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

Conflict of interest:
All of the authors have no conflicts to declare for this work.

Abstract:
Human papillomavirus (HPV)-induced cutaneous disease is a common complaint for patients presenting for dermatology evaluation. Infection by HPV is the major etiologic factor in the development of cutaneous warts, epidermodysplasia verruciformis, and possibly a subset of cutaneous squamous cell carcinoma. Carcinoma of the genitourinary tract, most notably cervical carcinoma, is the most severe manifestation of infection with specific serotypes of HPV. For this reason, the HPV immunization (Gardasil) was developed in 2006 and upgraded in 2018 to a nonavalent formulation that includes serotypes 6, 11, 16, 18, 31, 33, 45, 52, 58. While immunization is highly effective at preventing infection with serotypes included in the formulation, it is less clear if the immunization can aid in managing active HPV infection. This review examines the available literature regarding the role of HPV immunization in managing common warts, genital warts, keratinocyte carcinoma, and epidermodysplasia verruciformis.

Key Words:
human papillomavirus, HPV, HPV immunization, Gardasil, Cervarix, common warts, verruca vulgaris, genital warts, condyloma acuminata, epidermodysplasia verruciformis, keratinocyte carcinoma, squamous cell carcinoma

Introduction

Human papilloma virus (HPV) is a non-enveloped, double-stranded circular DNA virus. Transmission usually occurs through skin-to-skin contact, but the virus can also be transmitted vertically and via fomites, such as transvaginal ultrasounds and colposcopes.¹ Over 100 HPV strains exist. HPV types 1, 2, 4, 7, 27, 57, and 65 frequently cause common, plantar, and flat warts,² while types 6 and 11 are the usual agents behind genital warts and recurrent respiratory papillomatosis.^3,4 The high-risk HPV types, 16 and 18, are responsible for the majority of HPV-induced carcinomas of the cervix, vagina, vulva, anus, rectum, penis, and oropharynx, with a minority caused by the less prevalent high-risk types (31, 33, 35, 45, 52, 58).^4-6 Other dermatologic conditions associated with HPV infection include keratinocyte carcinomas of the skin^7,8 and epidermodysplasia verruciformis (EV), which is caused by mutations that increase susceptibility to β-genus HPV strains.⁹

The first formulation of the HPV vaccine (quadrivalent Gardasil®), US FDA approved in 2006, covered types 6, 11, 16, and 18. The vaccine was designed mainly to aid in the prevention of cervical carcinomas, as reflected in its initial target population of female patients aged 9-26 years. Like other non-living vaccines, the immunization employed an adjuvant (aluminum hydroxide, 225 mg) that served to amplify the immune response. In 2009, a bivalent formulation (Cervarix®) that covered just serotypes 16 and 18 was approved by the FDA. Cervarix contains a proprietary adjuvant (3-O-desacyl-4 monophosphoryl lipid A [AS04]) that has increased potencycompared to aluminum hydroxide.¹⁰ Also in 2009, FDA approval was extended to include males between 9-26 years of age. Most recently, Gardasil upgraded to a nonavalent formulation that includes 9 serotypes (6, 11, 16, 18, 31, 33, 45, 52, 58) as well as an increase in adjuvant dose to 500 mg of aluminum hydroxide.¹¹ Additionally, approved coverage was expanded by the FDA in 2018 to include all individuals (from 9 years of age), male and female, up to 45 years old.

The effectiveness of HPV immunization in preventing HPV infection in naive individuals and subsequent cervical dysplasia and carcinoma is excellent and well-documented.^5,12 An interesting question that has arisen since widespread acceptance of the HPV immunization is what role does immunization play, if any, in the management of active HPV infection. Anecdotal reports and case series have described improvement or resolution of common and genital warts with administration of HPV vaccination, but conflicting reports documenting little to no benefit have also been published. This article provides a brief review of the literature exploring the potential utility of the HPV immunization in treating HPV-related dermatologic conditions.

Cutaneous Warts

Common, plantar, and flat warts are notoriously difficult to treat, many recurring or failing to regress with multiple treatment modalities.¹³ For this reason, additional treatments for recalcitrant warts would benefit patients and physicians. Nofal et al. published a study documenting their use of the bivalent HPV vaccine (Cervarix) in 44 patients with common warts who were randomly assigned to receive either standard Cervarix immunization (0, 1, and 6 months) or intralesional injection of Cervarix into the largest wart every 2 weeks until complete clearance or for a maximum of 6 sessions.¹³ Each participant had multiple, recalcitrant common warts that had been present for more than 2 years duration and failed to respond to at least 2 treatment modalities. Complete clearance was observed in 18 patients (81.8%) of the intralesional group and 14 patients (63.3%) of the intramuscular group; however, this was not statically significant. No recurrence was noted in the 6-month follow-up period. Additionally, a retrospective analysis of 30 patients documented complete clearance of common and plantar warts for 14 patients (46.67%) following administration of 3 doses of quadrivalent Gardasil.¹⁴ An additional 5 patients (16.67%) showed a partial response while 11 patients (36.67%) showed no response at all. Although the HPV strains most associated with common warts are not specifically targeted in the HPV vaccinations, the therapeutic effect is possibly due to antigenic similarity of the L1 capsid proteins across types or by nonspecific immune stimulation by the adjuvant contained within the formulation. The latter may partially explain the higher clearance rate observed with administration of Cervarix compared to Gardasil since a more potent adjuvant (AS04) is utilized in the Cervarix formulation.^5,13 Alternatively, the vaccine may alter the cytokine environment enhancing the native immune response.^4,13

Additional literature examining the role of HPV immunization in treating conventional warts is limited to case reports and small case series.^15-21 Abeck & Holst studied the effect of quadrivalent HPV immunization on 6 children with a 2-year history of recalcitrant extragenital warts.¹⁵ After the second dose, all but 1 child had complete resolution of warts, the sixth child was noted to respond after the third dose. A similarly designed study documented complete clearance of chronic verruca vulgaris in 4 patients following quadrivalent HPV administration intramuscularly.¹⁶ Moscato et al. described a single case of complete remission of plantar warts after 2 of 3 doses of the HPV quadrivalent vaccine. Interestingly, this patient also had genital condylomata, which did not regress following HPV vaccination.¹⁷ Kreuter et al. described an immunocompromised patient with disseminated cutaneous extragenital warts that significantly regressed starting 4 weeks after single dose of HPV quadrivalent vaccine with further regression noted 1 year after the third dose. This patient also had concurrent genital warts, which did not regress with treatment.¹⁸ Finally, a more recent case report described remarkable improvement of disseminated verruca vulgaris in an immunosuppressed patient after administration of the nonavalent formulation of Gardasil.¹⁹

Genital Warts

The quadrivalent and nonavalent formulations of the HPV immunization specifically cover serotypes 6 and 11, which are implicated in most genital warts. Large studies reporting significant efficacy of Gardasil or Cervarix for treatment of condyloma acuminatum are lacking. Lee at al. reported responses to quadrivalent Gardasil in a 44-year-old male with significant perianal condylomata recalcitrant to imiquimod therapy.²² Near complete resolution of perianal warts was observed 8 weeks after the first dose of quadrivalent Gardasil. Resolution was confirmed by biopsies and histologic analysis and there was no evidence of recurrence at his 3-month follow-up. In a more recent 2019 exploratory study, 10 patients with condyloma acuminata were treated with all 3 doses of quadrivalent Gardasil.²³ Of these 10 patients, 6 (60%) had a complete response, 1 (10%) had a partial response, and 3 (30%) did not respond at all.

Although few published case studies and small trials point to a possible benefit with administration of HPV immunization, larger trials with adequate control arms are necessary to better understand the extent of their effects.

Keratinocyte Carcinomas

Clinicians have long suspected HPV as having an etiologic role in the development of cutaneous squamous cell carcinoma (SCC). A meta-analysis by Wang et al. confirmed this association and suggested HPV may serve as a co-carcinogen in conjunction with other factors that increase the risk of cutaneous SCC.⁷ Nichols et al. examined the effect of quadrivalent Gardasil vaccination in 2 patients with a history of multiple keratinocyte carcinomas.⁸ Both patients were immunocompetent and received standard schedule HPV immunization with full skin examinations performed every 3 months during the study period. Each patient subsequently demonstrated a reduced rate in the development of new SCCs and basal cell carcinomas (BCC) compared to their baseline rates. Patient 1 experienced a decrease in SCC by 62.5% per year and a decrease in BCC incidence from 1 to 0 per year. Patient 2 experienced a decrease in SCC incidence by 66.5% per year and had a similar decrease in BCC incidence.⁸

Nichols et al. subsequently employed the 9-valent HPV vaccine in the treatment of an immunocompetent female in her 90s with numerous basaloid SCCs on her right leg.²⁴ The patient was treated with 2 intramuscular injections of nonavalent Gardasil (given 6 weeks apart) followed by intratumoral injection into 3 of the largest tumors. She subsequently received 3 additional intratumoral injections over the following 8 months. Clinical improvement in size and number of tumors was noted within 2 weeks of administration of the second intratumoral dose. Eleven months after the first intratumoral dose, the patient had no remaining SCCs and sustained clinical remission for at least 24 months.

Epidermodysplasia Verruciformis

Epidermodysplasia verruciformis (EV) is a rare autosomal recessive condition caused by mutations in the EVER1 and EVER2 genes on chromosome 17q25. These mutations confer increased susceptibility to certain β-HPV types, resulting in persistent infections.²⁵ There is also an acquired form of EV, which is seen in immunocompromised patients with a predisposing condition.^9,25,26 Ninety percent of patients with EV are identified as having chronic infection with HPV 5 and/or 8, and persistent infection of these and other β-HPV strains can lead to nonmelanoma skin cancers.^9,25 Maor et al. described the efficacy of quadrivalent Gardasil in the treatment of acquired EV in a 50-year-old female with medical immunosuppression following renal transplant.²⁶ Her EV had progressed despite initial treatment with topical tretinoin and imiquimod, as well as oral acitretin. Twenty-seven months after initial presentation, 3 doses of quadrivalent Gardasil were administered over a 6-month period. During this time, the patient continued tretinoin, imiquimod, and acitretin therapy. One month following the final Gardasil dose, the patient’s clinical disease was significantly improved and HPV DNA was negative by PCR of a skin swab. Although there are several confounding factors, this is the only report examining the use of HPV immunization for treatment for EV.

Conclusion

In conclusion, HPV vaccines (Gardasil and Cervarix) may indeed have a therapeutic role in patients who suffer from dermatologic conditions that are associated with various strains of HPV. Anecdotal reports and case series have described improvement or resolution of cutaneous lesions with administration of HPV immunization, but conflicting reports documenting little to no benefit have also been published. An additional, ancillary question is whether the improvement in HPV-related disease is solely due to immune sensitization to viral antigen or if nonspecific stimulation of the immune system by the vaccine adjuvant plays a role. While the studies cited in this review are suggestive of potential benefit, larger, randomized trials with matched control groups are the necessary next steps to confirm the utility of HPV immunization in managing common cutaneous conditions associated with HPV.

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¹Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
²Section of Dermatology, Department of Internal Medicine, Carilion Clinic, Roanoke, VA, USA

Conflict of interest:
Mr. Svoboda, Dr. Johnson, and Dr. Phillips have no conflicts of interest to disclose

Abstract:
Janus kinase inhibitors, also known as JAK inhibitors or jakinibs, represent a new class of medication that have broad potential to treat dermatologic disease. Currently, the only FDA-approved dermatologic indication for this class of medications is psoriatic arthritis; however, their utility in treating other immune-mediated skin conditions including atopic dermatitis, vitiligo, alopecia areata, and systemic and cutaneous lupus is actively being investigated. Overall, these drugs appear to be well-tolerated and have a safety profile similar to that of other biologics commonly used in dermatologic practice, although an increased risk of thromboembolism has been associated. While risk of mild infection and herpes zoster appears to be increased regardless of JAK selectivity, risk of thrombosis and malignancy based on the subtype of JAK inhibition remains to be seen. Certainly, safety concerns warrant further investigation; however, early data from ongoing clinical trials offer promise for the broad utility of these medications within future dermatologic practice.

Key Words:
Janus kinase inhibitors, JAK inhibitors, jakinibs, baricitinib, ruxolitinib, tofacitinib, dermatologic applications, adverse effects

Background

Janus kinase inhibitors, also known as JAK inhibitors or jakinibs, are a class of medication that offers promise for a number of immunologically driven conditions. Originally developed for the treatment of hematologic diseases, jakinibs have demonstrated efficacy in various autoimmune and autoinflammatory disorders.^1-3 Currently FDA-approved jakinibs include tofacitinib (Xeljanz^®) for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis, baricitinib (Olumiant^®) for rheumatoid arthritis, and ruxolitinib (Jakafi^®) for myelofibrosis and polycythemia vera.²

As their name implies, JAK inhibitors function by inhibiting the activity of one or more of the Janus kinase family of enzymes, of which there are four presently identified – JAK1, JAK2, JAK3, and TYK2. These JAK enzymes are tyrosine kinases that play a critical role in mediating the signal transduction of cytokines, particularly those that bind to and activate the type 1 and type 2 cytokine receptors on the surface of cells. More specifically, the phosphorylation of these cytokine receptors by Janus kinases leads to recruitment of Signal Transducer and Activation of Transcription (STAT) proteins which modulate gene expression. It is the immunoregulatory role of cytokines and the aberrant production of cytokines observed in many autoimmune disorders that makes interruption of the JAK-STAT signaling pathway an attractive therapeutic strategy.^1-3

The first JAK inhibitor to reach clinical trials was tofacitinib, an antagonist of JAK1 and JAK3 primarily.¹ It was granted initial approval in 2012 for the treatment of rheumatoid arthritis in patients who had an inadequate response to methotrexate, and since entering into commercial use, its approval has been extended to treatment-resistant psoriatic arthritis and moderate-to-severe active ulcerative colitis as well.^1,2 Other first generation jakinibs that have demonstrated clinical efficacy for these conditions among others include ruxolitinib and baricitinib; however, these agents differ in that their selectivity is for both JAK1 and JAK2.^2,4-7

Due to the variable activity and, in some cases, limited efficacy of the commercially available JAK inhibitors, 2nd generation agents with novel selectivity for Janus kinases are being developed and investigated.^1-3 Unfortunately, the exact relationship between inhibition of specific Janus kinase enzymes and therapeutic effect on target diseases is currently unknown.^1-3,6,8 However, as our understanding of the specific JAK/STAT pathways involved in the pathogenesis of dermatologic disease evolves, selective targeting of Janus kinases may allow for improved treatment precision and avoidance of adverse off-target effects.

Clinical Applications in Dermatology

Within dermatology, JAK inhibitors have been most extensively studied in psoriasis and psoriatic arthritis and have demonstrated clinical efficacy for these patients.⁶ However, their utility in treating other autoimmune/autoinflammatory skin conditions including atopic dermatitis, alopecia areata, vitiligo, and systemic lupus erythematosus is actively being investigated in clinical trials with various 1st and 2nd generation jakinibs (Table 1).

Psoriasis and Psoriatic Arthritis

Excessive activation of the JAK1/JAK2/STAT1 and JAK1/ TYK2/STAT3 pathways – and resultant amplification of proinflammatory genes – triggered by interferon (IFN)-gamma and interleukin (IL)-22, respectively, has been implicated in the pathogenesis of psoriasis.⁹ Therefore, inhibition and subsequent blockade of these overactive signaling pathways represents an attractive therapeutic target. Out of all the jakinibs, tofacitinib has been most widely studied in psoriasis and is currently the only jakinib with FDA-approval for the treatment of psoriatic arthritis.^6,10 This regulatory approval for this indication was granted in 2017 after statistically significant improvements in the American College of Rheumatology 20 (ACR20) assessment were observed in two phase III trials.^11,12 Subsequently, phase III trials demonstrated both 5 mg and 10 mg twice daily tofacitinib to be more effective than placebo in achieving a 75% reduction in the Psoriasis Area and Severity Index (PASI 75), with improvement seen in a dose-dependent manner (46.0, 59.6, and 11.4%, respectively for OPT Pivotal 2).^12,13 These doses also provided significant improvements in nail psoriasis and were sustained for up to 52 weeks.^11-13 Moreover, a phase III noninferiority trial found the 10 mg twice daily dose of tofacitinib to be noninferior to etanercept, 50 mg subcutaneously twice per week, with a similar side effect profile.¹⁴ Unfortunately, a topical tofacitinib 2% ointment did not demonstrate improvement over placebo after a 12 week phase II trial in patients with mild-to-moderate psoriasis.¹⁵

Several other jakinibs have also shown promising early results. Phase II trials of baricitinib, filgotinib, itacitinib, and BMS- 986165 have all have yielded improved outcomes in the PASI 75 and Physician’s Global Assessment when compared to placebo.^16-18 Also, a phase II trial of topical ruxolitinib 1.5% cream was found to be efficacious in reducing the area of psoriatic plaques. However, it was only as effective as standard of care topical calcipotriene and betamethasone dipropionate.¹⁹ Results from ongoing clinical trials of upadacitinib and brepocitinib (PF-06700841) are eagerly awaited. Head-to-head randomized controlled trials comparing the efficacy between jakinibs and existing treatments for psoriasis or psoriatic arthritis have not been conducted.

Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common inflammatory skin conditions and is driven by barrier dysfunction and abnormal immune activation predominantly of T helper (Th) 2 and Th22 cells, but to a lesser degree Th1 and Th17 subtypes as well.²⁰ JAK inhibition may, therefore, be a viable therapeutic approach as the JAK-STAT pathway underlies the activation of these T helper subsets.²⁰ Both oral and topical formulations of JAK inhibitors have been shown to decrease AD severity and symptoms.²⁰ In 2015, Levy et al. demonstrated efficacy of oral tofacitinib in six patients with moderate-to-severe, recalcitrant AD, noting that overall disease severity decreased by approximately 55% as judged by the SCORing Atopic Dermatitis (SCORAD) index. Additionally, patients had even greater average reductions in sleep loss and pruritus scores.²¹ Though encouraging, this study was inadequately powered to allow for major conclusions about the efficacy of oral JAK inhibitors in treating AD. In 2016, a phase II placebo-controlled trial showed significant improvement in the Eczema Area and Severity Index (EASI) score after 4 weeks of topical tofacitinib in 69 patients.¹⁶ While evidence for the clinical efficacy of JAK inhibitors for A still remains limited at this time, the literature is anticipated to rapidly expand as several phase II and III trials with oral and topical JAK inhibitors are ongoing and near completion. Current agents under investigation include baricitinib, upadacitinib, ruxolitinib (topical), brepocitinib (topical), and abrocitinib (PF-04965842).²⁰

Alopecia Areata

Alopecia areata (AA) is an autoimmune disease of the hair follicle characterized by patchy hair loss of the scalp, and, in some patients, has potential to progress to total scalp hair loss (alopecia totalis) and total body hair loss (alopecia universalis). Numerous case reports have documented the efficacy of oral and topical jakinibs for AA; however, clinical trials thus far have been limited.^6,22-26 A phase I, placebo-controlled, double-blind study in patients with alopecia universalis found significant hair regrowth with two topical JAK inhibitors, 2% tofacitinib and 1% ruxolitinib after 28 weeks. However, only about half of patients responded to the medication, and the response rate was inferior to topical clobetasol.²⁷ In contrast to the topical formulations, an open-label clinical trial comparing the efficacy of oral tofacitinib and ruxolitinib in 75 patients with severe AA found that both medications induced remarkable hair regrowth at the end of 6 months, with a mean change in the Severity of the Alopecia Tool (SALT) score of 93.8 ± 3.25 in the ruxolitinib group and 95.2 ± 2.69 in the tofacitinib group.²⁶ There was no statistically significant difference between the groups regarding hair regrowth at the end of the 6-month treatment, and relapse rate at the end of the 3-month follow-up was the same for both medications. While both drugs were well tolerated with no serious adverse effects reported, approximately two-thirds of cases experienced relapse after drug discontinuation.²⁶

Vitiligo

Numerous case reports, case series, and open-label studies have documented the efficacy of both oral and topical JAK inhibitors for vitiligo, an acquired depigmenting disorder caused by autoimmune destruction of melanocytes.^28-31 In a phase II open-label study of 11 patients, application of ruxolitinib 1.5% cream for 20 weeks resulted in significant improvement in the overall Vitiligo Area Scoring Index (VASI) with facial vitiligo demonstrating the best response.³⁰ Follow-up of five patients at 6 months after treatment cessation revealed that all had maintained their response. While reports of cases employing oral tofacitinib and ruxolitinib documented significant repigmentation during medication administration, both also noted regression within weeks after treatment discontinuation.^28,31 Clinical trials of topical ruxolitinib and two 2nd generation oral jakinibs, brepocitinib and PF-06651600, are currently underway.

Systemic Lupus Erythematosus

Inhibition of JAK2/3 has shown promise in animal models of lupus dermatitis and nephritis.³² While clinical studies are limited, one randomized phase II trial of oral baricitinib 4 mg reported modest efficacy for arthritis and rash severity after 24 weeks in patients with active systemic lupus erythematosus (SLE) who were not adequately controlled despite standard of care therapy.³³ Unfortunately, these improvements were only observed with the 4 mg and not the 2 mg dose. While these preliminary results are promising, data from ongoing trials of 2nd generation jakinibs will help ascertain effectiveness of this drug class for cutaneous lupus.³² To date, there have been no published reports assessing the efficacy of JAK inhibitors in specifically treating subacute and chronic forms of cutaneous lupus erythematosus.

Lichen Planopilaris

As is the case for AA, upregulation of interferons and JAK signaling play an etiologic role in lichen planopilaris (LPP), an inflammatory cicatricial alopecia. A retrospective study found that eight out of ten patients with recalcitrant LPP had clinically measurable improvement after treatment with oral tofacitinib 5 mg twice or three times daily for 2 to 19 months.³⁴ There was a greater than 50% mean reduction of LPP activity index in the eight patients that did observe a benefit. The only adverse effect reported was a 10-pound weight gain in one patient after treatment for 12 months.³⁴

Other Dermatologic Diseases

Evidence from case reports suggests that JAK inhibitors may provide benefit for patients with treatment-refractory or rare diseases without effective therapies such as cutaneous sarcoidosis, dermatomyositis, pemphigus, hidradenitis suppurativa, chronic mucocutaneous candidiasis, hypereosinophilic syndrome, polyarteritis nodosa, mastocytosis, and severe chronic actinic dermatitis.^35-40

Adverse Effects and Safety Considerations

The relatively broad and nonspecific anti-inflammatory and immunosuppressive properties of jakinibs, which allow for their potential efficacy across many indications, are mirrored in the wide array of potential adverse effects seen across this drug class. The primary safety concerns surrounding their use include the risk of infection, malignancy, and thromboembolic events. Nevertheless, jakinibs currently appear to have an acceptable safety profile comparable to that of the biologics already being used to treat many of the same conditions.^10,41 The majority of this safety data originates from clinical trials of tofacitinib and baricitinib in patients with rheumatoid arthritis.

Infection

The most commonly reported adverse events for those taking JAK inhibitors are mild upper respiratory infections and nasopharyngitis. For patients on tofacitinib, these mild infections occur at rates of approximately 10% or less.^6,20,42,43 There is also an increased risk of serious bacterial, fungal, mycobacterial, and viral infections, occurring at rates of 2.6 to 3.6 events per 100 patient-years for those on tofacitinib.²⁹ More specifically, the rates of tuberculosis and non-disseminated herpes zoster is 0.2 and 3.8 to 5.2 events per 100 patient-years, respectively.^43-45 Fortunately, the risk of tuberculosis is extremely low, especially for individuals residing in nonendemic areas. One study found that 21 out of 26 new tuberculosis cases in 5671 patients taking tofacitinib, occurred in countries with a high prevalence of tuberculosis.⁴⁵ Additionally, of 263 patients with latent tuberculosis, none developed active tuberculosis when they took tofacitinib and isoniazid concurrently.⁴⁵

The safety profile of baricitinib appears similar to that of tofacitinib with mild infection, namely nasopharyngitis, being the most common adverse event. In a 24-week, phase II study of 301 patients, only 1% developed a serious infection, but all recovered and continued with the study.⁴⁶ In a 52-week, phase II study of 142 patients, herpes zoster occurred in 11 patients and tuberculosis occurred in none.^46,47 Clinical trials of the 2nd generation jakinibs are reporting similar, if not improved, rates of infection to the 1st generation drugs.⁴⁸ However, phase IV studies and head-to-head trials between jakinibs will be required to establish any differences in risk.

Although the rates of herpes zoster in those taking jakinibs are similar to those of other biologic disease-modifying antirheumatic drugs, immunization with the recombinant zoster vaccine prior to initiating treatment may reduce the risk of this infection. While it is not specifically approved for patients using JAK inhibitors, it has been studied in individuals who are immunocompromised and found to be both safe and efficacious.¹⁰

Malignancy

There is concern about the theoretical increased risk for developing cancer with the use of jakinibs as a result of blocking the action of interferons and natural killer cells, which play an important role in tumor surveillance. While there have been reports of lymphoma and other malignancies associated with tofacitinib and baricitinib, multiple large studies have failed to demonstrate an increased risk of malignancy, with a mean follow-up of 3.5 years.^6,42,44,49 Moreover, a 128-week open-label extension study of tofacitinib did not show any cases of malignancy with prolonged treatment.⁵⁰ Yet, one study of myelofibrosis patients did find a slightly higher rate of aggressive B cell lymphoma in those treated with ruxolitinib. In response to this association, a bioinformatics study evaluating gene expression data from numerous lymphoma cell lines discovered that ruxolitinib can increase the pathological expression of transcription factors important in lymphoma genesis.⁵¹ Consequently, longer-term studies are necessary to further assess the correlation between jakinib therapy and cancer risk. Quantification of these risks based on dosage, duration of treatment, subtype of JAK inhibition, and disease type should be explored.

Thromboembolism

While the potential risks for infection and malignancy have been the primary safety considerations surrounding the use of jakinibs, more recently, concern for increased risk for thromboembolic events has arisen. In July 2019, the FDA issued a black box warning for the 10 mg, twice-daily dose of tofacitinib after a post-market safety review of the FDA’s Adverse Event Reporting System (FAERS) noted an increased rate of pulmonary thrombosis (OR = 2.46, [95% CI = 1.55-3.91]), though not pulmonary embolism (PE) or deep venous thrombosis (DVT), in patients with rheumatoid arthritis.⁵² However, a 2019 systematic review comparing complications associated with 5 mg versus 10 mg tofacitinib twice daily for the treatment of various autoimmune diseases found no difference in the rate of any serious adverse events at the end of the 3- and 6-month follow-up periods.⁵³ To date, approval of the 10 mg dose of tofacitinib is limited to those with treatment-refractory ulcerative colitis.

Baricitinib also has a black box warning denoting the risk for thromboembolic events, as clinical studies have observed an increased incidence of DVT and PE compared to placebo.⁵⁴ However, this risk of thromboembolic events appears to be quite low as it is estimated to be approximately five events per 1000 patient-years for the 4 mg daily dose in patients with RA. For non-RA patients, this risk is estimated to be even less, with one to four events per 1000 patient-years.⁵⁴ It should be noted that patients with RA also carry increased risk for thromboembolic events independent of JAK inhibitor therapy, although marginally increased risk has also been observed in patients with psoriatic arthritis and ulcerative colitis taking tofacitinib.^55,56

Nevertheless, this entire class of medication has come under closer scrutiny in light of these findings. Therefore, future trials of JAK inhibitors should ensure accurate and detailed documentation of any thromboembolic events that occur. Additionally, given the low incidence of thromboembolic events, large observational studies will likely be required to arrive at more definitive conclusions. Furthermore, it is crucial to differentiate whether these thromboembolic risks are attributable to JAK inhibitors or to the disease process itself and its comorbidities.

Lab Abnormalities

JAK inhibitors have also been associated with various laboratory abnormalities including anemia, neutropenia, and thrombocytopenia.^{8,43,44,47,57} These effects may be a consequence of JAK2 inhibition as erythropoietin and colony stimulating factor act through this pathway. Elevations in liver transaminases, high- and low-density lipoproteins, creatinine, and creatine phosphokinase may also be observed.^47,50,58 Importantly, many of these effects have been found to be dose-dependent, and all were reversible upon treatment discontinuation.^53,57,58 Also, long-term use does not appear to progressively worsen these abnormalities, and few patients discontinue treatment as a result of them.^47,50,53 Furthermore, a meta-analysis assessing the cardiovascular risks associated with the hyperlipidemia seen in psoriasis patients treated with baricitinib, found that there was no increased risk of major adverse cardiovascular events for these patients.⁵⁸

Discussion

JAK inhibitors appear to be a viable treatment option for a number of dermatologic conditions. With good oral bioavailability and lack of immunogenicity, they address some of the limitations of biologics. For most patients, jakinibs seem to be well-tolerated as discontinuation rates for safety issues are less than 10%.⁵⁹ The vast majority of adverse events are related to infection, but ensuring that patients are up to date on their immunizations can mitigate this risk to some degree. In particular, live-attenuated vaccines should be administered prior to initiation of therapy, as these should generally be avoided while taking JAK inhibitors. Historically, the live-attenuated zoster immunization was particularly important to administer prior to starting JAK inhibitor therapy; however, with the advent of the killed zoster vaccine (Shingrix), this is less of a concern. Moreover, closely monitoring patients for signs of infection and checking their complete blood count, liver transaminases, creatinine, and creatine phosphokinase may help prevent associated complications.⁶⁰

Nevertheless, additional research is needed to assess long-term efficacy and safety. While the increased risk of malignancy and thromboembolism attributable to JAK inhibitors appears to be quite low, large observational studies will likely be required to obtain a more accurate risk assessment.⁵⁴ Although it is not yet fully understood how selective inhibition of the JAK subtypes may affect the safety profile of these medications, it seems plausible that adverse effects may be influenced by the level and type of JAK inhibition. Head-to-head trials of these various 1st and 2nd generation jakinibs at varying dosages and durations of treatment are necessary to elucidate these risk differences, if any. Given the number of jakinibs in development and currently being tested in randomized trials for both dermatologic and non-dermatologic diseases, we remain optimistic regarding the benefit-risk profile of this class of medication.

Conclusion

Although the only dermatologic condition that is currently approved for treatment with a JAK inhibitor is psoriatic arthritis, their potential applications within dermatology are numerous. These drugs appear to be well-tolerated and have a safety profile relatively similar to that of biologics, excepting the increased risk of thromboembolism, and superior to many disease-modifying anti-rheumatic drugs. Moreover, these drugs seem to have a large overlap in their safety profiles despite differences in JAK selectivity. While risk of mild infection and herpes zoster appears to be increased regardless of JAK selectivity, risk of thrombosis and malignancy based on the subtype of JAK inhibition remains to be seen. Furthermore, thromboembolic and oncologic risk may also be dependent on a number of others factors including dosage, duration of treatment, concurrent treatments, disease type and severity, and comorbidities. While these significant safety concerns certainly warrant further investigation, ongoing clinical trials offer promise for the widespread application of these medications within future dermatologic practice.

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ABSTRACT
Hereditary angioedema is characterized by severe, episodic edema of the subcutaneous and mucosal tissue. The disease carries significant morbidity and mortality due to involvement of the gastrointestinal tract and upper airway. Recent advances in the treatment of hereditary angioedema include new techniques used to isolate and purify human-derived C1 inhibitor, the production of a recombinant form of C1 inhibitor, and the development of drugs that target the kallikrein-kinin pathway. This paper reviews the mechanisms, efficacy, and adverse reactions associated with these medications. 

Key Words:
hereditary angioedema, C1 inhibitor, Berinert, Cinryze, conestat alfa, Ruconest, Rhucin, ecallantide, Kalbitor, icatibant, Firazyr

Introduction

Hereditary angioedema (HA) is a rare genetic disease characterized by repeated episodes of non-pitting edema that can affect any cutaneous or mucosal surface. Swelling of the face, larynx, tongue, extremities, stomach, bowels, and genitals is common and can be associated with significant morbidity and mortality. The most common form of HA is autosomal dominant and results from a loss-of-function mutation in the gene that codes for C1 inhibitor protein. Under normal circumstances, a functional level of C1 inhibitor in plasma prevents over-activation of the complement system and over-production of the vasoactive mediator, bradykinin. Deficiency of C1 inhibitor allows for excessive release of bradykinin and complement anaphylatoxins, which results in increased endothelial permeability and edema.^1,2

In terms of disease management, synthetic androgens and protease inhibitors are useful in preventing episodes of angioedema through the stimulation of endogenous synthesis and reduced degradation of functional C1 inhibitor, respectively. Unfortunately, these agents are associated with significant adverse effects that limit their use.^3,4 Acute attacks are treated quite effectively by serum supplementation with exogenous humanderived C1 inhibitor, as initially demonstrated by Agostoni and colleagues in 1976.⁵ Human derived C1 inhibitor is not available in the United States, despite acceptance in Europe, due to concerns over possible virus transmission.

Relatively new developments have led to vast improvements in prevention and acute management of HA (Table 1). This paper reviews advances in the production of safer forms of humanderived C1 inhibitor (Berinert^®, Cinryze^®), the development of a recombinant form of C1 inhibitor (conestat alfa, Ruconest^®/Rhucin^®) and drugs that decrease the production of bradykinin (ecallantide, Kalbitor^®) or block its activity at the receptor level (icatibant, Firazyr^®).

Table 1: Summary of new treatments in hereditary angioedema

Discussion

The first advance in the treatment of HA came with improvement in techniques to filter and purify plasma-derived C1 inhibitor concentrate. Pasteurized preparations of C1 inhibitor were approved by the US FDA in 2009 for acute attacks. Numerous safety studies and small phase II trials showed a complete absence of viral transmission.⁶ This pasteurized form of C1 inhibitor is marketed as Berinert^® in the US, and Berinert^® P elsewhere. These agents require intravenous administration and patients can be trained in self-administration since the successful treatment of an acute attack depends on administering C1 inhibitor as soon as possible.⁷

In an effort to further decrease the risk of transmitting a viral illness with C1 inhibitor replacement, Cinryze^® was developed. In addition to the pasteurization used in the production of Berinert, the production of Cinryze utilizes a nanofiltration mechanism that has been proven to eliminate most viruses. Modern preparations of Berinert are also produced using this nanofiltration technique. Several placebo-controlled trials demonstrated the efficacy of administering this nanofiltered C1 inhibitor during acute attacks, with considerable reduction in duration of symptoms with a single injection. Further, in patients with regular attacks, Cinryze demonstrated a 50% reduction in frequency with twiceweekly administration.^8,9 Despite its efficacy as both an abortive and prophylactic agent, Cinryze is currently only approved for prophylaxis of angioedema. Like Berinert, Cinryze is only administered intravenously, however, it can be self-administered with appropriate training.

Both forms of purified C1-inhibitor, Berinert and Cinryze, demonstrate efficacy compared to placebo in remittance of acute attacks, with symptom relief occurring as early as 30 minutes after injection. Importantly, both agents also demonstrate significant efficacy in treating even the most severe attacks or those with predominant oropharyngeal, laryngeal, or abdominal edema.^10,11 Berinert and Cinryze are well tolerated, although common side effects include nonspecific symptoms, like nausea, vomiting, diarrhea, and headache. Rare adverse effects include worsening laryngeal edema and laryngospasm with Berinert, and stroke while using Cinryze have been reported. The only absolute contraindication to the use of C1 inhibitor replacement
is previous anaphylaxis.

In addition to the availability of safer forms of human-derived C1 inhibitor concentrate, the development of conestat alfa marked the creation of the first recombinant form of the protein. Conestat alfa contains an identical amino acid sequence to that of human C1 inhibitor, and thus serves as an analogue. It is obtained from the milk of transgenic rabbits expressing the gene for human C1 inhibitor.¹² Several randomized, double-blind clinical trials have demonstrated the improved efficacy of conestat alfa over placebo, citing significant reductions in duration of angioedema and quicker symptomatic relief, although the reported degree of effect varies.¹³

Despite similarities in terms of efficacy to purified human C1 inhibitor options, several differences exist. First, although the two options appear to be equal in terms of potency, the recombinant form of C1 inhibitor has a much shorter half-life compared to the plasma-derived option (3 hours vs. 24+ hours). Secondly, there exists the potential for allergic reaction to host-related impurities (HRIs), as patients with rabbit allergy have reacted to conestat alfa. Therefore, patients must be screened using rabbit-specific immunoglobulin E (IgE) immunoassay prior to administration, and those testing positive should not be given the drug. Finally, while viral transmission with human-derived C1 inhibitor has proven to be mostly a theoretical risk, conestat alfa truly eliminates this potential adverse outcome.

Even with the advent of effective and safe forms of replacement C1 inhibitor, several other pharmaceuticals have been developed that utilize alternative therapeutic mechanisms to control angioedema attacks. Recall that the symptomatology of HA is only secondarily caused by a lack of C1 inhibitor; endothelial permeability and edema are primarily mediated by an increase in bradykinin. It was with this understanding that icatibant was developed, which functions as an antagonist at bradykinin B2 receptors. Of note, this peptide has no affinity for bradykinin B1 receptors, which are also postulated to play a role, albeit a lesser one, in the production of angioedema.¹⁴ Icatibant was approved by the FDA in 2011 for use only in adults during acute episodes. Phase III trials demonstrated a quicker time to clinically significant relief when patients receiving icatibant were compared to both placebo and tranexamic acid, a protease inhibitor and antifibrinolytic commonly used to treat acute episodes. Additionally, two studies isolated the few patients who presented with laryngeal attacks and noted particular efficacy in improvement of airway obstruction. In these patients, administration of icatibant led to noticeable improvement within 0.6 to 1 hour and complete resolution in 4 hours.¹⁵

Proven and theoretical concerns exist regarding the use of icatibant. One advantage of icatibant is that it is administered subcutaneously in the abdominal area and is, thus, more easily self-administered by patients or caregivers. However, most patients, as many as 97% according to one source, experience a wheal and flare type injection-site reaction with swelling, pain, burning, and pruritus with each administration.¹⁵ Studies
suggest that this reaction is caused by icatibant’s role in release of preformed mast cell mediators, and can be diminished by prophylactic administration of antihistamines.¹⁶ Additionally, a theoretical concern exists regarding icatibant’s effect on blood pressure and heart rate, given that bradykinin normally acts as a potent vasodilator; however, studies have shown no significant effect on hemodynamics.

Another therapeutic target for treatment of HA is kallikrein, the protease that directly mediates the production of bradykinin. Decreased levels of C1 inhibitor result in unchecked kallikrein activity, which in turn converts kininogen to active bradykinin. This understanding led to the development and subsequent FDA approval of ecallantide, a 60-amino acid polypeptide derived from Pichia pastoris yeast cells that functions as a powerful and specific inhibitor of plasma kallikrein.⁶ Ecallantide has demonstrated efficacy in leading to significantly quicker onset of improvement, as well as quicker time to complete resolution during acute attacks. The study of ecallantide also made use of a patient reported severity index, which noted marked decreases in severity scores for patients taking ecallantide compared to placebo.¹⁷

Like icatibant, a limitation of ecallantide is that it is only useful in the treatment of acute attacks. Unlike icatibant, ecallantide does
not typically result in an injection-site reaction, although mild adverse effects are common with its administration, including headache, nausea, and diarrhea. Anaphylaxis is also a concern, since it has been observed to occur in as many as 4% of patients receiving ecallantide, which has led to the recommendation that ecallantide only be administered in a medical facility equipped to treat this adverse effect.¹⁸ Unfortunately, this eliminates ecallantide as an option for self-treatment by patients and caregivers at home.

Conclusion

The past decade has been marked by the development of new treatment options for the management of HA. Many international and national consensus guidelines exist, but none recommend specific therapies, citing a lack of head-to-head trials. The decision to use prophylactic therapy requires weighing the patient’s disease burden with the benefits and risks of therapy. For those patients who do require preventative therapy, Cinryze (C1 esterase inhibitor) appears to be equally as effective as synthetic androgens, and neither is recommended above the other.¹⁹ Berinert (C1 esterase inhibitor), Ruconest (conestat alfa), Firazyr (icatibant), and Kalbitor (ecallantide) appear to be equally efficacious, and the decision of which particular agent to use should depend on patient factors, including setting of administration and responsiveness to a particular agent during previous acute episodes.²⁰

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