¹Dermatology Research Institute, Calgary, AB, Canada
²Faculty of Medicine, University of Western Ontario, London, ON, Canada
³Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
⁴Department of Dermatology, McMaster University, Hamilton, ON, Canada
⁵Dermatrials Research Inc. & Venderm Consulting, Hamilton, ON, Canada
⁶Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
⁷Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
⁸Sunnybrook Health Sciences Centre, Toronto, ON, Canada
⁹Probity Medical Research, Waterloo, ON, Canada
¹⁰Skin Health & Wellness Centre, Calgary, AB, Canada
¹¹Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
¹²Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Conflict of interest: Ronald Vender has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, Aralez, Arcutis, Astellas, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Centocor, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Innovaderm, Janssen, Kabi-Care, LEO Pharma, Merck, Novartis, Palladin, Pfizer, Regeneron, Sandoz, Sun Pharma, Takeda, UCB, and Viatris-Mylan. Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, LEO Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. Alim R. Devani has been an advisor, consultant, speaker, and/ or investigator for AbbVie, Amgen, AnaptysBio, Arcutis, Arena, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Takeda, Tribute, UCB, and Valeant. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Apogee Therapeutics, Aralez, Arcutis, Arena, Asana, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, CorEvitas, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, RAPT Therapeutics, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Takeda, Tribute, UCB, and Valeant. Tuba Bukhari, Mariya Markovina, Abrahim Abduelmula, and Brian D. Rankin have no relevant disclosures. Funding sources: None.

Abstract: Generalized pustular psoriasis (GPP) is a rare, immune-mediated inflammatory disease with characteristic cutaneous and systemic manifestations. Mutations in the interleukin-36 receptor antagonist (IL36RN) gene have been implicated in its pathogenesis. Spesolimab is a novel systemic biologic therapy that selectively inhibits interleukin-36. It was recently approved by Health Canada and the US FDA for the treatment of GPP flares in adults. Results from phase 1 and 2 studies have been promising. Herein, we review the efficacy and safety of spesolimab for the treatment of GPP flares, as demonstrated in clinical trials.

Keywords: spesolimab, generalized pustular psoriasis, clinical trial, biologics, interleukin-36

Introduction

Generalized pustular psoriasis (GPP) is a rare, immune-mediated inflammatory disease with characteristic cutaneous and systemic manifestations, which, if left untreated, can be life-threatening in certain instances.^1,2 According to the European Rare and Severe Psoriasis Expert Network (ERASPEN) criteria, GPP is defined by the presence of “primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques)”, with 3 subclassifications, including “with or without systemic inflammation”, “with or without psoriasis vulgaris”, and “either relapsing (>1 episode) or persistent (>3 months)”.³ The prevalence of GPP varies with geographic location, where it was reported to be higher in Italy, impacting 180 cases per million, but lower in Japan, Germany, and France with 7.5, 5.0, and 1.8 cases per million, respectively.^4,5 GPP can have a pediatric- or adult-onset, and there is a slight female predilection.³ GPP adversely affects patient quality of life (QoL) and can also have a profound negative impact on families.⁶

Homozygous, heterozygous, and compound heterozygous lossof- function mutations in the interleukin (IL)-36 (IL-36) receptor antagonist gene (IL36RN), as well as mutations in other genes involved in the IL-36 signaling pathway, including, CARD14, AP1S3, and SERPINA3, have been identified in a proportion of patients with GPP.^7-9 Moreover, genotype-phenotype studies revealed that 24% of patients with GPP had IL36RN gene variants. The latter was associated with earlier age of onset/diagnosis, a greater degree of inflammation, and more severe disease.^10,11

Presently, there are no universally-accepted international consensus guidelines regarding the management of GPP. In the majority of countries, current first-line systemic therapies are being used offlabel. These include non-biologics, such as acitretin, cyclosporine, methotrexate, and apremilast, as well as biologics, including inhibitors of tumor necrosis factor-alpha, IL-12/23, IL-23, and IL-17.^12-14 Thus, there remains a significant unmet need for an advanced targeted systemic therapy that effectively treats acute GPP flares. Recently, Health Canada and the US FDA approved spesolimab, a novel IL-36 inhibitor, for the latter indication in adults.1 This biologic is the first commercially available IL-36 inhibitor for any indication.

Background

Spesolimab (Spevigo®) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively inhibits the IL-36 receptor (IL-36R), thereby preventing activation of the IL-36 signaling pathway which leads to release of the pro-inflammatory cytokines (IL-36A, IL-36B, and IL-36G) that cause GPP.¹ By inhibiting the overexpression of IL-36 cytokines, clinical resolution of acute flares can be observed.¹⁵

Available as single-use vials containing 450 mg of spesolimab in a 7.5 mL solution (60 mg/mL), spesolimab is administered as an intravenous (IV) infusion.⁶ The recommended dosage for adult patients is a single 900 mg IV dose over 90 minutes.¹

Non-medicinal ingredients of the spesolimab product include arginine hydrochloride, glacial acetic acid, polysorbate 20, sodium acetate, sucrose, and water. No data is currently available for its use in pediatric or pregnant patients; therefore, spesolimab has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended in pregnant or nursing women.¹

Supporting Evidence from Clinical Trials

Results from Phase 1 Studies

In a phase 1, multicenter, single-arm, open-label, proof-of-concept clinical trial, a single 10 mg/kg IV dose of spesolimab (formerly named BI 555130) was evaluated in adult patients (n=7) with a GPP flare.² The latter was defined as adult patients with an overall Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 3 or greater (GPPGA total score ≥3) and a GPPGA pustulation subscore of 2 or greater (GPPGA pustulation subscore ≥2). Safety and tolerability were the primary endpoints, with efficacy, including improvements in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) and GPPGA, as the secondary endpoints.

At week 2, improvements in GPPASI were achieved by all patients, with 73.2% of patients achieving a score of clear (GPPASI 0) and pustules being completely cleared (GPPGA pustulation subscore of 0) in 85.7% of patients. In addition, the proportion of patients achieving a GPPGA total score of clear or almost clear (GPPGA 0/1) was achieved by 71.4% of patients by week 1 and 100% of patients by week 4. There were also improvements seen in patient-reported outcomes (PROs) at week 2, with the mean (standard deviation [SD]) change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F) being 12.3 (10.1) and mean (SD) change from baseline in the Visual Analog Scale for pain (Pain-VAS) being -45.9 (32.3). Safety evaluation revealed that by week 20, four patients experienced treatment-emergent adverse events (TEAEs), all of which were mild or moderate in intensity. The most commonly reported TEAEs included eosinophilia and upper respiratory tract infection in two patients each. There were no serious AEs or deaths.²

In this study, patients underwent screening for mutations in genes thought to be involved in the pathogenesis of GPP, including IL36RN, CARD14, and AP1S3. Genetic testing revealed that two patients had homozygous loss-of-function mutations in IL36RN, and one patient had a homozygous mutation in IL36RN as well as a heterozygous mutation in CARD14. Treatment responses were consistent across all patients, irrespective of genetic mutation status.²

Table 1: Summary of the efficacy and patient-reported outcomes data for spesolimab from phase 1 clinical trial.

Results from Phase 2 Studies

In a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial (Effisayil™ 1), the efficacy and safety of a single 900 mg IV dose of spesolimab (n=35) versus placebo (n=18) were evaluated in adult patients with a GPP flare.¹⁶ The latter was defined as a GPPGA total score ≥3, GPPGA pustulation subscore ≥2, and affected body surface area (BSA) ≥5%. All patients were followed for 12 weeks.

At week 1, the primary efficacy endpoint of GPPGA pustulation subscore of 0 (clearance of pustules) was achieved by 54% and 6% of patients treated with spesolimab and placebo, respectively (p<0.001); in addition, the GPPGA total score 0/1 was achieved by 43% and 11% of patients treated with spesolimab and placebo, respectively (p=0.02). On day 8, in addition to patients who received spesolimab on day 1 (n= 35), including those who received a second, optional dose of spesolimab on day 8 (n=12), a proportion of placebo-treated patients also received open-label spesolimab (n=15). The secondary efficacy endpoint of 75% improvement in GPPASI (GPPASI75) was achieved by 51.4% of patients by week 4 and 57% of patients by week 12.¹⁶ PROs also improved by week 4, with a median (interquartile range [IQR]) change from baseline in Pain-VAS score of -53.4 (-77.9, -20.2), a median (IQR) change from baseline in the Psoriasis Symptom Scale (PSS) score of -7.0 (-10.0, -3.0), and a median (IQR) change from baseline in FACIT-F score of -22.0 (1.0, 31.0). In addition, patients from the placebo group who received open-label spesolimab on day 8 had comparable positive outcomes in physician-rated outcomes and PROs to those who received spesolimab at the start of the study.¹⁶

After one week, safety evaluations revealed similar rates of AEs between the treatment groups (spesolimab: 66%; placebo: 56%). In addition, TEAEs were similar between the spesolimab (29%) and placebo (28%) treatment groups. Among AEs in the spesolimab-treated group, infections (17%) were the most common AE reported after week 1, with the incidences increasing by week 12 (47.1%). After week 1, infections included: urinary tract infection (n=2), bacteremia (n=1), bacteriuria (n=1), cellulitis (n=1), herpes dermatitis (n=1), oral herpes (n=1), pustule (n=1), and upper respiratory tract infection (n=1). Serious AEs were reported in 6% and 12% of spesolimab-treated patients by week 1 and week 12, respectively. Two patients receiving spesolimab reported drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome; however, based on the Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring criteria (score <2: no DRESS; score of 2 or 3: possible DRESS; score of 4 or 5: probable DRESS; score >5: definite DRESS), these diagnoses and casual associations are not certain. In the first patient, the RegiSCAR score was 1, suggesting that the diagnosis was not compatible with DRESS. In the second patient, the RegiSCAR score was 3, indicating possible DRESS; yet, in addition to spesolimab, the patient received concomitant spiramycin and paracetamol (acetaminophen), then experienced a recurrence of the same signs/symptoms with a spiramycin rechallenge months after resolution of the first episode, suggesting spiramycin as a potential causative agent. No AEs led to treatment or study discontinuation.¹⁶

Table 2: Summary of the efficacy and patient-reported outcomes data for spesolimab from phase 2 clinical trial.

Summary of Results from Phase 1 and Phase 2 Studies

In summary, clinical trial results suggest that IL-36 inhibition with spesolimab leads to rapid and sustained improvements in GPP flares in adult patients with a favorable safety profile. Results from both the phase 1 and phase 2 studies demonstrated rapid clearance of pustules, with many patients experiencing clear or almost clear skin after one dose of spesolimab. The safety profile of spesolimab revealed slightly higher rates of infection compared to placebo. There were also two reports of DRESS in the phase 2 clinical trial, although both cases were determined to be non-definitive. Larger sample sizes are required to confirm the safety risks associated with spesolimab use in GPP; in addition, given that this is a rare condition, long-term efficacy and safety data from clinical trials and real-world studies will be of utmost importance in order to elucidate spesolimab’s place in the therapeutic paradigm for GPP.

Spesolimab was also shown to have a positive impact on PROs in GPP patients, including pain, fatigue, and QoL in both phase 1 and phase 2 studies. In the phase 2 clinical trial, PROs particularly improved after one week in comparison to the placebo, with scores continuing to improve past week 4 and maintained until the end of the study at week 12. Despite the individual differences in the clinical progression of GPP, there were rapid and maintained overall improvements in PROs.

Specific Populations

Data on the treatment of GPP using spesolimab is not yet available in children or adolescents (<18 years of age); however, a phase 2b, multicenter, double-blind, placebo-controlled clinical trial (Effisayil™ 2) evaluating the efficacy and safety of maintenance treatment with subcutaneous spesolimab in patients aged 12-75 years is currently ongoing.¹⁷ Although 6% of patients were aged 64-75 years in the phase 2 clinical trial, due to insufficient sample size, efficacy and safety have not been determined in elderly populations.¹

Counselling: Practical Tips to Optimize Use

In preparation for injection, spesolimab must be diluted with 15 mL of sterile 0.9% sodium chloride solution and promptly used. Spesolimab is administered as a single 900 mg dose by continuous IV infusion over a period of 90 minutes in an outpatient setting by a healthcare provider. If the infusion is slowed or interrupted, the total infusion time should not exceed 180 minutes. Pre-existing IV lines may be used as long as they are flushed with a sterile 0.9% sodium chloride solution prior to and after spesolimab administration. If GPP flare signs/symptoms continue, this dosing regimen can be repeated one week after the initial dose.¹

Patients must be informed about the importance of disclosing their complete history of chronic and recurrent infections to their healthcare provider, as spesolimab can increase the risk of infection. Patients should be advised to seek immediate medical attention if they develop new signs/symptoms of infection or infusion-related hypersensitivity reactions, such as anaphylaxis or DRESS after spesolimab use. Patients should also be advised against receiving live vaccines after spesolimab treatment has started, as no studies have been conducted in spesolimab-treated patients that have previously received live bacterial or viral vaccines.¹

Conclusions

A single IV dose of spesolimab is an effective and safe treatment for adult patients presenting with GPP flares. Results of clinical trials using spesolimab indicate that medications targeting the IL-36 pathway can be successful therapeutic interventions to improve the clinical signs and symptoms of GPP. Further long-term studies with larger sample sizes, the inclusion of more pediatric and elderly patients, and the exploration of various dosing regimens for maintenance treatment are required to more accurately assess the efficacy and safety of spesolimab.

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¹Faculty of Medicine, University of Western Ontario, London, ON, Canada
²Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
³Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
⁴Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
⁵Sunnybrook Health Sciences Centre, Toronto, ON, Canada
⁶Probity Medical Research, Waterloo, ON, Canada
⁷Dermatology Research Institute, Calgary, AB, Canada
⁸Skin Health & Wellness Centre, Calgary, AB, Canada
⁹Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
¹⁰Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Conflict of interest:
Abrahim Abduelmula has no relevant disclosures. Brian D. Rankin has no relevant disclosures. Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, LEO Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Arena, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant.

Funding sources: None.

Abstract:
Atopic dermatitis (AD) is a common, chronic, recurrent, immune-mediated inflammatory skin disease. Targeted treatment options remain limited. Tralokinumab (Adtralza^®) is a promising, new systemic therapy that inhibits interleukin-13. It was recently approved by Health Canada and the US FDA for the treatment of moderate-to-severe AD in adults and may be used alone or with topical corticosteroids. Herein, we review the efficacy and safety of tralokinumab in adults, as demonstrated in clinical trials.

Keywords:
Adtralza^®, tralokinumab, immunomodulator, therapeutics, biologic, atopic dermatitis, eczema, clinical trial

Introduction

Atopic dermatitis (AD) is a common, chronic, recurrent, immune-mediated inflammatory skin disorder affecting between 5-10% of adults, with moderate-to-severe disease accounting for approximately 20-30% of cases.^1,2 This condition can have a significant negative impact on psychosocial well-being, health-related quality of life (QoL), and work/school productivity. In addition, uncontrolled AD is associated with a substantial financial burden on the patient and their family as well as the health care system.³

Topical therapies are employed as first-line treatment for the majority of AD cases, but lack of response can necessitate the use of phototherapy and/or systemic therapies. With respect to systemic therapies, recent advances have led to the development of new targeted treatments, of which four are now approved by Health Canada and the US FDA for moderate-to-severe AD. This includes two biologics (dupilumab [Dupixent^®], an interleukin (IL)-4/IL-13 inhibitor, and tralokinumab [Adtralza^®], an IL-13 inhibitor) and two small molecules (upadacitinib [Rinvoq^®] and abrocitinib [Cibinqo^®], both selective Janus kinase 1 [JAK1] inhibitors).

Background

Tralokinumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that binds with high affinity to IL-13, thereby blocking its interaction with the IL-13Rα1/IL-4Rα1 heterodimer and IL-13Rα2 homodimer receptor complexes and subsequently leading to downstream STAT-6 inhibition.⁴ The latter results in reduced inflammation, improved skin barrier function (reductions in epidermal thickness and increased epithelial barrier integrity), as well as restoration of the microbiome (a near 10-fold reduction in Staphylococcus aureus colonization of the skin).^4,5

Tralokinumab may be given alone or in combination with a topical corticosteroid (TCS).^6,7 It was approved by both Health Canada and the US FDA in 2021 for the treatment of moderate-to-severe AD in adult patients whose disease is not adequately controlled with prescription topical therapies or when those prescription topical therapies are not advisable.⁶ Available as a single-use prefilled syringe containing 150 mg of tralokinumab in 1 mL solution (150 mg/mL), tralokinumab is administered as a subcutaneous (SC) injection.⁶ The recommended dosage for adult patients is an initial 600 mg loading dose followed by 300 mg maintenance doses every other week (Q2W). According to the product monograph, the prescriber may choose to administer tralokinumab every fourth week (Q4W) in adult patients who achieve clear or almost clear skin after 16 weeks of treatment; however, there is an increased probability that maintenance efficacy may be decreased with Q4W dosing.⁶

Non-medicinal ingredients of the product include acetic acid, polysorbate 80, sodium acetate trihydrate, sodium chloride, and water. No published data is currently available for its use in pediatric or pregnant patients, and, as such, tralokinumab has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended for pregnant women.⁶

Supporting Evidence from Clinical Trials (Figures 1-5)

Results from Pivotal Phase 3 Monotherapy Studies

In a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=802) with moderate-to-severe AD (ECZTRA 1), the efficacy and safety of tralokinumab 300 mg SC Q2W (n=603) versus placebo (n=199) was evaluated.⁸ At week 16: the primary endpoint of an Investigator Global Assessment (IGA) score of clear or almost clear (IGA 0/1) was achieved by 15.8% and 7.1% of patients treated with tralokinumab and placebo, respectively (p<0.002) (Figure 1); an improvement of ≥75% and ≥90% in the Eczema Area and Severity Index (EASI75 and EASI90, respectively) was achieved by 25.0% and 14.5% of patients treated with tralokinumab versus 12.7% and 4.1% of patients treated with placebo (p<0.001 and p<0.05, respectively) (Figure 2); pruritus Numerical Rating Scale (NRS) improved by 20.0% with tralokinumab versus 10.3% with placebo (p=0.002); and there was a reduction in Dermatology Life Quality Index (DLQI) scores by 7.1 with tralokinumab and 5.0 with placebo, respectively (p=0.002) (Figure 3). Safety evaluation revealed similar adverse event (AE) profiles between the tralokinumab and placebo groups, with the majority of treatment-emergent AEs (TEAEs) being mild and self-limiting in nature. The most observed TEAEs with tralokinumab included viral upper respiratory tract infection (URTI) (23.1%), conjunctivitis (10.0%), and eczema herpeticum (0.5%). One case of conjunctivitis led to treatment discontinuation. No injection-site reactions (ISRs) were observed in either treatment group.⁸

In another phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=794) with moderate-to-severe AD (ECZTRA 2), the efficacy and safety of tralokinumab 300 mg SC Q2W (n=593) versus placebo (n=201) was evaluated.⁸ At week 16: the primary endpoint of IGA 0/1 was achieved by 22.2% and 10.9% of patients treated with tralokinumab and placebo, respectively (p<0.001) (Figure 1); EASI75 and EASI90 were achieved by 33.2% and 18.3% of patients treated with tralokinumab versus 11.4% and 5.5% of patients treated with placebo (p<0.001 and p<0.05, respectively) (Figure 2); pruritus NRS improved by 25.0% with tralokinumab versus 9.5% with placebo (p<0.001); and there was a reduction in DLQI by 8.8 with tralokinumab and 4.9 with placebo, respectively (p<0.001) (Figure 3). Safety evaluation revealed similar AE profiles between the tralokinumab and placebo groups, with the majority of TEAEs being mild and self-limiting in nature. The most observed TEAEs with tralokinumab included URTI (8.3%), conjunctivitis (5.2%), and eczema herpeticum (0.3%). No cases of conjunctivitis led to discontinuation. In addition, no ISRs were observed in either treatment group.⁸

By week 52, IGA 0/1 responses achieved at week 16 with tralokinumab Q2W were maintained, without any rescue therapy (including TCS), by 51% (ECZTRA 1) and 59% (ECZTRA 2) of patients who continued to receive tralokinumab Q2W versus 47% (ECZTRA 1) and 25% (ECZTRA 2) of patients who were rerandomized from tralokinumab Q2W to placebo (p=0.60 and p=0.004, respectively) (Figure 4). In addition, by week 52, EASI75 responses achieved at week 16 with tralokinumab Q2W were maintained by 60% (ECZTRA 1) and 56% (ECZTRA 2) of patients who continued to receive tralokinumab Q2W versus 33% (ECZTRA 1) and 21% (ECZTRA 2) of patients who were rerandomized from tralokinumab Q2W to placebo (p=0.056 and p<0.001, respectively) (Figure 5).⁸ A subset of patients following week 16 were downdosed from Q2W to Q4W dosing of tralokinumab. By week 52, 39% (ECZTRA 1) and 45% (ECZTRA 2) of patients maintained their week 16 IGA 0/1 responses despite being switched from Q2W to Q4W dosing (Figure 4). In addition, by week 52, 49% (ECZTRA 1) and 51% (ECZTRA 2) of patients maintained their week 16 EASI75 responses despite being switched from Q2W to Q4W dosing (Figure 5).

Results from Pivotal Phase 3 Combination Therapy Studies

In a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=380) with moderate-to-severe AD (ECZTRA 3), the efficacy and safety of tralokinumab 300 mg SC Q2W + TCS (n=253) versus placebo + TCS (n=127) was evaluated. The TCS utilized was mometasone furoate 0.1% cream. At week 16: the primary endpoint of IGA 0/1 was achieved by 38.9% and 26.2% of patients treated with tralokinumab + TCS and placebo + TCS, respectively (p=0.015) (Figure 1); EASI75 and EASI90 were achieved by 56.0% and 32.9% of patients treated with tralokinumab + TCS versus 35.7% and 21.4% of patients treated with placebo + TCS (p<0.001 and p<0.022, respectively) (Figure 2); pruritus NRS improved by 45.5% with tralokinumab + TCS versus 34.1% with placebo + TCS (p=0.037); and there was a reduction in DLQI by 11.7 with tralokinumab + TCS and 8.8 with placebo + TCS, respectively (p<0.001) (Figure 3). By week 32, in patients receiving tralokinumab Q2W + TCS, 89.6% and 92.5% maintained their week 16 IGA 0/1 and EASI75 responses, respectively (Figure 4 and 5, respectively). A subset of patients following week 16 were downdosed from tralokinumab Q2W to Q4W dosing. At week 32, 77.6% and 90.8% of patients maintained their week 16 IGA 0/1 and EASI75 responses, respectively, despite being switched from Q2W to Q4W dosing (Figure 4 and 5, respectively).⁹ Safety evaluation revealed similar AE profiles between the tralokinumab + TCS and placebo + TCS groups, with the majority of TEAEs being non-serious and self-limiting in nature. The most observed TEAEs with tralokinumab + TCS included URTI (19.4%), conjunctivitis (13.1%), and eczema herpeticum (0.4%). Six patients permanently discontinued treatment with tralokinumab due to non-serious AEs, one of which was conjunctivitis.⁹ No ISRs were observed in either treatment group.

In another phase 3 multicenter, parallel, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=277) with moderate-to-severe AD (ECZTRA 7), the efficacy and safety of tralokinumab 300 mg SC Q2W + TCS (n=140) versus placebo + TCS (n=137) was evaluated. The TCS utilized was mometasone furoate 0.1% cream.¹⁰ At week 16: the primary endpoint of EASI75 was achieved by 64.2% and 50.5% of patients treated with tralokinumab + TCS and placebo + TCS, respectively (p=0.018) (Figure 2); EASI90 was achieved by 41.1% of patients treated with tralokinumab + TCS versus 29.3% of patients treated with placebo + TCS (p<0.001) (Figure 2); pruritus NRS was reduced by 4 with tralokinumab + TCS versus 3.1 with placebo + TCS (p<0.001); and there was a reduction in DLQI by 11.2 with tralokinumab + TCS and 9.6 with placebo + TCS, respectively (p=0.009) (Figure 3). By week 26, in patients receiving tralokinumab + TCS, 68.8% achieved EASI75 and 48.6% achieved EASI90, compared with 55.3% and 36.4% for placebo + TCS (p=0.014 and p=0.027, respectively) (Figure 5). Safety evaluation once again showed similar AE profiles between the tralokinumab and placebo groups, with the majority of TEAEs being non-serious and self-limiting in nature. The most observed TEAEs with tralokinumab included URTI (26.8%), conjunctivitis (9.4%), and eczema herpeticum (0.7%). One patient permanently discontinued treatment with tralokinumab due to an AE that was not deemed serious.¹⁰ No ISRs were observed in either treatment group.

Summary of Results from Pivotal Phase 3 Monotherapy and Combination Therapy Study Results and Additional Analyses

In summary, tralokinumab was more effective than placebo in both monotherapy and combination therapy studies, with tralokinumab demonstrating greater efficacy than placebo for patients with moderate-to-severe AD across all phase 3 clinical trials. Interestingly, rates of eczema herpeticum were higher in the placebo groups as opposed to the tralokinumab groups.^8-10 An additional pooled analysis (n=1605) of five completed double-blind, randomized, placebo-controlled, phase 2 and 3 clinical trials of tralokinumab in adult patients with moderateto- severe AD examined the rates of conjunctivitis within these studies; it was found that tralokinumab had a slightly higher incidence of conjunctivitis (7.5%) in comparison to placebo (3.2%), with the majority of cases being mild-to-moderate in severity and 75% of events resolving before the treatment period was over in both groups.¹¹

Tralokinumab was also shown to have a significant impact on health-related QoL in a phase 2b randomized, double-blind, placebo-controlled clinical trial involving adult patients (n=204) with moderate-to-severe AD. At week 6, a 5.4-point reduction in DLQI was observed with tralokinumab monotherapy, while a 2.3-point reduction in DLQI was observed with placebo (p=0.05). At week 16, a 6.8-point reduction in DLQI was observed with tralokinumab monotherapy, while a 3.5-point reduction in DLQI was observed with placebo (p=0.006) (Figure 3).¹²

Tralokinumab may also help resolve other IL-13-associated skin abnormalities. In a phase 2 randomized, double-blind, placebo-controlled study (n=204), adult patients with moderate-to-severe AD treated with tralokinumab had lower rates of Staphylococcus aureus colonization, fewer skin infections requiring systemic antimicrobial therapy, and a lower frequency of eczema herpeticum when compared to placebo groups.⁷ In another phase 2, 30-week, double-blind, randomized, placebo-controlled clinical trial (n=215), it was shown that tralokinumab did not impair vaccine-induced immune responses in adult patients receiving tetanus-diphtheria-pertussis (Tdap) or meningococcal vaccines.¹³

Special Populations

Tralokinumab has not been approved for utilization in children/ adolescents (<18 years of age), although a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial in adolescent patients (12-17 years of age) with moderate-to-severe AD is still ongoing.¹⁴ Tralokinumab is currently not recommended in pregnant or breastfeeding women. It remains unknown if the drug is excreted in breast milk. There were no differences in terms of efficacy or safety with use in elderly patients (≥65 years of age).⁶

Table 1. Summary of the efficacy and quality of life data for tralokinumab from pivotal phase 2 and 3 clinical trials in adult patients with moderate-to-severe AD

Counselling: Practical Tips to Optimize Administration

Tralokinumab is administered as an SC injection. Optimal anatomic sites for the SC injection include the lower limb (specifically thigh) or trunk (specifically abdomen, excluding a 5 cm radius around the navel); the upper limb (specifically lateral upper arm) may also be used if another individual can administer the medication. Multiple doses should be delivered in the same anatomic site but at different points within that anatomic site. Doses should be rotated to different anatomic sites with each subsequent set of SC injections. Tralokinumab should not be injected into tender or damaged skin. If a patient and/or a caregiver wishes to administer the SC injection, proper training should be provided. If a dose is missed, the missed dose should be administered as soon as possible and the scheduled dosing regimen continued.⁶

Conclusion

Tralokinumab is an effective and safe treatment for adult patients with moderate-to-severe AD. It may be used alone or in combination with TCS. This biologic can be considered first-line treatment after failure of or intolerance to topical therapies, and, as such, represents an important tool in our therapeutic armamentarium.

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¹Faculty of Medicine, University of Western Ontario, London, ON, Canada
²Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
³Department of Dermatology, McMaster University, Hamilton, ON, Canada
⁴Dermatrials Research Inc. & Venderm Innovations in Psoriasis, Hamilton, ON, Canada
⁵Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
⁶Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
⁷Sunnybrook Health Sciences Centre, Toronto, ON, Canada
⁸Probity Medical Research, Waterloo, ON, Canada
⁹Dermatology Research Institute, Calgary, AB, Canada
¹⁰Skin Health & Wellness Centre, Calgary, AB, Canada
¹¹Probity Medical Research, Calgary, AB, Canada
¹²Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
¹³Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
¹⁴Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Conflict of interest:
Abrahim Abduelmula and Brian D. Rankin have no relevant disclosures. Ronald Vender has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, Astellas, Celgene, Dermira, Eli Lilly, Galderma, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, and Takeda. Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, LEO Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. Alim R. Devani has been an advisor, consultant, speaker, and/or investigator for AbbVie, Amgen, AnaptysBio, Arcutis, Arena, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Arena, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant. Funding sources: None.

Abstract:
A novel topical corticosteroid, halobetasol propionate (HP) 0.01% lotion (Bryhali™), has recently been introduced for the treatment of plaque psoriasis and corticosteroid-responsive dermatoses in adults. Once daily application of HP 0.01% lotion is indicated for use up to 8 weeks. Treatment success for plaque psoriasis in the pivotal phase 3 clinical trials (defined as an Investigator Global Assessment [IGA] of clear/almost clear [IGA 0/1] with ≥2-grade improvement from baseline) occurred in over one-third of patients by week 8. Treatment-emergent adverse events were typically mild-to-moderate in intensity and usually limited to the application site(s). No treatment-related cases of skin atrophy have been reported from the studies. Counselling should be considered to optimize treatment outcomes.

Key Words:
Bryhali™; halobetasol; topical; therapeutics; corticosteroid; psoriasis; clinical trial

Introduction

Topical corticosteroids are a mainstay in the management of plaque psoriasis and other corticosteroid-responsive dermatoses. Bryhali™ is a super-potent topical corticosteroid lotion with halobetasol propionate (HP) 0.01% as the active ingredient. It was approved by the US FDA in 2018 for plaque psoriasis and by Health Canada in 2021 for both plaque psoriasis and corticosteroid-responsive dermatoses. Available in 45 g, 60 g, and 100 g tubes containing 0.1 mg of HP 0.01% per gram, HP 0.01% lotion is applied once daily to affected areas (maximum dose of 50 g per week).^1,2 It has a safety profile allowing for extended use up to 8 weeks without physician re-evaluation (provided there are observed improvements in the condition being treated).³ Non-medicinal ingredients of this product include carbomer copolymer type b, carbomer homopolymer type a, diethyl sebacate, edetate disodium dihydrate, light mineral oil, methylparaben, propylparaben, purified water, sodium hydroxide, sorbitan monooleate, and sorbitol solution 70%. No data is currently available for its use in pediatric or pregnant patients; therefore, HP 0.01% lotion has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended in pregnant women.¹

Background

Plaque psoriasis and certain corticosteroid-responsive dermatoses, such as atopic dermatitis, are chronic, immunemediated, inflammatory skin diseases that vary in severity. Topical corticosteroids are used across all severities, although moderate-to-severe disease often requires the addition of phototherapy or systemic therapies.⁴ Despite their efficacy, these conditions can quickly recur if treatment is discontinued; however, extended use of topical corticosteroids can also result in adverse events (AEs) that are either local (e.g., skin atrophy, folliculitis, striae, and telangiectasia) or systemic (e.g., hypothalamic-pituitary-adrenal [HPA] axis suppression).⁵

HP 0.05% cream or ointment (Ultravate^®) is a commonly prescribed topical corticosteroid applied once or twice daily per physician direction (maximum dose of 50 g per week).⁶ According to the product monograph, patients should limit use to a maximum of 2 weeks unless re-evaluated by a physician. However, considering the chronic nature of plaque psoriasis and many other corticosteroid-responsive dermatoses, such as atopic dermatitis, this limited treatment duration can become an issue for long-term utilization and compliance.⁶ Studies on HP 0.01% lotion have shown that despite demonstrating comparable efficacy to HP 0.05% cream, the safety profile allows it to be used for intervals longer than 2 weeks without the need for physician re-evaluation at 2 weeks.⁷

HP is a water-insoluble synthetic corticosteroid thought to act via the induction of lipocortins, a group of phospholipase A2 inhibitory proteins. It is theorized that these proteins act on pro-inflammatory mediators, such as prostaglandins and leukotrienes, via inhibition of the precursor arachidonic acid.⁸ HP has anti-inflammatory, anti-proliferative, antipruritic, and vasoconstrictive effects.^1,7

The once daily HP 0.01% lotion is formulated with proprietary PRISMATREX™ technology, a novel polymeric emulsification system that features oil droplets containing the active ingredient and other hydrating/moisturizing excipients dispersed evenly in an oil-in-water emulsion and separated by a 3-dimensional mesh matrix.^1,9 This allows for uniform distribution and enhanced penetration when applied onto the skin surface. The latter may provide rationale for the comparable efficacy of HP 0.01% lotion and HP 0.05% cream despite a 5-fold difference in the concentration of HP.⁷

Supporting Evidence from Clinical Trials (Table 1)

Table 1

Plaque Psoriasis

In a phase 2 multicenter, randomized, double-blind, vehicle-controlled clinical trial (n=150), the efficacy and safety of HP 0.01% lotion (n=60) versus HP 0.05% cream (n=57) was evaluated in adult patients with moderate-to-severe plaque psoriasis (Investigator Global Assessment [IGA] score: moderate [3] or severe [4]; affected body surface area [BSA]: 3% to 12%).⁷ At week 2: the primary endpoint of an IGA score of clear or almost clear (IGA 0/1) with ≥2-grade improvement from baseline (treatment success) was achieved by 30.0% and 31.6% of patients treated with HP 0.01% lotion and HP 0.05% cream, respectively (p=0.854); a 2-grade improvement from baseline in the 3 key signs of plaque psoriasis—erythema, elevation, and scaling—at the target lesion site (treatment success for specific psoriasis signs) was achieved by 38.3%, 40.0%, and 43.3% of patients treated with HP 0.01% lotion versus 31.6%, 36.8%, and 47.4% of patients treated with HP 0.05% cream, respectively (p=0.446, p=0.727, and p=0.663, respectively); and BSA improved by 22.3% with HP 0.01% lotion versus 20.9% with HP 0.05% cream (p=0.787). Both HP 0.01% lotion and HP 0.05% cream were more effective than vehicle at all time points, with HP 0.01% lotion demonstrating greater efficacy than HP 0.05% cream for patients with more severe disease (IGA=4) at baseline. Safety evaluation revealed AEs of treatment-related dermatitis (n=1) and severe itching (n=1) with HP 0.01% lotion as well as treatment-related severe itching (n=2) and severe burning/ stinging (n=1) with HP 0.05% cream. No treatment-related cases of skin atrophy, folliculitis, striae, or telangiectasia were observed in either treatment group.⁷ In summary, HP 0.01% lotion was comparable to HP 0.05% cream in terms of overall treatment success, treatment success for specific psoriasis signs at the target lesion site, and reduction in BSA, with both treatments demonstrating a favorable safety profile.

In a pooled analysis of 2 phase 3 multicenter, double-blind, randomized, parallel-group clinical trials (n=430), the efficacy and safety of HP 0.01% lotion (n=285) versus vehicle (n=145) was evaluated in adult patients with moderate-to-severe plaque psoriasis (IGA score: 3 or 4; affected BSA: 3% to 12%).⁹ At week 8: the primary endpoint of treatment success was achieved by 36.5% (Study 1) and 38.4% (Study 2) of patients treated with HP 0.01% lotion versus 8.1% (Study 1) and 12.0% (Study 2) of patients treated with vehicle (p<0.001 for both comparisons versus vehicle), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2 (Study 1) and week 4 (Study 2); HP 0.01% lotion achieved treatment success for specific psoriasis signs at the target lesion site in 46.7% (Study 1) and 56.3% (Study 2) of patients for erythema, 52.5% (Study 1) and 62.7% (Study 2) of patients for elevation, as well as 54.9% (Study 1) and 63.1% (Study 2) of patients for scaling (p<0.001 for all comparisons versus vehicle); BSA improved by 34.2% (Study 1) and 36.2% (Study 2) with HP 0.01% lotion (p<0.001 for both comparisons versus vehicle), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2 (both Study 1 and Study 2); mean Dermatology Life Quality Index (DLQI) score was reduced by 57.7% (Study 1) and 58.7% (Study 2) with HP 0.01% lotion (p=0.001 and p=0.004, respectively, versus vehicle); mean IGAxBSA composite score (calculated by multiplying the IGA by the BSA; range: 9-48) was reduced by 49.5% with HP 0.01% lotion versus 13.4% with vehicle (p<0.001), with HP 0.01% lotion demonstrating statistically significant superiority over vehicle as early as week 2; and the proportion of patients achieving ≥50%, ≥75%, and ≥90% reduction in IGAxBSA composite score from baseline (IGAxBSA-50, IGAxBSA-75, and IGAxBSA-90, respectively) was 56.8%, 39.3%, and 19.3% with HP 0.01% lotion versus 17.2%, 9.7%, and 2.8% with vehicle (p<0.001 for all comparisons versus vehicle).^3,9 Safety evaluation revealed similar rates of AEs between the treatment groups: 21.5% with HP 0.01% lotion and 23.9% with vehicle. Most AEs (90.2%) were mild-to-moderate in intensity. No cases of treatment-related skin atrophy, folliculitis, or striae were reported.¹⁰ There was one AE of telangiectasia with HP 0.01% lotion, not deemed to be treatment-related. In summary, HP 0.01% lotion was superior to vehicle in terms of overall treatment success, treatment success for specific psoriasis signs at the target lesion site, reduction in BSA, as well as improvements in mean DLQI and mean IGAxBSA composite scores, with HP 0.01% lotion demonstrating a favorable safety profile.

Corticosteroid-Response Dermatoses

There are no clinical trials investigating the efficacy and safety of HP 0.01% lotion for corticosteroid-responsive dermatoses.

Dosage and Administration

The on-label recommendation is to apply a thin layer of Bryhali™ once daily to areas affected by plaque psoriasis or other corticosteroid-responsive dermatoses until disease control is achieved.¹ The total amount used should not exceed 50 g per week due to the concern for HPA axis suppression. Uninterrupted treatment beyond 8 weeks is not recommended.¹

Counselling: Practical Tips to Optimize Use

A thin layer of HP 0.01% lotion should be applied, just enough to cover the areas affected by plaque psoriasis or other corticosteroid-responsive dermatoses. It is essential to rub in gently and inform patients that applying excessive amounts will not improve treatment efficacy. If HP 0.01% lotion is applied after bathing, the treatment site(s) should be dry before application.

It is also important to allow sufficient time for the medication to dry before putting clothes on to prevent inadvertent spread onto unaffected skin. HP 0.01% lotion should not be used with occlusive dressings unless recommended by a physician. It is for external use only and must be kept away from the eyes, nose, mouth, and other mucosal sites. HP 0.01% lotion should not be applied to the scalp or sensitive sites, such as the face, groin, and axillae, nor on ulcers or wounds.¹ It is also advised to avoid application on areas affected by untreated bacterial, tubercular, fungal and viral infections involving the skin.¹

Conclusion

Once daily application of HP 0.01% lotion (Bryhali™) is a convenient topical therapy with comparable efficacy to HP 0.05% cream (Ultravate^®), despite a 5-fold difference in concentration of HP. One of the main advantages is its ability to be used safely for up to 8 weeks without concern for AEs (especially skin atrophy) and the requirement for physician re-evaluation (provided there are observed improvements in the condition being treated). Counselling with application tips should be considered for all patients.

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Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

ABSTRACT

The pemphigus variants represent a group of potentially life-threatening autoimmune mucocutaneous blistering diseases. Though systemic corticosteroids have dramatically reduced the rate of disease mortality, current therapeutic options are limited by their toxicity profiles. Advancements in our understanding of the molecular mechanisms involved in the pathogenesis of pemphigus have translated into the development of novel therapies. However, few treatments have been subject to randomized controlled trials to firmly establish therapeutic efficacy. Herein, we focus on the new and emerging therapies in the management of pemphigus.

Key Words:
pemphigus, autoimmune skin disease

Pemphigus represents a group of rare autoimmune mucocutaneous blistering disorders. The 2 main subtypes are pemphigus vulgaris (PV) and pemphigus foliaceus (PF), each with its own clinical variants. Less common forms include paraneoplastic pemphigus, IgA pemphigus, and pemphigus herpetiformis. Since PV is the most common subtype of pemphigus worldwide, it will be the focus of this article.

PV affects both genders equally and has a mean age of onset of 50-60 years. A higher prevalence has been noted in individuals of Ashkenazi Jewish, Mediterranean, Northern Indian and Persian descents.1 Patients often present with multiple, painful erosions or flaccid bullae on the skin and/or mucous membranes. Mucosal disease precedes cutaneous involvement in the majority of the cases.²

The disease is mediated by circulating immunoglobulin G (IgG) autoantibodies against the desmosomal cadherins, desmogleins 1 and 3.³ Histopathology reveals a loss of cell-cell adhesion (acantholysis) in the suprabasilar layer of the epithelium and direct immunofluorescence (DIF) of perilesional skin reveals intercellular deposition of IgG +/– C3. As antibodies often correlate with disease activity, indirect immunofluorescence (IIF), immunoblots, and enzyme-linked immunosorbent assays (ELISA) are commonly used to quantify circulating antibody levels.⁴

If left untreated, PV is frequently fatal with a mortality rate ranging from 60% to 90%.5-8 While systemic corticosteroid use and other therapeutic advances have reduced this mortality rate to approximately 10%, complications from treatment are now the primary cause of morbidity and mortality in this population.^6,7 The goal of managing pemphigus patients is, therefore, to induce and maintain remission with the lowest possible doses of medication, so as to minimize the risk of serious and potentially fatal adverse effects.²

Conventional Therapies

Systemic corticosteroids remain the treatment of choice for pemphigus as they are both effective and capable of inducing a rapid remission. However, adverse effects of corticosteroids are both time- and dose-dependent.⁹ They include weight gain, diabetes, hypertension, glaucoma, cataracts, osteoporosis, avascular necrosis, peptic ulcer disease, adrenal insufficiency, electrolyte and lipid abnormalities, psychosis, immunosuppression, and increased susceptibility to infections.⁹ Adjuvant therapies are, therefore, used to provide a steroid-sparing effect. As these treatments typically have a slower onset of action (i.e., 4-6 weeks), they are most beneficial as maintenance therapies. Conventional adjuvants include various immunosuppressive agents such as azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, chlorambucil and cyclopsorine, as well as anti-inflammatory agents such as gold, dapsone, colchicine and a variety of tetracycline antibiotics (Table 1).^2,4,10 Unfortunately, these medications are often associated with significant toxicities and must be used with caution. Though the majority of patients will ultimately respond to conventional therapies, few patients develop recalcitrant disease.

Emerging Therapies

Over the years, advances have been made to expand our therapeutic armamentarium for pemphigus. Emerging therapies include intravenous immunoglobulin (IVIg), plasmapheresis, immunoadsorption (IA), extracorporeal photochemotherapy (ECP), rituximab, tumor necrosis factor-alpha (TNF-á) antagonists (infliximab and etanercept), cholinergic agonists, and other experimental therapies such as desmoglein 3 peptides and KC706.

Intravenous Immunoglobulin (IVIg)

IVIg is a fractionated and purified blood product derived from the plasma of between 1,000 and 15,000 healthy donors per batch.4 It contains a high concentration of IgG and has a broad range of antibodies directed against pathogens, foreign antigens, and self-antigens.11 Although its exact mechanism of action remains unclear, IVIg is associated with a rapid and selective decline in the serum levels of pathogenic PV autoantibodies.¹²

Three case series and 1 retrospective analysis document the efficacy of IVIg in PV.13-16 The dosage and frequency of IVIg infusions were comparable between the studies. In all 4 studies, treatment with IVIg resulted in a rapid clinical response and a corticosteroid-sparing effect.^13-16 In 2 retrospective analyses, however, IVIg demonstrated a less favorable response.17,18 As the published studies are limited by their methodologies and small sample sizes, a Canadian multi-centre randomized controlled trial is underway to establish the role of IVIg in the management of PV patients.

Plasmapheresis

Plasmapheresis is the process by which plasma is removed from blood using a cell separator. The blood cells and an appropriate plasma substitute are then returned to the patient undergoing treatment. As antibodies are contained within plasma, plasmapheresis results in the removal of the pathogenic PV autoantibodies. In a multicenter study, PV patients (n=40) were randomized to receive prednisolone alone or prednisolone plus large-volume plasma exchange.¹⁹ While plasmapheresis failed to demonstrate a therapeutic benefit in this study, it has been suggested that an additional immunosuppressive (i.e., cyclophosphamide) or immunomodulatory (i.e., IVIg) therapy may be required to prevent the rebound production of pathogenic autoantibodies associated with disease flares. Multiple case series have evaluated the efficacy of plasmapheresis in treating PV.20-23 Of the 28 patients evaluated in these studies, 18 (64%) experienced complete remission, 6 (33%) experienced partial remission and 4 (22%) had no clinical improvement. Adverse effects encountered included systemic infections, acute hepatitis, thrombocytopenia, anemia, hypocalcemia, nausea, dizziness, urticaria, fever, and hypotension.^20-24

Immunoadsorption (IA)

IA consists of collecting patient plasma, passing it through an adsorber column (i.e., Protein A) to remove circulating immune complexes and IgG and then returning the filtered plasma to the patient.²⁵ Four case series and 2 case reports document the efficacy of IA for the treatment of recalcitrant PV.^26-31 Though patients were allowed to remain on concomitant immunosuppressive therapies, IA resulted in a dramatic clinical response and a rapid decline in desmoglein-specific IgG autoantibodies.^26-31 In the study by Schmidt, et al., a corticosteroid-sparing effect was observed.²⁷ More recently, a small case series demonstrated that IA, administered in combination with rituximab, may result in long-term remission.³² In all studies, IA was safe and well tolerated.

Extracorporeal Photochemotherapy (ECP)

In ECP, also known as photopheresis, a patient’s white blood cells are collected (leukapheresis), exposed to 8-methoxypsoralen, irradiated with ultraviolet-A light and reinfused into the patient. The proposed mechanism of action may involve inhibition of pathogenic autoantibody production by B lymphocytes.¹⁰ There are only 2 small case series and 2 case reports in the literature that document the use of ECP for refractory PV.^33-36 Of the 9 PV patients treated with ECP in these studies, all experienced significant clinical improvement, and no adverse effects from ECP were noted.

Rituximab

Rituximab is a chimeric murine/human IgG1 anti-CD20 monoclonal antibody that targets pre-B and mature B lymphocytes, resulting in complement and antibody-dependent cytotoxicity and apoptosis. Rituximab reduces circulating B cells, thereby preventing their maturation into antibody-producing plasma cells. Multiple case reports suggest that rituximab is an effective treatment option for PV.³⁷ Of the 18 patients with refractory PV reviewed, 3 (17%) experienced complete remission, 4 (22%) experienced clinical remission with further therapy required and 11 (61%) experienced partial remission. Systemic infections occurred in 4 of the 18 patients, resulting in 1 fatal outcome.

The largest clinical study evaluating the use of rituximab in PV has been a case series of 14 patients with refractory PV in which 12 (86%) experienced a complete remission at 3 months after a single cycle of rituximab.³⁸ This agent was also shown to be effective when used in combination with IVIg. In a series of 11 patients with extensive, recalcitrant PV, 9 (82%) experienced a clinical remission lasting between 22-27 months with combination therapy.³⁹

Tumor Necrosis Factor-alpha (TNF-á) Antagonists

TNF-á antagonists may be beneficial for the treatment of PV as experimental studies have demonstrated that TNF-á plays a role in the acantholytic process.^40,41 Two case reports document the successful use of infliximab for refractory PV.^42,43 Two additional case reports have shown clinical improvement of PV with the use of etanercept.^44,45 Clinical trials for both infliximab and etanercept are currently underway.

Cholinergic Agonists

Research suggests that acetylcholine and its receptors are involved in the acantholytic process of pemphigus.² To date, only 2 clinical studies have been performed.^46,47 In a case series of 6 patients with active PV, 3 (50%) experienced clinical improvement with the cholinergic agonist pyridostigmine bromide (Mestinon®, Valeant Pharmaceuticals).⁴⁶ Two of the 3 responders were able to control their disease with pyridostigmine bromide alone and 1 patient was able to remain in remission without any medications. In a recent double-blind, placebo-controlled trial of 3 PV patients with a total of 64 lesions, those lesions treated with 4% pilocarpine gel were found to have a significantly higher epithelialization index compared with placebo.⁴⁷

Other Experimental Therapies

Selective therapy using intravenous desmoglein 3 peptides was developed to suppress the production of anti-desmoglein 3 antibodies through inactivation and/or deletion of disease-associated CD4+ T lymphocytes.⁴⁸ However, an open-label phase I clinical trial of PI-0824 failed to demonstrate significant changes in anti-desmoglein 3 antibody titres following treatment with 2 IV infusions of desmoglein 3 peptides.⁴⁸

A novel therapy, KC706 (Kémia, Inc.) is an oral allosteric p38 mitogen-activated protein kinase (p38MAPK) inhibitor. In a murine model of pemphigus, p38MAPK inhibition prevented blister formation.⁴⁹ A clinical trial is underway to determine the safety and efficacy of KC706 in the management of PV.

Conclusion

While corticosteroid therapy remains the mainstay of treatment for PV, the morbidity associated with its use is significant. Conventional immunosuppressive and anti-inflammatory therapies are further associated with serious and potentially life-threatening adverse events. With an improved understanding of PV pathogenesis, a number of novel therapies have been developed. Though many of these therapies appear promising, case reports and case series dominate the dermatologic literature. Randomized controlled trials are urgently required to establish their efficacy and safety in the management of pemphigus patients.

References

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19. Guillaume JC, Roujeau JC, Morel P, et al. Controlled study of 19. plasma exchange in pemphigus. Arch Dermatol 124(11):1659-63 (1988 Nov).
20. Blaszczyk M, Chorzelski TP, Jablonska S, et al. Indications for 20. future studies on the treatment of pemphigus with plasmapheresis. Arch Dermatol 125(6):843-4 (1989 Jun).
21. Roujeau JC, Andre C, Joneau Fabre M, et al. Plasma exchange 21. in pemphigus. Uncontrolled study of ten patients. Arch Dermatol 119(3):215-21 (1993 Mar).
22. Sondergaard K, Carstens J, Zachariae H. The steroid-sparing 22. effect of long-term plasmapheresis in pemphigus: an update. Ther Apher 1(2):155-8 (1997 May).
23. Turner MS, Sutton D, Sauder DN. The use of plasmapheresis and 23. immunosuppression in the treatment of pemphigus vulgaris. J Am Acad Dermatol 43(6):1058-64 (2000 Dec).
24. Tan-Lim R, Bystryn JC. Effect of plasmapheresis therapy on 24. circulating levels of pemphigus antibodies. J Am Acad Dermatol 22(1):35-40 (1990 Jan).
25. Eming R, Hertl M. Immunoadsorption in pemphigus. 25. Autoimmunity 39(7):609-16 (2006 Nov).
26. Ogata K, Yasuda K, Matsushita M, et al. Successful treatment of 26. adolescent pemphigus vulgaris by immunoadsorption method. J Dermatol 26(4):236-9 (1999 Apr).
27. Schmidt E, Klinker E, Optiz A,27. et al. Protein A immunoadsorption: a novel and effective adjuvant treatment of severe pemphigus. Br J Dermatol 148(6):1222-9 (2003 Jun).
28. Luftl M, Stauber A, Mainka A, et al. Successful removal of 28. pathogenic autoantibodies in pemphigus by immunoadsorption with a tryptophan-linked polyvinylalcohol adsorber. Br J Dermatol 149(3):598-605 (2003 Sep).
29. Frost N, Messer G, Fierlbeck G, et al. Treatment of pemphigus 29. vulgaris with protein A immunoadsorption: case report of long-term history showing favorable outcome. Ann NY Acad Sci 1051:591-6 (2005 Jun).
30. Shimanovich I, Herzog S, Schmidt E, et al. Improved 30. protocol for treatment of pemphigus vulgaris with protein A immunoadsorption. Clin Exp Dermatol 31(6):768-74 (2006 Nov).
31. Eming R, Rech J, Barth S, et al. Prolonged clinical remission 31. of patients with severe pemphigus upon rapid removal of desmoglein-reactive autoantibodies by immunoadsorption. Dermatology 212(2):177-87 (2006).
32. Shimanovich I, Nitschke M, Rose C, et al. Treatment of severe 32. pemphigus with protein A immunoadsorption, rituximab and intravenous immunoglobulins. Br J Dermatol 158(2):382-8 (2008 Feb).
33. Rook AH, Jegasothy BV, Heald P, et al. Extracorporeal 33. photochemotherapy for drug-resistant pemphigus vulgaris. Ann Intern Med 112(4):303-5 (1990 Feb).
34. Liang G, Nahass G, Kerdel FA. Pemphigus vulgaris treated with 34. photopheresis. J Am Acad Dermatol 26(5 Pt I):779-80 (1992 May).
35. Gollnick HP, Owsianowski M, Taube KM, et al. Unresponsive 35. severe generalized pemphigus vulgaris successfully controlled by extracorporeal photopheresis. J Am Acad Dermatol 28(1):122-4 (1993 Jan).
36. Wollina U, Lange D, Looks A. Short-time extracorporeal 36. photochemotherapy in the treatment of drug-resistant autoimmune bullous diseases. Dermatology 198(2):140-4 (1999).
37. Schmidt E, Hunzelmann N, Zillikens D, et al. Rituximab in 37. refractory autoimmune bullous diseases. Clin Exp Dermatol 31(4):503-8 (2006 Jul).
38. Joly P, Mouquet H, Roujeau JC, et al. A single cycle of 38. rituximab for the treatment of severe pemphigus. N Eng J Med 357(6):545-52 (2007 Aug).
39. Ahmed AR, Spigelman Z, Cavacini LA, et al. Treatment of 39. pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 355(17):1772-9 (2006 Oct).
40. Feliciani C, Toto P, Amerio P, et al. In vitro and in vivo expression 40. of interleukin-1alpha and tumor necrosis factor-alpha mRNA in pemphigus vulgaris: interleukin-1alpha and tumor necrosis factor-alpha are involved in acantholysis. J Invest Dermatol 114(1):71-7 (2000 Jan).
41. Lopez-Robles E, Avalos-Diaz E, Vega-Memije E, et al. TNFalpha 41. and IL-6 are mediators in the blistering process of pemphigus. Int J Dermatol 40(3):185-8 (2001 Mar).
42. Pardo J, Mercader P, Mahiques L, et al. Infliximab in the 42. management of severe pemphigus vulgaris. Br J Dermatol 153(1):222-3 (2005 Jul).
43. Jacobi A, Shuler G, Hertl M. Rapid control of therapy-refractory 43. pemphigus vulgaris by treatment with the tumour necrosis factor-alpha inhibitor infliximab. Br J Dermatol 153(2):448-9 (2005 Aug).
44. Berookhim B, Fischer HD, Weinberg JM. Treatment of recalcitrant 44. pemphigus vulgaris with tumor necrosis factor alpha antagonist etanercept. Cutis 74(4):245-7 (2004 Oct).
45. Lin MH, Hsu CK, Lee JY. Successful treatment of the recalcitrant 45. pemphigus vulgaris and pemphigus vegetans with etanercept and carbon dioxide laser. Arch Dermatol 141(6):680-2 (2005 Jun).
46. Grando SA, Dahl MV. Activation of keratinocyte muscarinic 46. acetylcholine receptors reverses pemphigus acantholysis. J Eur Acad Dermatol Venereol 2(2):72-86 (1993 May).
47. Iraji F, Yoosefi A. Healing effect of pilocarpine gel 4% on skin 47. lesions of pemphigus vulgaris. Int J Dermatol 45(6):743-6 (2006 Jun).
48. Anhalt G, Werth V, Strober B, et al. An open-label phase I clinical 48. study to assess the safety of PI-0824 in patients with pemphigus vulgaris. J Invest Dermatol 125(5):1088 (2005 Nov).
49. Berkowitz P, Hu P, Warren S, et al. p38MAPK inhibition prevents 49. disease in pemphigus vulgaris mice. Proc Natl Acad Sci USA 103(34):12855-60 (2006 Aug).

Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

ABSTRACT

Rituximab (Rituxan^®, Genentech/ Biogen Idec) is a genetically engineered chimeric murine/human monoclonal antibody directed against CD20, a B lymphocyte-specific antigen. Initially approved for the treatment of relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma (NHL), rituximab has been increasingly used to treat a variety of immune-mediated and autoimmune diseases. While anecdotal case reports recommend its “off-label” use in dermatology, randomized clinical trials are required to firmly establish the safety and efficacy of this emerging biologic therapy.

Key Words:
Rituximab, Rituxan^®, immune skin disease, monoclonal antibody

In 1994, Reff and colleagues developed a chimeric murine/ human anti-CD20 monoclonal antibody which induced the rapid depletion of CD20+ B lymphocytes in vivo.1 By 1997, rituximab (Rituxan^®) was approved by the US FDA for the treatment of relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma (NHL). Originally developed for the treatment of B cell malignancies, rituximab has since been used to treat a variety of immune-mediated and autoimmune diseases (i.e., rheumatoid arthritis, systemic lupus erythematosus, and idiopathic thrombocytopenic purpura). Herein, we review the potential applications and limitations of rituximab use in dermatology.

Mechanism of Action/ Pharmacology

Rituximab is an immunoglobulin G1 (IgG1) kappa monoclonal antibody composed of a murine variable region (Fab portion) that is fused onto a human constant region (Fc portion). The Fab portion binds specifically to the CD20 antigen, located exclusively on the surface of pre-B and mature B lymphocytes. Once bound, the Fc portion of rituximab recruits immune effector cells to help mediate cell lysis of the CD20+ B lymphocytes via 3 possible mechanisms:

• complement-dependent cytotoxicity (CDC)
• antibody-dependent cell-mediated cytotoxicity (ADCC)
• apoptosis.¹

The exact contribution of each mechanism remains unclear, and different mechanisms may prevail in different diseases.²
The use of rituximab results in the rapid depletion of both normal and malignant CD20+ B lymphocytes in the peripheral blood and, to a lesser extent, the lymph nodes.1 The CD20 antigen is not expressed on the surface of hematopoietic stem cells or pro-B cells; thus, the capacity of these precursor cells to regenerate the B lymphocyte population remains intact.1 As the majority of plasma cells fail to express the CD20 antigen, plasma cells are generally spared and serum immunoglobulin levels tend not to fall dramatically.³ Here lies the selective advantage of rituximab.

Pharmacokinetics

In patients receiving rituximab intravenously, serum levels are dose-proportional, correlate with patient response to therapy, and increase with each successive infusion.3-5 The half-life of rituximab is also proportional to the dose, increases with each subsequent infusion, and varies greatly from patient to patient. The wide variability in elimination half-lives may reflect differences in tumor burden and changing CD20+ B cell populations with repeated administrations. Though the mechanisms involved in the metabolism and elimination of rituximab are not fully understood, it is postulated that rituximab is degraded nonspecifically in the liver and excreted in the urine.⁶

Dosage

In adults, the standard dosing schedule for rituximab is 375mg/m2 given intravenously once per week for 4 consecutive weeks. Premedication with an antipyretic (i.e., acetaminophen) and an antihistamine (i.e., diphenhydramine) should be administered prior to and throughout each infusion to reduce the likelihood of infusion-related reactions.7
In order to minimize the risk of tumor lysis syndrome, bulky tumors require higher doses of rituximab to be staggered over several weeks. As there is a limited number of CD20+ B cells in the normal immune system, an alternate dosing regimen was developed for patients with rheumatoid arthritis (RA). In RA patients, rituximab may be given as two-1000mg intravenous infusions separated by 2 weeks.⁸

Recently, a few cases of primary cutaneous B-cell lymphoma have been treated successfully with intralesional injections of rituximab. The dose ranged from 1-3mL of a 10mg/mL solution and variable numbers of injections were administered.^9-12

Rituximab is currently supplied at a concentration of 10mg/mL in either 100mg (10mL) or 500mg (50mL) single-use vials.⁷

Adverse Effects/ Drug Interactions

Rituximab is generally well tolerated, though most patients experience mild-to-moderate infusion-related reactions with their first treatment. The most common symptoms include fever (48%), chills (32%), weakness (18%), nausea (17%), headache (13%), pruritus (12%), and rash (11%).7 The symptoms are usually reversible by temporarily discontinuing the infusion and providing symptomatic relief. Infusion-related side-effects tend to diminish or disappear with subsequent infusions.

Severe and potentially fatal adverse events, though rare, have been associated with rituximab therapy. These include severe infusion-related reactions, tumor lysis syndrome, mucocutaneous reactions such as Stevens-Johnson Syndrome (SJS), anaphylaxis, serious pulmonary events, cardiac arrythmias, renal failure, hematological abnormalities, bowel obstruction/perforation, and significant infections, such as bacterial sepsis, reactivation of hepatitis B with fulminant hepatitis, and progressive multifocal leukoencephalopathy (PML).⁷ With regard to PML, a recent safety warning was issued by the US FDA regarding the development of this potentially fatal viral infection in the central nervous system (CNS) in 2 patients with systemic lupus erythematosus (SLE) who were being treated with rituximab.¹³ Patients should be urged to seek prompt medical attention if they develop any new neurological symptoms (i.e., changes in vision, balance, or cognition).

The use of rituximab in children and in patients with renal or hepatic failure has not been studied extensively. Rituximab should be avoided during pregnancy unless the potential benefit justifies the potential risk to the fetus (Pregnancy Risk Category C). As human IgG is excreted in breast milk, lactating mothers should be advised to discontinue nursing until circulating blood levels are no longer detectable. Though there have been no formal drug interaction studies performed with rituximab, the concomitant use of rituximab and cisplatin should be avoided as this combination has been associated with renal failure.⁷

Clinical Uses

Although approved for the treatment of relapsed or refractory low-grade or follicular NHL, the list of “off-label” indications for rituximab continues to grow. Case reports and small case series document its use in the dermatologic literature. Potential indications are listed in Table 1, and select dermatologic diseases are reviewed.

Primary Cutaneous B-Cell Lymphoma (PCBCL)

In a recent review, more than 40 individual cases of PCBCL were treated with rituximab intravenously.2 In the two largest case series, 10 patients were enrolled in each study. The overall response rate was 70% (20% complete response, 50% partial response) in the first study and 90% (70% complete response, 20% partial response) in the second study.14,15

Nineteen cases of PCBCL treated with intralesional rituximab were found in the literature.9-12,16 A complete response was seen in 84% of patients, while a variable response was seen in the remaining 16%. Relapse rates were found to be higher with intralesional therapy when compared with standard systemic therapy.

Dermatologic Disease

• Primary cutaneous B-cell lymphoma
• Immunobullous disease
• Pemphigus vulgaris
• Pemphigus foliaceus
• Paraneoplastic pemphigus
• Bullous pemphigoid
• Mucous membrane pemphigoid
• Epidermolysis bullosa acquisita
• Chronic graft versus host disease
• Dermatomyositis
• Systemic lupus erythematosus
• Vasculitis
• Small vessel vasculitis
• Hypocomplementemic urticarial vasculitis Antineutrophil cytoplasmic antibody-vasculitis
• Cryoglobulinemia
• Schnitzler syndrome
• Waldenstrom’s macroglobulinemia
• Angioedema
• Vitiligo

Table 1: Potential dermatological uses of rituximab

Pemphigus Vulgaris (PV)

Multiple case reports suggest that rituximab is an effective treatment option for PV. In a recent review of 18 patients with refractory PV, 3 patients (17%) experienced complete remission (no further therapy required), 4 patients (22%) experienced clinical remission (healing of all lesions but further therapy required), and 11 patients (61%) experienced partial remission.17 The standard course of rituximab was administered in all but 2 patients who received additional infusions. Serious infections occurred in 4 of the 18 patients, of which 1 was fatal. Notably, patients were allowed to remain on concomitant immunosuppressive therapy.

In 11 patients with extensive, recalcitrant PV, efficacy was noted using a combination of rituximab and intravenous immunoglobulin (IVIG).¹⁸ Rituximab (375mg/m2) was administered once weekly for 3 weeks and followed by an infusion of IVIG (2g/kg) in the fourth week. The cycle was repeated once and, upon completion of the induction therapy, monthly rituximab and IVIG infusions were given for 4 consecutive months. Of the 11 patients, 9 patients had a clinical remission lasting between 22–27 months; no serious adverse events were noted. Taken together, the data suggest that rituximab may be effective for patients with severe, refractory PV.

Other Immunobullous Diseases

Case reports document the successful use of rituximab in other immunobullous diseases, including: pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita.19-24 In most cases, complete remission was achieved with the standard therapeutic regimen. However, several cases of PNP have shown resistance to rituximab therapy.

Chronic Graft Versus Host Disease (CGVHD)

The use of rituximab in the treatment of refractory CGVHD has been documented in multiple case series with mixed results. In one case series, 8 patients with extensive CGVHD were treated with the standard course of rituximab.²⁵ Four of these patients (50%) responded to rituximab therapy whereas the other 4 patients (50%) were nonresponders. In the largest series of 21 patients with steroid-refractory CGHVD, the overall response was 70% and included 2 patients who experienced a complete remission.²⁶ In these patients, rituximab facilitated a statistically significant reduction in the median dose of steroid use from 40mg/day to 10mg/day (p<0.001). A steroid-sparing effect was therefore demonstrated in patients with CGVHD.

Dermatomyositis (DM)

In an open-label pilot study of 6 patients with longstanding refractory DM, patients received four weekly intravenous infusions of rituximab at a dose of 100mg/m2 (three patients) or 375mg/m2 (three patients).²⁷ All patients experienced marked clinical improvement in both cutaneous and muscle disease. Overall, rituximab was well tolerated in this patient group and no major adverse events were reported.

In another study, three patients with refractory DM experienced marked clinical improvement of their cutaneous disease.²⁸ In this small cohort, the heliotrope rash and the violaceous poikiloderma were most responsive to therapy.

Other Dermatologic Disease

Rituximab has been shown to benefit other dermatologic conditions including systemic lupus erythematosus (SLE), cryoglobulinemia, Waldenstrom’s macroglobulinemia, Schnitzler syndrome, vitiligo, angioedema as well as cutaneous vasculitides such as small vessel vasculitis, hypocomplementemic urticarial vasculitis and antineutrophil cytoplasmic antibody-associated vasculitis.^21,29-31

Conclusion

Though approved for the treatment of low-grade or follicular NHL, rituximab has demonstrated therapeutic efficacy in a variety of recalcitrant immune-mediated and autoimmune skin disorders. Few therapeutic failures have been described, possibly resulting from long-lived CD20- plasma cells capable of producing pathogenic autoantibodies. In most patients, rituximab is safe and tolerable with infusion-related reactions and infectious complications dominating the adverse-event profile. Clinical trials with long-term follow-ups are warranted to firmly establish the efficacy, tolerability and dosing of rituximab in the treatment of dermatologic disease.
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