The Role of Allergen Immunotherapy and Biologicals in the Treatment of Atopic Dermatitis John Oppenheimer MD Div Allergy and Immunology UMDNJ-Rutgers
Potential Conflicts of Interest Consultant GSK, Teva, DBV, Kaleo, Sanofi, AZ, Regeneron, Church & Dwight Adjudication committee Quintiles, PRA, ICON Assoc Editor Annals of Allergy, Allergy Watch Chief Editor Medscape (pulmonary) Reviewer Up to Date (reviewer) *Please note, the majority of this talk with be off label discussion of approved therapy (all from peer reviewed literature).
Learning Objectives Following completion of this discussion, the attendee should be: familiar with the importance of the skin microbiome in atopic dermatitis Comfortable with the appropriate use of allergy immunotherapy in AD Comfortable with the appropriate use of biologic agents in AD
AD and immunomodulators Studies suggest approximately 20-30% of affected individuals will have moderate-to-severe disease and that these individuals may have more persistent disease. Ballardini Br J Dermatol. 2013;168:588-94. Silverberg Pediatr Allergy Immunol. 2013;24:476-86. Mild eczema is frequently managed with regular administration of emollient therapy and judicious use of low-potency topical glucocorticoids. Moderate-to-severe atopic dermatitis may require use of moderate to high-dose glucocorticoids, calcineurin inhibitors, environmental modifications, phototherapy or wet wrap application. Horiukai JACI 2014;134(4):824-30 Where might IT and Biologics fit in this paradigm of care?
The role of the skin microbiome in atopic dermatitis: a systematic review Dysbiosis is a hallmark of atopic dermatitis (AD). The composition of skin microbiome communities and the causality of dysbiosis in eczema have not been well established. The objective of this analysis was to describe the skin microbiome profile in AD and address whether there is a causal relationship between dysbiosis and AD. Bjere Br Jl Derm 2017;177:1272-8
The role of the skin microbiome in atopic dermatitis: a systematic review The authors utilized standard Cochrane like analysis and found 5735 references, of which 32 met the inclusion criteria (17 published: 11 human and six animal studies). The studies varied in quality and applied different methodology. Bjere Br Jl Derm 2017;177:1272-8
What did this analysis find? AD skin has low bacterial diversity, high non-malassezia fungal diversity, high abundance of S. aureus and S. epidermidis reduced abundances of other genera. An mouse study indicated that dysbiosis is a driving factor in eczema. More data are warranted for better characterization of the role of the microbiome in AD and the influence of methodological approaches needs to be resolved. Bjere Br Jl Derm 2017;177:1272-8
Skin Colonization by S. aureusprecedes the Clinical Diagnosis of Atopic Dermatitis in Infancy assessed infants clinically and collected axillary and antecubital fossa skin swabs for culture-based analysis at birth and at seven time points over the first 2 years of life. at age 3 months, S.aureus was more prevalent on the skin of infants who developed AD later on. S.aureus prevalence was increased on infants skin at the time of AD onset and also 2 months before it, when compared with age-matched, unaffected infants. Furthermore, at AD onset, infants testing positive for S.aureus were younger than uncolonized subjects. suggesting that specific changes in early-life skin colonization may actively contribute to clinical AD onset in infancy Meylan Jl Invest Derm 2017;137:2497-2504
Allergy Immunotherapy
Allergen Immunotherapy and AD Summary Statement 50: On the basis of several studies of dust mite immunotherapy, the clinician might consider allergen immunotherapy in selected patients with AD with aeroallergen sensitivity. (B) Several studies suggest that immunotherapy could be effective for the treatment of AD associated with aeroallergen sensitivity. In a systematic review of immunotherapy for AD that included 4 comparable placebo-controlled studies involving a small number of patients, statistical analysis showed significant improvement in symptoms in patients with AD who received SCIT Schneider JACI 2013;131:295-9 Bussmann JACI 2006;118:1292-8 Glover Clin Exp Allergy 1992;22:440-6
Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose response study Methods: 89 adults with a chronic atopic dermatitis, SCORAD 40 and allergic sensitization to house dust mites [CAP-FEIA 3] were included, of whom 51 completed the study. SCIT with HDM (DP and DF) applying maintenance doses of 20, 2000 and 20,000 SQ-U in weekly intervals for 1 year. The main outcome measure was the change of the SCORAD as average of the values after 9 and 12 months of SIT in comparison with the value at baseline. Results: The SCORAD declined in the three dose groups in a dose-dependent manner (P = 0.0368,) and was significantly lower in the two high-dose groups (2000, 20000 SQ-U) compared with the low-dose group of 20 SQ-U (P = 0.0379) after 1 year of SCIT. The use of topical corticosteroids was significantly reduced with higher doses (P = 0.0007). Werfel Allergy 2006;61:202-5
Fig 2. Differences from baseline (Δ) in SCORAD during 1-year specific immunotherapy with: 20 SQ-U (n = 19), 2000 SQ-U (n = 14), and 20 000 SQ-U (n = 18) *P < 0.05, **P < 0.01 Werfel Allergy 2006;61:202-5
Fig 3. Changes in the use of topical corticosteroids (P = 0.0007) and systemic antihistamines (P = 0.0594) during specific IT Werfel Allergy 2006;61:202-5
Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose response study Conclusions: Allergen-SIT for 1 year with a house dust mite preparation is able to improve the eczema in patients with atopic dermatitis who are sensitized to house dust mite allergens and reduces the need for topical corticosteroids. SCIT may be valuable in the treatment of this chronic skin disease. Werfel Allergy 2006;61:202-5
Sublingual immunotherapy in mite-sensitized children with atopic dermatitis: A randomized, double-blind, placebo-controlled study Methods Children age 5 to 16 years with atopic dermatitis (SCORAD > 7) and sensitization to dust mites alone, without food allergy or chronic asthma, were enrolled in a randomized, DBPC trial stratified according to disease severity. SLIT or placebo was given for 18 months in addition to standard therapy. SCORAD, visual analog scale, and rescue medication use were recorded at 3-month intervals. Pajno JACI 2007;120:164-70
Sublingual immunotherapy in mite-sensitized children with atopic dermatitis: A randomized, double-blind, placebo-controlled study Results 56 children were enrolled, and 28 were allocated to SLIT. The difference from baseline in the SCORAD was significant (P =.025) between the 2 groups starting from month 9. There was a significant reduction in the use of medications only in the active group. A significant difference in the considered parameters was found only in patients with a mild-moderate disease, whereas severe patients had only a marginal benefit. Forty-eight completed the study, with 2 dropouts in the active and 6 in the placebo group. SLIT had to be discontinued in 2 patients because of exacerbation of dermatitis. Pajno JACI 2007;120:164-70
Fig 1. Change from baseline (Δ SCORAD) in the SLIT and placebo groups at the different time points. * P =.0025 Pajno JACI 2007;120:164-70
Fig 3. Change from baseline (Δ SCORAD) in the SLIT and placebo groups at the different time points. The patients are subdivided according to AD severity (A, mildmoderate; B, severe). p=.001 Pajno JACI 2007;120:164-70
Fig 5. Total drug consumption (means, SEMs) in the whole population, in mild-moderate AD, and in severe AD. Pajno JACI 2007;120:164-70
Crisaborole is a boron-based, small-molecule, topical phosphodiesterase 4 (PDE4) inhibitor that was approved by the FDA in December 2016 for the treatment of mild to moderate atopic dermatitis. Preliminary studies in adolescents and adults indicated that crisaborole 2% ointment improved the clinical signs of atopic dermatitis, including erythema, excoriation, exudation, lichenification, and, in particular, pruritus Adverse effects of topical crisaborole were mild and mainly limited to application site reactions (pain, paresthesia). Systemic exposure to crisaborole appears to be limited even after maximal use (3 mg/cm2) Zane Pediatr Dermatol. 2016;33:380-7.
Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of AD in children and adults Objective: sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies Methods: Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1 crisaborole:vehicle) patients aged 2 years or older with an Investigator s Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. Paller J Am Acad Dermatol. 2016;75:494-503
Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of AD in children and adults Results: More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with >2-grade improvement: AD-301: 32.8% vs 25.4%, P =.038; AD-302: 31.4% vs 18.0%, P<.001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P =.005; 48.5% vs 29.7%, P <.001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P <.001). Treatment-related adverse events were infrequent and mild to moderate in severity. Paller J Am Acad Dermatol. 2016;75:494-503
Fig 2. Atopic dermatitis. Efficacy analysis. Paller J Am Acad Dermatol. 2016;75:494-503
Fig 3. Improvements in pruritus Paller J Am Acad Dermatol. 2016;75:494-503
Immunomodulators http://www.gmoutlook.com/
Anti-CD20 Rituximab is a chimeric murine/human recombinant monoclonal antibody that binds to CD20. Elimination of pre-b cells and mature B-cells is a consequence of antibody binding. Elevated levels of IgE in many patients with atopic dermatitis suggests the utility of B-cell modulation as a therapeutic target. The use of rituximab in atopic dermatitis is limited to case series.
Anti-CD20 An open label pilot study was performed in 6 subjects with severe atopic dermatitis. All subjects had failed topical corticosteroid and/or calcineurin inhibitor therapy. Subjects underwent a 2-week washout of all topical therapy except corticosteroids and a 4-week washout of systemic therapy aside from antihistamines. 1 gram of Rituximab was administered twice, 2 weeks apart, with a 22- week observation period after therapy. Significant improvement of all subjects was noted within 4 weeks of treatment with sustained response through the 22-week observation period despite B cells being detectable in 50% of subjects during that time. Noda JACI 2015;136(5):1254-64.
Anti-CD20 case series evaluated the use of rituximab in 5 adult subjects with atopic dermatitis with persistent lesions on >50% of the body surface for the last year despite high-dose oral corticosteroids and use of an additional systemic immunosuppresor. All subjects had a diagnosis of atopic dermatitis from childhood. Subjects with 50-75% of body surface area affected were placed on a crossover protocol of omalizumab administered in 450mg every 2 weeks for 3 months followed by a course of rituximab cycle (375mg/m2) at first relapse. Significant improvement was seen in all enrolled patients although occasional relapse was noted. Simon JACI 2008;121:122-8
Anti-CD20 The response to rituximab in severe atopic dermatitis individuals demonstrates, at least, a partially B cell driven disease state. Insufficient data exists at this time to identify a specific patient population where therapy is most likely to be effective. Data best supports use of anti-cd20 therapy in severe refractory atopic dermatitis patients with significant disease burden who are refractory to other immunosuppressive therapies.
Anti-IgE Omalizumab is a humanized monoclonal anti-ige antibody that binds to the IgE molecule at the high-affinity IgE receptor binding site. Initial case reports suggested improvement in select patients with atopic dermatitis and prompted additional small randomized placebocontrolled trials. J Am Acad Dermatol. 2006;54(1):68-72., J Am Acad Dermatol. 2006;55(1):168-70.
Anti-IgE In a double-blind placebo-controlled trial 20 adult subjects were randomized 2:1 to receive either omalizumab 150mg q 2 weeks x 5 mos. or placebo. Subjects were required to have an IgE between 30 and 1300 IU/mL, positive skin test for allergen, and stable active dermatitis for more than 9 months out of the year. Topical corticosteroids were allowed for use during omalizumab dosing period. At the end of the study period the number of subjects complaining of pruritus actually increased from 9 to 11. Also, the EASI did not vary significantly between the active and placebo groups. EASI-eczema area and severity index Belloni JACI 2007;120:1223-5.
Anti-IgE A randomized, double-blind, placebo-controlled trial evaluated 8 subjects ages from 4-22 years and serum IgE s ranging from 218-1890. All subjects had a history of severe eczema refractory to prior therapy. At enrollment, prior eczema medications were changed to include only cetirizine, triamcinolone ointment and pimecrolimus. After a run-in period, all medications were discontinued 1 week prior to the first dose of either omalizumab or placebo, which was then dosed every 2-4 weeks for 24 weeks. Subjects in the omalizumab group had a SCORAD reduction of approximately 20-50% compared with 45-80% in the placebo group. Iyengar Arch Allergy Immunol. 2013;162:89-93.
Anti-IgE conclusions Controlled trial data regarding the use of omalizumab in atopic dermatitis is limited. Current data suggests that omalizumab is no more effective than placebo in reducing severity of atopic dermatitis. The limited number of study subjects raises significant concerns regarding possible confounders or an insufficiently targeted phenotype. More data is required, but currently the use of omalizumab for the treatment of atopic dermatitis is not recommended.
Anti-IL-5 recombinant humanized monoclonal antibody (Mepolizumab) for the treatment of atopic dermatitis Methods: Two single doses of 750 mg mepolizumab, given 1 week apart, were studied in patients with moderate to severe AD using a randomized, placebo controlled parallel group design. The primary endpoint of success to treatment was defined as the percentage of patients with at least marked improvement after 2 weeks as assessed by the Physician s Global Assessment of Improvement (PGA). Furthermore, SCORAD, pruritus scoring, number of blood eosinophils and serum thymus and activation-regulated chemokine (TARC) values served as secondary endpoints. Topical CS once daily could be used as rescue medication from day 16 if no improvement was recorded. TARK CCL17 Th2 chemokine binds to CCR4 Oldhoff Allergy 2005: 60: 693 696
Anti-IL-5 recombinant humanized monoclonal antibody (Mepolizumab) for the treatment of atopic dermatitis Results: Eighteen patients received mepolizumab and 22 placebo treatment. Peripheral blood eosinophil numbers were significantly reduced in the treatment group compared with placebo (P < 0.05). No clinical success was reached by PGA assessment (P = 0.115), SCORAD (P = 0.293), pruritus scoring and TARC values in the mepolizumab-treated group compared with placebo. However, modest improvement (<50% improvement) assessed by PGA was scored significantly more in the mepolizumab-treated group compared with placebo (P < 0.05). Oldhoff Allergy 2005: 60: 693 696
Table 2. Study-specific parameters Oldhoff Allergy 2005: 60: 693 696
Anti-IL5 conclusions Insufficient data exists regarding the efficacy of mepolizumab in atopic dermatitis. More trials are required, although initial data did not show a marked significant improvement compared with placebo, further studies are required with consideration of potential phenotypic stratification.
Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis sx and Th2 sx and Th2 sx and Th2 sx and Th2 Thijs JACI 2017;140:730-7
Anti-IL-4a receptor Dupilumab is a monoclonal antibody which binds to the IL-4a receptor resulting in inhibition of both IL-4 and IL-13 production. Data supporting the role of the Th2 response in atopic dermatitis prompted study of the use of dupilumab in affected patients.
March 28, 2017 The U.S. Food and Drug Administration today approved dupilumab injection to treat adults with moderate-to-severe eczema (atopic dermatitis). Dupilumab is intended for patients whose eczema is not controlled adequately by topical therapies, or those for whom topical therapies are not advisable. Dupilumab can be used with or without topical corticosteroids. https://newdrugapprovals.org/tag/dupilumab/
Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis METHODS randomized, double-blind, placebo-controlled trial involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator s global assessment score, pruritus, safety assessments, and serum biomarker levels. Beck N Engl J Med 2014;371:130-9.
Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis RESULTS In the 4-week monotherapy studies, dupilumab resulted in rapid and dosedependent improvements in clinical indexes, and biomarker levels. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator s global assessment (P<0.001); pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). Beck N Engl J Med 2014;371:130-9.
Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis RESULTS In the combination study, 100% of the patients in the dupilumab group, as compare with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P = 0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids compared to the placebo group (P = 0.16). Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity Adverse events: skin infection occurred more frequently with placebo nasopharyngitis and headache were the most frequent AEs with dupilumab. Beck N Engl J Med 2014;371:130-9.
Key Efficacy End Points in Studies M4A and M4B Combined Beck N Engl J Med 2014;371:130-9.
Key Efficacy End Points in Study M12. Beck N Engl J Med 2014;371:130-9.
Efficacy and safety of dupilumab in adults with moderate tosevere atopic dermatitis inadequately controlled by topical treatments: a randomized, placebo-controlled, dose-ranging phase 2b trial Methods In this randomized, placebo-controlled, double-blind study, enrolled patients aged 18 years or older who had an EASI score of 12 or higher at screening and inadequate response to topical rx Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator s Global Assessment) and region to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, Or placebo once a week for 16 weeks. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Thaçi Lancet 2016; 387: 40 52
Efficacy and safety of dupilumab in adults with moderate tosevere atopic dermatitis inadequately controlled by topical treatments: a randomized, placebo-controlled, dose-ranging phase 2b trial Results 452 patients were assessed for eligibility, and 380 patients were randomly assigned. EASI score improvements favored all dupilumab regimens versus placebo (p<0 0001): 300 mg once a week ( 74% [SE 5 16]), 300 mg every 2 weeks ( 68% [5 12]), 200 mg every 2 weeks ( 65% [5 19]), 300 mg every 4 weeks( 64% [4 94]), 100 mg every 4 weeks ( 45% [4 99]); placebo ( 18% [5 20]). Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose dependent manner, without significant safety concerns. 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events nasopharyngitis was the most frequent (28% and 26%, respectively). Thaçi Lancet 2016; 387: 40 52
Figure 2: Least-squares mean percentage change from baseline for (A) EASI, (B) SCORAD (last observation carried forward analysis) Thaçi Lancet 2016; 387: 40 52
Putting it all together https://images.search.yahoo.com/search/images;_ylt=a2klfsf.
Conclusions: Microbiome More data are needed for better characterization of the role of the microbiome in AD and the influence of methodological approaches needs to be resolved IT In patients with allergen sensitivity Appears most appropriate in mild to moderate disease Potential for flaring of illness
Topical PDE4 antagonists Effective in mild to moderate AD Conclusion Biologic therapy can be considered in patients who are unable to attain sufficient control with topical therapies or in patients whose lifestyle is strongly impeded by their disease activity. Individuals with Atopic AD may manifest a Th2 skewed immunophenotype with varied regulatory effects from the other pathways. The inclusion of biologics to the therapeutic armamentarium will necessitate eventual reclassification of atopic dermatitis phenotypes.
https://images.search.yahoo.com/search/images;_ylt=a2klfr7zd_da.