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.

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¹Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
²Carilion Clinic Dermatology and Mohs Surgery, Roanoke, VA, USA

Conflict of interest: Mariana Phillips is an investigator for Castle Biosciences. Neha Singh has no disclosures.

Abstract: Toxic epidermal necrolysis (TEN) is an immune mediated, severe cutaneous adverse drug reaction characterized by epidermal detachment affecting greater than 30% body surface area. The mortality rate of TEN exceeds 20% and is usually caused by infection and respiratory compromise. Withdrawal of the causative drug, supportive care, and adjuvant therapy improve prognosis. Over the past decade, randomized controlled trials and meta-analyses have supported a role for cyclosporine, tumor necrosis factor alpha inhibitors, and combination therapy with intravenous immune globulin and corticosteroids. This review summarizes the medical management of TEN in adult patients.

Key Words: toxic epidermal necrolysis, TEN, Stevens-Johnson syndrome, SJS, intravenous immunoglobulin, IVIG, etanercept, cyclosporine, corticosteroids

Introduction

Toxic epidermal necrolysis (TEN) is a severe, life-threatening, adverse drug reaction characterized by widespread epidermal necrosis. The global mortality rate for TEN approaches 20-40%.^1-5 Stevens-Johnson syndrome (SJS) and TEN are on the same spectrum and are clinically distinguished by percentage of body surface area detached. Patients are classified as SJS, SJS/TEN, or TEN if there is <10%, 10-30%, and >30% skin detachment, respectively.⁶

Initial manifestations of SJS and TEN include a prodrome of high fever and flu-like symptoms for 1-3 days followed by rapidly progressive mucocutaneous involvement. Ill-defined, targetoid, dusky macules that coalesce to form flaccid vesicles and bullae that eventually slough are typical. Blistering and detachment of the epidermis at the dermal epidermal junction can be induced with light pressure.⁷ Epidermal detachment may occur anywhere on the skin and mucosa, and commonly involves the ocular and respiratory epithelium. Complications include sepsis from loss of the skin barrier and respiratory compromise. Individuals with compromised immune systems (i.e., malignancies, human immunodeficiency virus (HIV), etc.) are at greater risk of developing TEN. Advanced age and comorbidities are associated with increased mortality.⁸

The exact pathogenesis of TEN remains unclear. It is traditionally considered to be a delayed type IV hypersensitivity immune reaction that results in cytotoxic CD8 T-cell mediated keratinocyte apoptosis.^9-12

Drugs commonly associated with TEN include antibiotics like sulfonamides, tetracyclines, quinolones, as well as antiepileptics, antivirals, non-steroidal anti-inflammatory drugs (NSAIDs), and allopurinol.⁴ In the pediatric population, a TEN-like clinical presentation can be associated with Mycoplasma pneumoniae. Pharmacogenetic susceptibility to the development of TEN is present in certain populations. The human leukocyte antigen (HLA) B 15:02 confers an increased risk of TEN in Asian patients taking carbamazepine.¹⁰ Another allele, HLA-B 58:01, has been linked with allopurinol-induced TEN in European and Asian populations.¹¹

The severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is a well-validated specific predictor of mortality for patients with TEN.^12-15 Aside from supportive care, the medical management of TEN is dependent upon the clinician’s critical appraisal of the available literature, and availability of various treatments.^16-20 The primary purpose of this article is to provide a concise but comprehensive review on the medical management of SJS/TEN and TEN.

Treatment Modalities

Supportive Measures

Due to the rapid progression and complex nature of TEN, early intervention, close surveillance and multidisciplinary support are key to management. Patients may require observation in the intensive care and/or burn units.^21-23 Supportive measures are aimed at maintaining thermoregulation and pain control, preventing major fluid loss, electrolyte imbalance, secondary infection, and scarring. Patients should be closely monitored for signs and symptoms of infection. Empiric antibiotics are associated with a poor prognosis and are therefore not indicated in the management of TEN. The most common organisms causing early infection are Staphylococcus aureus and Pseudomonas aeruginosa. Despite the importance in supportive measures, there is a lack of standardization among treating centers.²⁴

Intravenous Immunoglobulin (IVIG)

Enthusiasm for IVIG in the treatment of TEN resulted from an initial study published by Viard et al., that showed IVIG preparations containing Fas-blocking antibodies could effectively inhibit the interaction of the Fas-ligand (FasL) with Fas-receptor, an established pathway of keratinocyte apoptosis.²⁵ The same group reported an open, uncontrolled trial of 10 TEN patients who received 0.2-0.75 g/kg of IVIG per day for 4 consecutive days (Table 1). In all patients, disease progression ceased within 48 hours and rapid skin healing was noted.²⁶ The popularity of IVIG for TEN increased since its introduction in 1998 and became the standard treatment for many years.

Aside from the pediatric population where IVIG is considered safe and effective, recent studies have challenged the use of IVIG in the management of TEN.^27-29 Selected publications examining the use of IVIG for TEN are summarized in Table 1. Although IVIG was once considered the first-line treatment for SJS/TEN, a large meta-analysis concluded that administration of IVIG does not correlate with mortality reduction in multivariate regression analysis when adjusting for age, total body surface area involved, and delay in treatment compared to predicted mortality in adult patients.³⁰ One prospective study examined the efficacy of a total dose of 2 g/kg IVIG (infused at a rate of 1 g/kg/day to 0.4 g/kg/day dependent on renal function) in 34 patients (9 with SJS, 5 with SJS/TEN, and 20 with TEN). No significant reduction in SCORTEN predicted mortality was noted (11 observed vs. 8.2 predicted). Disease progression was not interrupted by IVIG administration.³¹ Furthermore, a multicenter study that reviewed 377 SJS/TEN patients from 18 academic medical centers between 2000 and 2015 found no significant difference in mortality between treatment subgroups which included steroid monotherapy, IVIG monotherapy, and the combination of IVIG and corticosteroids.³² In one of the largest network meta-analyses to date, IVIG monotherapy showed no improvement in mortality rate when compared to supportive care.²⁷ This network meta-analysis incorporated 67 studies published between 1999 to 2019 and included 2079 patients with SJS/TEN overlap or TEN. Regarding mortality rate and standardized mortality ratio, the surface under the cumulative ranking curve (SUCRA) score for IVIG rated below supportive care.²⁷ Overall, the efficacy of IVIG in treating TEN remains uncertain and further prospective evaluation is warranted.

Table 1. Summary of studies reporting IVIG use in TEN*

Systemic Corticosteroid Therapy

Systemic steroids may be effective in treating SJS/TEN by the following mechanisms: 1) rapid acting: inhibiting the arachidonic acid cascade signaling pathway resulting in suppression of the inflammatory response and 2) slow acting: promoting transcription factors that suppress expression of inflammatory cytokines.⁴¹

The use of high-dose steroids in early SJS/TEN inhibits inflammation and decreases biomarkers of inflammation.⁴² Among 96 studies reviewed in a meta-analysis between the years 1990-2012, three studies suggested the benefit of corticosteroid treatment when compared to supportive care.⁴³ Studies were variable in the duration of corticosteroids administration, most ranging from days 1-5 with an average of 3 days. A separate European multicenter retrospective study and meta-analysis of observational studies also highlighted the benefits of steroids.^37,43

In contrast, several studies report no difference in prognosis between corticosteroid therapy and supportive care, due to the increased risk of infection caused by the immunosuppressive agent.^2,44 More recently, a retrospective SCORTEN-based comparison was performed on patients who received low-doses (<2 mg/kg/day) and high-doses (>2 mg/kg/day) of either prednisone, or prednisone-equivalents of methylprednisolone, hydroprednisone, or dexamethasone (Table 2). Results revealed lower mortality rates in the low-dose steroid treatment group than those predicted by SCORTEN.⁴⁵ In the high-dose steroid group, difference between the expected and actual mortality was not statistically significant; however, the actual mortality rate was 40% lower than the expected rate. A large retrospective study analyzing 366 patients for ocular sequelae found no benefit to steroid therapy.⁴⁶

Table 2. Summary of studies reporting corticosteroid use in TEN

Currently, there is conflicting data on the benefit of corticosteroids in SJS/TEN. The beneficial effects of high-dose steroids must be weighed against the risk of complications including gastrointestinal (GI) bleeds, prolonged wound healing thus increasing the risk of infection, and increased mortality.

Cyclosporine

Cyclosporine, a calcineurin inhibitor, has been reported to have therapeutic benefit in the setting of SJS/TEN. This drug works by inhibiting activation of T cells and thus downstream mediators including FasL, nuclear factor-kB, and tumor necrosis factor alpha (TNF-α).^48,49 Although less studied in comparison to other modalities discussed previously, cyclosporine has been shown to slow the progression of TEN and promote re-epithelialization.^50,51

Several studies have shown favorable outcomes in patients receiving cyclosporine (Table 3). Lee et al., reported 24 patients who received 3 mg/kg/day of cyclosporine for 10 days. Three deaths occurred in contrast to the SCORTEN-predicted mortality of 5.9.⁵² Valeyrie-Allanore et al., investigated the same dosage of cyclosporine and found that rate of disease progression decreased; 62% of patients receiving cyclosporine experienced no disease progression at day 3.⁵³ No deaths occurred in this study cohort which favorably contrasted with the SCORTEN-predicted mortality of 2.75.⁵³ In a meta-analysis of 9 studies comparing cyclosporine with supportive care, a survival benefit for patients treated with cyclosporine was found.⁵⁴ Cyclosporine is associated with hypertension and renal toxicity and both should be monitored during treatment.⁵⁵ In one trial with 29 patients, only 26 were able to complete treatment due to side effects. Reported adverse reactions included neutropenia, leukoencephalopathy, and severe infection.⁵³ Contraindications to cyclosporine include severe infections, internal malignancy, and renal dysfunction.⁵⁴ Due to the small number of patients reported, further studies are needed to validate the efficacy of cyclosporine as a therapeutic agent for TEN.

Table 3. Summary of studies reporting cyclosporine use in TEN

Plasmapheresis

The mechanism of action of plasmapheresis involves clearing the circulating pathogenic metabolites including drugs, FasL, and TEN-induced cytokines from the patient’s blood. These sessions are typically carried out daily or every other day until patients show no signs of disease progression. The safety profile of plasmapheresis makes this therapeutic modality particularly attractive.^50,51,61-65 Reported adverse events included transient paresthesias and urticaria. Most data on use of plasmapheresis in TEN come from case series and show improvement of disease progression (Table 4). In one case series involving 4 patients, those receiving plasmapheresis after unsuccessful treatment with corticosteroids and IVIG showed marked clinical improvement. Skin sloughing was interrupted and skin lesions began to heal after an average of 5.25 sessions.⁶⁶ This treatment modality is not widely available, thus limiting its use.

Table 4. Summary of studies reporting plasmapheresis use in TEN

TNF-α Inhibitors

Skin lesions and blister fluid in TEN are known to contain high levels of TNF-α which prompted the use TNF-α inhibitors in patients with SJS/TEN.^68,69 Both infliximab and etanercept have shown benefit.^50,51,70-78

One case series published in 2014 included 10 patients who received a single dose of etanercept, 50 mg, subcutaneously (Table 5). All patients responded without any complications or adverse effects.⁷² The median time to healing was 8.5 days. Wang et al. studied etanercept 25 mg or 50 mg twice weekly compared with steroids in 96 SJS/TEN patients in a randomized controlled trial (RCT) and found that re-epithelialization occurred more quickly in the etanercept group (14 days for etanercept vs. 19 days for steroids). Additionally, etanercept was associated with a 9.4% reduction in SCORTEN predicated mortality and a lower actual mortality (8.3% with etanercept vs. 17.7% with steroid treatment) and fewer adverse events (GI hemorrhage).⁷⁹ In the largest network metanalyses to date, etanercept was ranked the best among 10 treatments based on the SUCRA score for mortality rate.²⁷ The SUCRA score is a metric used to evaluate which treatment in a network meta-analyses is likely to be the most efficacious. Although there are case reports to support the use of infliximab, this medication has not been as well studied.⁷³

Table 5. Summary of studies reporting use of TNF-α inhibitors in TEN

Combination Therapies

The combination of IVIG and corticosteroids has shown promise in patients with SJS/TEN.27,55,82 One retrospective study included 39 patients who received an initial dose of 1.5 mg/ kg/day of methylprednisolone for 3 to 5 days combined with a total dose of 2 g/kg IVIG for 5 days.⁸³ Mortality rate with steroid monotherapy was 31% compared to 13% with combination therapy. Similarly, a network meta-analysis (2021) concluded that the combination of IVIG and corticosteroids was the only treatment that reduced the standardized mortality ratio with statistical significance.²⁷ Additionally, following etanercept, the combination of corticosteroids and IVIG was calculated to have the second highest SUCRA score for mortality rate. These results were supported by another meta-analysis of 24 studies suggesting combination therapy (IVIG + steroids) had better therapeutic effect compared to either therapy alone.⁸² Additional studies support these findings.^27,32,84,85 The combination of IVIG with etanercept was evaluated in 13 patients at a single institution from 2015 to 2018. There was no significant difference in mortality when compared to IVIG monotherapy. A systematic review supported the combination of corticosteroids and cyclosporine, although these findings warrant further investigation.³⁹ The combination of TNF-α inhibitors with a steroid was investigated in 25 patients with SJS/TEN. Ten patients received methylprednisolone (equivalent to 1 to 1.5 mg/kg/day of prednisolone) and 15 patients received the steroid regimen in combination with 25 mg of etanercept twice weekly.⁸⁶ Combination therapy significantly shortened the course of initial steroid treatment and time until skin re-epithelialization (median, 12 days) compared to steroid monotherapy (median, 16 days).

Conclusion

Over the past decade, there have been several meta-analyses detailing the efficacy of various treatments that serve to guide clinicians in the management of SJS/TEN and TEN.^{27,30,40,43,82,84} Early intervention is paramount. As soon as the diagnosis is considered, all potential offending drugs must be stopped. Transfer to a burn center and administration of systemic therapy should be considered. Management is heavily dependent on disease severity and rate of progression, patient comorbidities, available evidence, and physician experience.

Due to the complexity of the data and often conflicting results, no one treatment can be recommended at this time. Currently, there is not enough evidence to recommend IVIG or steroid monotherapy for adult patients with TEN. However, IVIG is still considered a safe and effective option for pediatric patients.^28,29 Several network meta-analyses suggest that combination therapy with corticosteroids and IVIG, cyclosporine, and/or etanercept can reduce mortality of TEN.^{27,30,40,43,82,84} These treatment recommendations are summarized in Table 6.

Table 6. Summary of therapies for TEN that have been shown to be more efficacious than supportive measures in reducing mortality

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Ruxolitinib cream 1.5%

HA-based dermal filler

Abrocitinib tablets

LetibotulinumtoxinA for injection

Berotralstat capsules

Mogamulizumab IV infusion

Avacopan capsules

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