level III for ECP treatment due to the lack of sufficient evidence, and the EDF stated that ECP can be used for PV when it is refractory to conventional systemic therapies.Therapeutic dosing includes one cycle every 2-4 weeks for 12 weeks, then one cycle every 4 weeks.Maintenance intervals include tapering off ECP by adding an additional week before ECP treatment every three months.The response assessment includes measuring auto-antibody titers against desmoglein proteins as well as conducting physical and clinical assessments.To this date, the ASFA and EDF have not recognized ECP as a treatment for PF, which warrants further exploration of the utilization of ECP for the treatment of pemphigus foliaceus.

Autoimmune Sub-Epidermal Bullous Diseases
Sub-epidermal bullous diseases consist of a large group of autoimmune bullae-forming diseases that include bullous pemphigoid and epidermolysis bullosa acquistia.The pathogenesis of sub-epidermal bullous diseases is attributed to auto-antibodies against the hemidesmosomes in the basement membrane, leading to the detachment of the epidermis from the basement membrane zone.This leads to blistering of the skin and mucosal membranes.To date, there is evidence of ECP in the treatment of epidermolysis bullosa acquisita and bullous pemphigoid but no evidence for the remaining sub-epidermal bullous diseases, such as pemphigoid gestationis, mucous membrane pemphigoid, linear IgA bullous dermatosis, and anti-p200 pemphigoid.

Bullous Pemphigoid
Bullous pemphigoid (BP) is the most common sub-epidermal blistering disorder that comprises 80% of the sub-epidermal cases [112].This disease is often seen in populations of older age and is characterized by tense bullae that can appear anywhere on the skin or mucosal membranes [112].Patients diagnosed with this condition also experience pruritis before the onset of the bullae.
There are only two studies that report the use of ECP for the treatment of BP (n = 5) [103,113].In addition to exploring the usage of ECP on PV and PF, Wollina et al. also administered ECP therapy to three patients with refractory BP.The results showed complete remission after 1-4 cycles, and immunosuppressive therapy was able to be lowered with no adverse effects.Tripodi et al. reported that a pediatric case of refractory BP achieved complete and long-term remission with ECP, administered alongside plasma exchange and corticosteroid therapy [113].Immunosuppressive therapy was also able to be tapered off at an 18-month follow-up.
Due to the lack of evidence, the ASFA and EDF have not recognized BP as a condition that has the potential to be effectively treated with photopheresis.

Epidermolysis Bullosa Acquisita
Epidermolysis bullosa acquisita (EBA) is a chronic blistering disease that affects 20,000-50,000 individuals worldwide [114].This autoimmune disease is characterized by auto-antibodies that target type VII collagen in the dermal-epidermal junction, leading to detachment of the epidermis.Symptoms of EBA include skin fragility, blisters, erosions, and scarring.The two most common types of EBA are classic mechanobullous, characterized by bullae and erosions at the affected site, and the inflammatory form, which presents as an inflammatory bullous eruption that looks similar to that of other sub-epidermal blistering diseases [115].
There are few prospective studies, retrospective studies, and case reports pertaining to ECP treatment for EBA.These publications have confirmed ECP's efficacy as a treatment for refractory and severe cases of this disease (n = 13) [104,[116][117][118][119][120].Camara et al. documented a case of severe EPA with severe refractory EBA with ocular involvement that was compromising the patient's vision [119].After 32 treatments of ECP, all of the patient's EBA symptoms disappeared, with the exception of his cicatricial alopecia, and the patient was able to cease all concomitant treatments.Additionally, the most recent ECP publication for EPA involved a 12-year-old girl whose integumentary symptoms were treated after several rounds of ECP treatment, suggesting the possibility that ECP can be used on pediatric patients to treat dermatologic diseases [117].
Due to the weak evidence that supports ECP treatment for this condition, the ASFA does not recognize this disease in their guidelines.In contrast, the EDF states that ECP can be used as an alternative treatment when other front-line treatments fail.The recommended therapeutic regimen includes one cycle every 2-4 weeks for 12 weeks, then one cycle every 4 weeks, with tapering maintenance therapy of additional 1-week intervals after every three months.An assessment of the treatment response includes clinical and photographic assessments.

Scleromyxedema
Scleromyxedema (SX), also known as Arndt-Gottron's disease, is a rare idiopathic chronic cutaneous disease that results in abnormal accumulation of mucin in the skin and affects adults 30-70 years of age, without any predilection for specific gender or race [121].Scleromyxedema is characterized by the eruption of symmetrical 2-3 mm waxy firm papules that have histological evidence of mucin deposition, fibroblast proliferation, as well as fibrosis [122].Although the pathophysiology is unknown, researchers have identified IgG paraprotein in SX patients' serology, although there has not been any relationship proven to be associated with decreased IgG paraprotein levels nor improvement in clinical manifestations [123].First-line therapies include IV immunoglobulin administration (IVIG) and systemic glucocorticoids [124].
The majority of studies on the potential use of ECP on SX have been explored through case reports and a retrospective study (n = 7).All of the studies reported that SX was successfully treated using ECP [106,[125][126][127][128][129].Some case reports even observed an almost complete remission of SX after 6-12 months of ECP therapy [125][126][127].Additionally, serologic evaluations also showed a significant drop to minimal or no IgG paraprotein levels [128,129].Although these publications encourage the use of ECP to treat SX, Durani et al. reported that one of the SX patients relapsed after 4 weeks of skin improvement with ECP monotherapy [126].Oral cyclophosphamide was added to his treatment regimen, and his skin continued to improve, suggesting ECP should be used in combination therapy.
Like many of the other dermatologic diseases, there is not enough evidence for the ASFA and EDF to recognize ECP as a safe and efficacious treatment for SX.The EDF recognizes that studies on scleromyxedema have been conducted but states there is inconclusive evidence.

Solar Urticaria
Solar urticaria is a very rare chronic allergic reaction to sun exposure that causes pruritis, wheals, and erythema in sun-exposed areas.The cause of solar urticaria is not clearly defined, but the pathogenesis is stated as a type 1 IgE-mediated hypersensitivity reaction that involves Th2 cells interacting with B-cells, causing an inflammatory response and mast-cell activation [130].First-line therapy includes antihistamines and corticosteroids.
To this date, there is only one case report on the treatment of solar urticaria utilizing ECP [131].This case report talks about a patient with severe solar urticaria who was extremely sensitive to both UVA radiation and visible light, with first-line treatments such as oral antihistamines and oral cyclosporin proving ineffective.After nine treatment cycles, the patient's minimal urticaria dose increased from 7 J/cm 2 to 22 J/cm 2 UVA.The clinical assessment included a significant improvement in the multitude and magnitude of wheals and associated symptoms, such as pain, pruritis, and fatigue.
Since there is only one study that discusses the usage of ECP on solar urticaria, the ASFA and EDF have not recognized photopheresis as a potential treatment for this disease.Therefore, more studies should be conducted in order to further increase our knowledge of the efficacy of ECP on solar urticaria.

Photopheresis Efficacy, Tolerability, and Cost Effectiveness
Although the preliminary evidence and case reports from the aforementioned publications state ECP can be a safe and efficacious treatment, there are not enough clinical trials to validate these findings for a majority of these dermatologic diseases.Additionally, the variation in ECP regimens in pilot studies to treat the same dermatologic disease makes it difficult to replicate and compare the clinical outcomes between studies.
ECP has been proven to be an efficacious treatment in autoimmune diseases that allows patients to decrease and even discontinue any concomitant immunosuppressive therapy, which can ultimately result in a decrease in morbidity and infection, leading to increased overall survival.Photopheresis can also lower the risk of infection due to T-cell retention of its antigen-specific responses, allowing ECP T-cells to continue to amount an immune response to vaccinations and other antigenic presentations [132,133].
Photopheresis has been observed as a safe and tolerable treatment, with relatively limited to no adverse side effects reported in the literature.The EDF also reported minimal side effects in its ECP guidelines, but some patients did report side effects such as hypotension, tachycardia, low-grade anemia, and thrombocytopenia [134].Additionally, a recent publication measured the effects of ECP on vitamin D levels and found that a vitamin D deficiency could result after long-term usage of ECP [135].Therefore, vitamin D levels are advised to be monitored during ECP treatment.Contradictions for ECP therapy include pregnancy, sensitivity to psoralen compounds, photosensitivity, aphakia, and a history of heparin-induced thrombocytopenia [134].
The potential drawbacks to using ECP for therapy include scheduling and geographical location.Some patients may find it difficult to come into a care center at frequent and regular intervals to receive treatment, especially if they live far away or have to make a long commute.Recent advancements to potentially address this lack of accessibility include the study of autologous cryopreserved mononuclear cells for ECP treatments [35,136].This will allow most of the treatment to be conducted in a care setting that is in close proximity to one's residence, resulting in a reduction in the number of photopheresis sessions conducted at the primary care center.Although this allows photopheresis to be more easily accessible, patients still run into the problem of ECP being too expensive.The average cost for ECP is USD 3045.61 per treatment, and therefore, patients have run into problems with insurance companies refusing to pay for these treatments [83,137].

Conclusions
This is the first review to our knowledge that provides a comprehensive analysis of all the dermatologic diseases that have been treated with ECP.Heidrum et al. conducted a brief review of the miscellaneous indications for ECP; however, it did not provide the in-depth analysis that we aimed to accomplish in this review.ECP has been recognized by the APSA and EDF as a safe and efficacious treatment for a variety of dermatologic and autoimmune diseases.Further evidence is needed in order to validate the current findings of ECP efficacy for the remaining dermatologic diseases that lack sufficient evidence for ECP approval.Further research could explore photopheresis in the treatment of other autoimmune dermatologic diseases, such as the remaining sub-epidermal bullous diseases and vitiligo, as psoralens such as MOP-8 have been hypothesized to stimulate melanogenesis in these patients [138].

Table 2 .
Summary of ECP treatment for atopic dermatitis.
* CR = complete remission; PR = partial remission; SCORAD = "SCORing Atopic Dermatitis" tool for assessing severity of AD; first-line therapies include but not limited to topical steroids, topical calcineurin inhibitors, and phototherapy (UVA, UVB, and PUVA); second-line therapies include but not limited to systemic steroids or cyclosporine; QoL = quality of life; FACT = Functional Assessment of Chronic Illness Therapy Survey; Pruritic VAS = Pruritus Visual Analog Scale.

Table 3 .
Summary of ECP treatment for cutaneous lupus erythematosus.

Table 4 .
Summary of ECP treatment for lichen planus.

Table 5 .
Summary of ECP treatment for localized scleroderma.

Table 6 .
Summary of ECP treatment for psoriasis.