REVIEW URRENT C OPINION
The use of biologicals in cutaneous allergies – present and future Michael P. Makris a,c, Evangelia Papadavid b, and Torsten Zuberbier c
Purpose of review Up-to-date biologicals in cutaneous allergies play – unfortunately – only a minor role. However, this situation might change. Recently, omalizumab was licensed for chronic urticaria; this article reviews recent advances in the use of biologicals in cutaneous allergies. Recent findings Interestingly, the mechanism of omalizumab appears to be different in urticaria and allergic asthma for which the drug has been licensed previously. In urticaria dosage is not dependent on serum IgE-levels and response is seen very often after only 12 h. Other indications in cutaneous allergy in which biologicals have been investigated, at least in case reports or small studies, are TNF-a-antagonists and rituximab in chronic urticaria, omalizumab, rituximab and TNF-a-antagonists in atopic dermatitis as well as mepolizumab in this disease. However, all these studies appear to show a benefit for individual patients but not a clear breakthrough for the whole group of patients involved. This, however, might also be one of the future approaches that sub-groups of patients who have different responses to biologicals may be identified, as apparently different cytokine patterns are predominantly involved in the individual patient. Summary In conclusion, although currently only one biological is approved in chronic urticaria, there is hope that a rapid better understanding of individual disease factors will support the development of other novel drugs in this field. Keywords atopic dermatitis, chronic urticaria, omalizumab, rituximab, TNF-a-antagonist
INTRODUCTION Biologicals are now a mainstay of modern therapy in many fields of medicine. In dermatology especially in the field of psoriasis, autoimmune diseases, and neoplasia of the skin, biologicals have already been licensed for several years. Especially in the field of psoriasis and psoriasis arthritis, biologicals have changed the quality of life and disease progression of patients considerably ensuring that invalidism still observed only 20 years ago in psoriasis arthritis is now only a ghost of the past. A similar success story can be hoped for those patients suffering from severe cutaneous allergies like urticaria in which with the licensing of omalizumab again the dream of Paul Ehrlich, who conceived antibody-based therapy calling the magic bullets, appears to come true. This review summarizes the current literature on the use of biologicals in cutaneous allergies, although it is limited to urticaria and atopic dermatitis, as these drugs have not been used in any other case of cutaneous allergic disease extensively.
GROWING EVIDENCE: CHRONIC SPONTANEOUS URTICARIA IS HIGHLY HETEROGENEOUS Chronic spontaneous urticaria (CSU) is a skin disorder characterized by spontaneous appearance of wheals, angioedema, or both for at least 6 weeks because of known or unknown causes [1 ]. CSU has an estimated prevalence of 0.5–1%, with predominance in females, and a heavy impact on the quality of life [2,3]. &&
a
Allergy Unit ‘D. Kalogeromitros’, b2nd Dpt. Of Dermatology and Venereology, University of Athens Medical School, University General Hospital ‘Attikon’, Athens, Greece and cDpt. of Dermatology and Allergy, Allergy Centre Charite´, Charite´ - Universita¨tsmedizin Berlin, Berlin, Germany Correspondence to Michael P. Makris, MD, PhD, University General Hospital ‘Attikon’, Rimini 1, Athens, Xaidari, PC 12462, Greece. Tel: +30 2105832450; e-mail: [email protected], mmakris. [email protected] Curr Opin Allergy Clin Immunol 2014, 14:409–416 DOI:10.1097/ACI.0000000000000096
1528-4050 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-allergy.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Skin allergy
KEY POINTS Omalizumab represents the first biological that was approved for treatment of chronic spontaneous urticaria. In atopic dermatitis the response to biologicals might depend on the disease phenotype and vary between individuals. The ongoing understanding of the pathophysiology of allergic cutaneous diseases might help to distinguish the patients that would benefit from use of biological.
The cause of CSU is unknown in approximately 50% of the cases, although studies during the last 2 decades identified the presence of anti-immunoglobulin (Ig)E and/or anti-FcRI IgG autoantibodies in a subgroup of patients, suggesting a possible underlying autoimmune mechanism [4 ]. In addition, it has been reported that patients with active chronic urticaria have abnormal basophil function, including suppression of the high-affinity IgE receptor (FceRI) pathway (related to altered expression of Src homology-2 containing inositol phosphatase), blood basopenia, and recruitment of basophils to skin lesion sites. In remission, these abnormalities revert toward normal [5]. Current European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network/European Dermatology Forum/ World Allergy Organization guidelines state that the aim of treatment for all types of urticaria is to achieve complete symptom relief. All scientific panels of experts organized their documents as a stepwise treatment to be adapted from one patient to another, based on the severity of the disease and on the response to therapy [1 ,6 ]. Second-generation antihistamines (bilastine, rupatadine, ebastine, cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, mizolastine) are unquestionably the cornerstone of treatment of CSU. The response rate to high-dose antihistamines is 40–50%; thus, alternative approaches for treatment have been sought for decades. Recent advances in the knowledge of CSU pathophysiology have provided the rationale for the use of immunomodulatory drugs and biologic agents in CSU [7]. &
&&
&&
Omalizumab: the facts Omalizumab, a recombinant humanized IgG1 noncomplement fixing monoclonal antibody that binds to the high-affinity receptor-binding domain (Ce3) on the Fc portion of free IgE, was the first 410
www.co-allergy.com
monoclonal antibody approved for patients with allergic disorders. Omalizumab is administered subcutaneously and is absorbed slowly; reaching peak serum concentrations after 7–8 days, it binds to IgE in a reversible reaction to form tiny, biologically inert complexes with a molecular mass and stoichiometry varying from 1 : 2, through 1 : 1, to 2 : 1 depending on the molar ratio of omalizumab and total IgE. Omalizumab is cleared via Fcg interaction in the reticuloendothelial system and has a half-life of around 26 days [8]. Its mechanism of action for asthma is well understood; complete reduction of free IgE within hours after administration combined with downregulation of expression of the high-affinity IgE receptor on basophils within 2 weeks and mast cells after 8 weeks abolishes the allergic response at its initial phase [9]. On the contrary, the mechanism by which omalizumab exerts its action in urticaria requires further investigation. The fact that it is effective in a wide spectrum of urticarias with different underlying pathogenic mechanisms raises the suspicion that it may exercise its action through different mechanisms or through an inhibitory message that leads to rapid and nonspecific desensitization of cutaneous mast cells. In addition, the subsequent down-regulation of the IgE receptor may help to sustain the response. However, recent studies have identified an unexpected effect occurring during treatment with omalizumab. Two clinical studies [10,11] have shown that peripheral blood basophils respond better to stimulation with a panspecific cross-linking anti-IgE antibody during omalizumab treatment. Saini et al. [12 ] extended their studies showing that the change in maximum release is not only a repeatable feature of basophil responsiveness, but also that a marked change in the intrinsic sensitivity of the basophil occurs. One interpretation of the various results is that omalizumab alters a process that serves to variably suppress the natural sensitivity and responsiveness of basophils. The clinical efficacy of omalizumab in CSU has been reported in numerous observational studies. Initially, in most case reports and case series the dose schedule was formed according to the Food Drug Administration approved label for asthma according to total serum IgE concentration and body weight [13–18]. As data from randomized controlled trials accumulated, the more recent observational studies [19,20] adopted the therapeutical strategy of ‘one size fits all’, administering a fixed dose of 150 mg or 300 mg in most cases, every 4 or 2 weeks. Interestingly enough, in some retrospective studies [17,18] given that dose-ranging studies were not available at the start of the administration, both therapeutic &
Volume 14 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The use of biologicals in cutaneous allergies Makris et al.
strategies were used depending on the time point of omalizumab onset. These studies [13–20] have clearly shown robust efficacy of omalizumab in refractory chronic urticaria patients. Occasionally, some fails have also been reported [21]. An interesting finding in these observational studies was the response time; in contrast to benefit in asthmatic subjects, salutary response to CSU patients was observed within 24 h in most cases and within days in the remaining. These studies provided the impetus for planning and conducting randomized controlled trials to evaluate efficacy and safety of omalizumab in patients with refractory CSU. The first proof-of-concept study was conducted by Kaplan et al. [22] in autoimmune urticaria not controlled by antihistamines. They included 12 patients with positive autologous serum skin and histamine release tests, who received omalizumab following 4 weeks of treatment with placebo, and showed significant improvement in clinical scores (complete resolution in seven cases), a significant decrease in consumption of drugs used for symptomatic relief, and improvement in quality of life, with only one patient not responding to treatment. A phase II, prospective, double-blind, placebocontrolled, dose-ranging study enrolled 90 adult patients with chronic idiopathic urticaria (CIU) who remained symptomatic despite H1-antihistamine therapy to evaluate efficacy and safety. Participants received a single dose of 75 300, or 600 mg of omalizumab or placebo and finally it was demonstrated that single-dose 300 or 600 mg provides rapid and effective treatment of CIU. Regarding safety, no new safety issues or concerns were released [23]. A second randomized, double-blind, placebocontrolled study was performed in 49 adult CSU patients with autoantibodies against thyroperoxidase. Patients were treated with 75–375 mg dose determined by using the approved asthma dosing table for 24 weeks. Complete protection from wheal development was observed in 19 (70.4%) patients in the omalizumab group compared with only 1 (4.5%) patient in the placebo group. The rate of adverse event was similar in both groups [24]. A recent multicenter, randomized, double-blind, phase III study evaluated the efficacy and safety of omalizumab in a large population of patients with moderate-to-severe CIU, who remained symptomatic despite antihistamine therapy at the licensed doses; 323 patients received three doses of 75 mg, 150 mg, or 300 mg, or placebo at 4-week intervals, followed by a 16-week observation period. At week 12, the mean change from baseline in weekly itch severity score was 5.1 5.6 in the placebo group, 5.9 6.5 in the 75 mg group (P ¼ 0.46), 8.1 6.4
in the 150 mg group (P ¼ 0.001), and 9.8 6.0 in the 300 mg group (P, 0.001). These results lead to a calculated number needed to treat for being hive free and itch free in association with receiving omalizumab at doses of 150 or 300 mg for 12 weeks of 5.9 and 2.6, respectively. The rate of serious adverse events observed in individuals randomized to 300 mg, which included melena, nephrolithiasis, and urticaria, was higher (6%) than the rates observed in those randomized to 150 mg (1%), 75 mg (1%), or placebo (3%); however, a number of the adverse events in this study [25 ] were observed during the follow up period when omalizumab administration had been suspended similarly across the groups. Another, phase III multicenter study evaluated the safety and efficacy of 24 weeks of treatment (six subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo) in patients with persistent CIU or CSU despite treatment with H1-antihistamines at up to four times the approved dose plus H2-antihistamines, leukotriene receptor antagonists, or both. Of 480 patients screened, 336 were randomized to treatment; at week 12, the mean change from baseline in weekly itch severity score was 28.6 [95% confidence interval (CI), 29.3 to 27.8] in the omalizumab group compared with 24.0 (95% CI, 25.3 to 22.7) in the placebo group (P < 0.001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24. The safety profile was consistent with omalizumab in patients with allergic asthma whereas headache and upper respiratory tract infections were the most frequently reported adverse effects [26 ]. The results of this study are of great importance as the population belongs in the subgroup of patients with poorly controlled CUA despite combination pharmacotherapy. In addition, patients enrolled in randomized controlled studies of omalizumab for CSA or CIU had a high disease burden, with a mean Urticaria Activity Score (UAS-7) of 31. On the basis of its design features, these randomised studies enhance the strength of evidence supporting the efficacy of omalizumab for patients with CSA or CIU. Conclusively, given the high cost of omalizumab, it will be prudent to consider omalizumab only in those refractory patients who have failed traditional first or second-line therapies [27]. With regard to safety, omalizumab was confirmed to be exceedingly safe as shown from studies in patients with both severe allergic asthma and chronic urticaria. &&
&&
Omalizumab: the queries Unambiguously, the most important issue that has been raised about omalizumab administration in CSU patients is to identify possible clinical or
1528-4050 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-allergy.com
411
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Skin allergy
laboratory markers that are related to the responsiveness to treatment. Although initially it was speculated that omalizumab might fit better for autoimmune urticaria, based on first studies [22,23] in this subgroup of patients, we now know that this is not true. Neither demographics (age, sex) and clinical course (duration, severity), nor laboratory findings (autologous serum and/or plasma skin test, histamine releasing activity, autoantibodies to IgE or FcERI, biomarkers) can predict salutary response to omalizumab [18]. In addition, it is well shown from both observational [14,15,17] and randomized studies [23,24, 25 ,26 ] that like asthma, patients with CSU experienced recrudescence of symptoms after stopping omalizumab therapy. Contrary to allergic asthma that is a chronic, usually lifelong, inflammatory disease, the natural course of CSU is unpredictable and may last from a few months to many years. So, it is of great clinical interest to identify optimal strategies for suspending omalizumab. Some preliminary observational studies [20,28] try to address this issue. Additionally, initial reports about successful retreatment with omalizumab after disease relapse have already appeared in the literature [29]. Hopefully, further understanding of the mechanism by which omalizumab is efficacious in CSU might provide clues for the subgroup of patients that will respond to treatment as well as the dosing and discontinuation schedule. &&
&&
Omalizumab in physical urticarias Physical or inducible according to the recent guidelines, urticarias [1 ] comprise up to 25% of chronic urticarias and occur more frequently in young adults. Although trigger avoidance and symptomatic treatment are the key therapeutic concepts for physical urticarias, in a large proportion of cases these therapeutic strategies are ineffective [30]. Randomized trials addressing the efficacy of omalizumab in physical urticarias have not been published; numerous case reports described improvement of varying degrees in different types of physical urticarias, including cholinergic [31], cold urticaria [32], delayed pressure urticaria [33], symptomatic dermographism [34], and solar urticaria [35]. Ineffectiveness has also been reported [36]. The feedback from these cases is strongly positive, eliciting enthusiasm for the expansion of omalizumab administration in refractory cases of physical urticarias. &&
Other biologicals in treatment of chronic spontaneous urticaria Although omalizumab accounts for the vast majority of biologic agents tested for efficacy in urticaria, other approaches have also appeared. 412
www.co-allergy.com
Rituximab, a chimeric monoclonal antibody that binds specifically to the CD20 antigen present on the surface of B cells, produces B-cell depletion via induction of apoptosis. Although approved only for Hodgkin lymphoma and rheumatoid arthritis [37], rituximab has been successfully used for several autoimmune diseases [38]. Three case reports are published; in two of them it was effective in two patients with evidence of autoimmune urticaria [39,40] whereas in another with a steroid-dependent patient, it failed to control the disease [41]. Wilson et al. [42] reported a case series of six patients who were recalcitrant to all other immunosuppressive therapies, and had dramatic improvement with different TNF-inhibitors (infliximab, etarnecept, and adalimumab) that lasted for several years.
ATOPIC DERMATITIS: CURRENT PERSPECTIVE Atopic dermatitis is the most common recurrent inflammatory skin disorder affecting more than 10% of children and 1–3% of adults [43]. Acute atopic dermatitis is characterized by erythematous and exudative lesions, whereas in chronic form lichenification, thickened skin and hyperpigmentation represent the main features of the disease [44]. As in other atopic diseases, atopic dermatitis is commonly associated with raised serum IgE whereas sensitizations to common inhalant and food allergens are also frequent. However, the role and the importance of IgE in the pathogenic mechanism of atopic dermatitis are, at present, unresolved [45]. Treatment of atopic dermatitis depends on the clinical severity. A wide range of topical agents, including bland emollients, torical steroids, and the calcineurin inhibitors tacrolimus and pimecrolimus are the main therapeutic options in mild-tomoderate atopic dermatitis. In addition, systemic modalities such as antibiotics, systemic corticosteroids, ciclosporin, methotrexate, mycophenolate mofetil, and others are mainly recommended for moderate-to-severe disease and especially in chronic atopic dermatitis, or for patients whose dermatitis causes significant psychosocial impact [46 ]. As our understanding of immune dysregulation of atopic dermatitis increases, new immunomodulatory drugs are emerging. In addition, the high degree of heterogeneity of underlying pathogenic mechanisms, triggers and clinical presentation in atopic dermatitis necessitates the stratification of patients and the selection of targeted treatment approaches [47,48]. &&
Volume 14 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The use of biologicals in cutaneous allergies Makris et al.
Omalizumab in atopic dermatitis: a choice for selected patients? Omalizumab, among various other conditions apart from asthma and spontaneous urticaria, has also been investigated in atopic dermatitis. However limited data exist to determine its efficacy in atopic dermatitis; a number of case series delivered conflicting results [49–51]. Heil et al. conducted one double-blind, placebo-controlled study for 16–20 week atopic dermatitis patients with omalizumab administered subcutaneously. They have shown that omalizumab reduced free serum IgE, lowered surface IgE and FceRI expression on different peripheral blood mononuclear cells, reduced the saturation of FceRI with IgE, increased the number of free FceRI, and lowered the number of IgEþ, but not of FceRIþ cells in skin but did not show clinical improvement in atopic dermatitis [52]. Kim et al. studied for a 6-month period, ten East Asian adult patients with atopic dermatitis who received anti-IgE treatment for persistent asthma with a fixed schedule of eight cycles of omalizumab 300 mg, administered subcutaneously at intervals of 2 weeks. There was a steady improvement in the objective SCORing Atopic Dermatitis (SCORAD), with significantly lower scores observed at the 6-month evaluation. At 2 months after the end of treatment no patient had worsening of the atopic dermatitis (increase of > 25% in SCORAD), and once a clinical improvement occurred, none of the patients experienced worsening of their eczema symptoms while on omalizumab. Noteworthy, those patients had serum IgE-levels of 5000 IU/ml or higher, far exceeding the approved limit for omalizumab treatment. Consequently, they were treated with omalizumab at a much lower dosage than that required for the complete removal of IgE from the circulation [53]. These results are in accordance with previous preliminary experience in 11 adult patients that regardless of their IgE values were treated with a fixed schedule of 10 cycles of 150 mg omalizumab subcutaneously in 2-week intervals. Six out of 11 showed very good or satisfying clinical response, suggesting that the effect of omalizumab in these patients seems to be a regulatory mechanism rather than simple blocking of IgE [54]. Notably, molecular changes such as a switch to reduced IgE IgG mRNA production initially seemed to be good indicators of which patients will have clinical response [55] but failed to identify all patients without clinical improvement [54]. In addition, this marker was not confirmed in larger cohorts. In a case series of subjects with seasonal allergic rhinitis (SAR) with (IgE 3528 2723 IU/ml) and without (IgE 212 224 IU/ml) atopic dermatitis, it
was reported that in the subgroup with SAR or atopic dermatitis, the atopic dermatitis-related quality of life (DLQl) following 2 months of omalizumab treatment had significantly improved and that effective oral corticosteroid use was better (9/9) than in the subjects with SAR only (9/13) [56]. Furthermore, Hotze et al. [57 ] have recently published a prospective 28-week open-label trial on 20 adults with moderate-to-severe atopic dermatitis aiming to evaluate the efficacy of omalizumab in atopic dermatitis and to identify markers associated with treatment response . In brief, all patients, regardless of their total IgE values, were treated with a fixed schedule of 14 cycles of 150 mg omalizumab in 2-week intervals. Patients who did not achieve a reduction in SCORAD at least 25% after seven applications received 300 mg from visit eight onwards. Of the 20 patients who completed the study, four patients showed a very good clinical response (SCORAD reduction 50%) and four patients responded with satisfying results (SCORAD reduction 25–50%), whereas five patients showed no relevant clinical changes (reduction or increase in SCORAD < 25%), and seven patients experienced a deterioration of the disease (SCORAD increase). Of note, none of the seven patients carrying a filaggrin mutation responded to therapy, whereas all eight responders were non-filaggrin-mutation carriers (P ¼ 0.05, Fisher’s test), indicating that patients with a primary skin barrier deficiency are less likely to benefit from an immunomodulatory therapy with anti-IgE. Additionally, targeted metabolite quantification in fasting serum showed significantly higher baseline levels of three glycerophospholipids as well as lower total sphingomyelin/total phosphatidylcholine ratio in responders when compared with nonresponders. In a small case series, administration of omalizumab in combination with IVIg has been applied to patients with severe atopic dermatitis resulting in drastic clinical improvement and long-term effects [58]. In general, the successful trials had longer treatment periods. Although it is well known that free IgE is extensively and very rapidly suppressed after omalizumab administration, it takes up to 3 months before this suppression has an effect on eczema symptoms. Thus, the treatment as well as the follow up period must be sufficiently long to allow an effect to be seen. In addition, recent data suggest that metabolic profiling can potentially assist the classification of patients and the prediction of treatment response. Large, randomized, double-blind, placebocontrolled, multicenter trials are warranted to adequately assess the efficacy of omalizumab in atopic
1528-4050 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-allergy.com
413
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Skin allergy
dermatitis and to determine the clinical phenotypes that might benefit more than others. To our knowledge, there are no ongoing studies in clinicaltrials. gov addressing these issues.
Anti-CD20 (rituximab) in atopic dermatitis Six patients with severe angioedema that received two i.v. applications of rituximab, each 1000 mg, 2 weeks apart resulted in a rapid reduction in skin inflammation in all patients with a sustained effect over 5 months in five of six patients, although specific IgE-levels were not affected [59]. On the contrary, in two cases affected by very severe atopic dermatitis, rituximab failed to show clinical effectiveness [60]. Interestingly enough, a recent pilot study proposes a sequential therapeutic strategy with two monoclonal antibodies, omalizumab and rituximab (anti-CD20), in selected individuals with atopic dermatitis. The authors report six cases of severe atopic dermatitis refractory to conventional therapy that underwent sequential switch therapy with omalizumab and rituximab. With the proposed switch therapy, four out of six patients achieved a dramatic clinical improvement [61]. However, safety and costeffectiveness studies are essential prerequisites before using such combination treatments with biologicals.
Anti interleukin-5 and atopic dermatitis Bearing in mind that eosinophils play a major role in the pathogenesis of atopic dermatitis a randomized, placebo-controlled parallel-group study was performed in 40 adult patients with moderate-to-severe atopic dermatitis, to evaluate the effect of a shortterm therapy with an anti-IL-5 antibody (mepolizumab; 2 750 mg). Unfortunately, despite a significant decrease in peripheral blood eosinophils, two single doses of 750 mg mepolizumab did not result in clinical success in atopic dermatitis patients [62]. Other studies have not been performed so far.
As far as our knowledge in the mechanisms of atopic dermatitis deepens, new molecules are potential therapeutic targets like IL-4, IL-13 and their receptors as well as histamine receptor 4 [65]. A randomized, double-blind, placebo-controlled, parallel-group study investigating the efficacy, safety, serum concentration, and biomarker profile of an anti-IL-4 antibody, dupilumab administered to adults with moderate-to-severe atopic dermatitis is registered in clinicaltrials.gov.
OTHER CUTANEOUS ALLERGIES In other cutaneous allergies biologicals have not been extensively used nor have case reports been published. However, there is one exception. This is toxic epidermal necrolysis in which anti-TNF-aantagonists have been discussed in the literature [66]. Because of the extremely rare incidence of the disease however randomized larger trials are missing.
CONCLUSION Although companies for a long time have concentrated on developing biologicals in the field of dermatological diseases like psoriasis, now apparently interest is growing also to look at cutaneous allergies. With the licensing of omalizumab in urticaria a huge step forward has been made. Especially as again like in psoriasis, this biological is able to prove in double-blind placebo-controlled trials an enormous efficacy to control this disease and a very high number of total responders. It can be hoped for that this trend is ongoing with current research concepts targeting cytokines involved, for example, in atopic dermatitis new biologicals will hopefully be available within the next 5 years. Acknowledgements This study was not funded by any grant or other sources.
Other biological agents in atopic dermatitis Although anti-TNF-a antibody has been shown to significantly decrease atopic dermatitis severity and pruritus, the effect proved to be transient and disease relapse occurred shortly [63]. In addition, inadequate effects or even severe exacerbations of atopic dermatitis upon anti-TNF-a therapy have been also reported. Inhibition of IL-6 signaling theoretically has potential to dampen inflammation at the level of CD4þ T-Helper 2 and T-Helper 17 polarization. A preliminary report of blocking the IL-6 receptor by the mAb tocilizumab in three patients affected with severe atopic dermatitis however, led to adverse severe infections [64]. 414
www.co-allergy.com
Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA2LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014; 69:868–887. This guideline is the result of a systematic literature review using the ‘Grading of Recommendations Assessment, Development and Evaluation’ methodology and a structured consensus conference. It clearly outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.
&&
Volume 14 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The use of biologicals in cutaneous allergies Makris et al. 2. Greaves MW, Tan KT. Chronic urticaria: recent advances. Clin Rev Allergy Immunol 2007; 33:134–143. 3. O’Donnell BF, Lawlor F, Simpson J, et al. The impact of chronic urticaria on the quality of life. Br J Dermatol 1997; 136:197–201. 4. Konstantinou GN, Asero R, Ferrer M, et al. EAACI task force position paper: & evidence for autoimmune urticaria and proposal for defining diagnostic criteria. Allergy 2013; 68:27–36. A position article of Dermatology section of the European Academy of Allergy and Clinical Immunology about autoimmune urticaria. A systematic in depth review of published data with consensus and recommendations from the experts’ panel. 5. Vonakis BM, Saini SS. New concepts in chronic urticaria. Curr Opin Immunol 2008; 20:709–716. 6. Bernstein JA, Lang DM, Khan DA. The diagnosis and management of acute && and chronic urticaria: 2014 update. J Allergy Clin Immunol 2014; 133:1270– 1277. The urticaria practice parameter workgroup using a systematic literature review in conjunction with consensus expert opinion and workgroup-identified supplementary documents developed practice parameters that provide a comprehensive approach for the assessment and management of urticaria with or without concomitant angioedema. 7. Asero R, Tedeschi A, Cugno M. Treatment of Chronic Urticaria. Immunol Allergy Clin N Am 2014; 34:105–116. 8. Babu KS, Polosa R, Morjaria JB. Anti-IgE–emerging opportunities for omalizumab. Expert Opin Biol Ther 2013; 13:765–777. 9. Eckman JA, Sterba PM, Kelly D, et al. Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge. J Allergy Clin Immunol 2010; 125:889–895. 10. Zaidi AK, Saini SS, Macglashan DW Jr. Regulation of Syk kinase and FcRb expression in human basophils during treatment with omalizumab. J Allergy Clin Immunol 2010; 125:902–908; e7. 11. MacGlashan DW Jr, Savage J, Wood RA, et al. Suppression of the basophil response to allergen during treatment with omalizumab is dependent on two competing factors. J Allergy Clin Immunol 2012; 130:1130–1135. 12. Macglashan DW, Saini SS. Omalizumab increases the intrinsic sensitivity of & human basophils to IgE-mediated stimulation. J Allergy Clin Immunol 2013; 132:906–911. A study that provides a better quantitative sense of the phenotypic change that occurs in basophils during omalizumab treatment, which has both mechanistic and clinical implications. 13. Young-Hee N, Joo-Hee K, Hyun Jung J, et al. Effects of omalizumab treatment in patients with refractory chronic urticaria. Allergy Asthma Immunol Res 2012; 4:357–361. 14. Buyukozturk S, Gelincik A, Demirturk M, et al. Omalizumab markedly improves urticaria activity scores and quality of life scores in chronic spontaneous urticaria patients: a real life survey. J Dermatol 2012; 39:439–442. 15. Groffik A, Mizel-Kaoukhov H, Magerl M, et al. Omalizumab: an effective and safe treatment of therapy resistant chronic spontaneous urticaria. Allergy 2011; 66:303–305. 16. Vestergaard C, Deleuran M. Two cases of severe refractory chronic idiopathic urticaria treated with omalizumab. Acta Derm Venereol 2010; 90:443–444. 17. Metz M, Ohanyan T, Church MK, et al. Omalizumab is an effective and rapidly acting therapy in difficult to treat chronic urticaria: a retrospective clinical analysis. J Dermatol Sci 2014; 73:57–62. 18. Viswanathan RK, Moss MH, Mathur SK. Retrospective analysis of the efficacy of omalizumab in chronic refractory urticaria. Allergy Asthma Proc 2013; 34:446–452. 19. Song CH, Stern S, Giruparajah M, et al. Long-term efficacy of fixed dose omalizumab for patients with severe chronic spontaneous urticaria. Ann Allergy Asthma Immunol 2013; 110:113–117. 20. Sussman G, Hebert J, Barron C, et al. Real-life experiences with omalizumab for the treatment of chronic urticaria. Ann Allergy Asthma Immunol 2014; 112:170–174. 21. Altman M, Naimi D. Omalizumab for chronic urticaria [letter]. N Engl J Med 2013; 368:2528–2530. 22. Kaplan AP, Joseph K, Maykut RJ, et al. Treatment of chronic autoimmune urticaria with omalizumab. J Allergy Clin Immunol 2008; 122:569–573. 23. Saini S, Rosen KE, Hsieh HJ, et al. A randomized, placebo-controlled, dose ranging study of single-dose omalizumab in patients with H1-antihistamine refractory chronic idiopathic urticaria. J Allergy Clin Immunol 2011; 128:567– 573. 24. Maurer M, Altrichter S, Bieber T, et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol 2011; 128:202–209. 25. Maurer M, Rosen K, Hsin-Ju HJ, et al. Omalizumab for the treatment of chronic && idiopathic or spontaneous urticaria. N Engl J Med 2013; 368:924–935. A phase-3, multicenter, randomized, double-blind study, which shows that omalizumab at doses of 150 mg and 300 mg significantly improved outcomes. 26. Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic && chronic idiopathic/spontaenous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013; 132:101–109. A phase-3, multicenter, randomized, double-blind study that proves efficacy and tolerability of omalizumab in patients with CIU or CSU who remain symptomatic despite receiving H1-antihistamines at up to four times the approved dose plus H2-antagonists, leucotriene receptor antagonists, or both.
27. Kaplan AP. Treatment of chronic spontaneous urticaria. Allergy Asthma Immunol Res 2012; 4:326–331. 28. Uysal P, Eller E, Mortz CG, et al. An algorithm for treating chronic urticaria with omalizumab: dose interval should be individalized. J Allergy Clin Immunol 2014; 133:914–915. 29. Metz M, Ohanyan T, Church MK, et al. Retreatment with omalizumab results in rapid remission in chronic spontaneous and inducible urticaria. JAMA Dermatol 2014; 150:288–290. 30. Abajian M, Mlynek A, Maurer M. Physical urticaria. Curr Allergy Asthma Rep 2012; 12:281–287. 31. Metz M, Bergmann P, Zuberbier T, et al. Successful treatment of cholinergic urticaria with anti-immunoglobulin E therapy. Allergy 2008; 63:247–249. 32. Brodska P, Schmid-Grendelmeier P. Treatment of severe cold contact urticaria with omalizumab: case reports. Case Rep Dermatol 2012; 4:275–280. 33. Bindslev-Jensen C, Skov PS. Efficacy of omalizumab in delayed pressure urticaria: a case report. Allergy 2010; 65:130–139. 34. Krause K, Ardelean E, Kessler B, et al. Antihistamine resistant urticaria factitia successfully treated with anti-immunoglobulin E therapy. Allergy 2010; 65:1494–1495. 35. Guzelbey O, Ardelean E, Magerl M, et al. Successful treatment of solar urticaria with anti-immunoglobulin E therapy. Allergy 2008; 63:1563–1565. 36. Sabroe RA. Failure of omalizumab in cholinergic urticaria. Clin Exp Dermatol 2009; 35:e127–e129. 37. Hauser SL, Waubant E, Arnold DL, et al., HERMES Trial Group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358:676–688. 38. Joly P, Mouquet H, Roujeau JC, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007; 357:545–552. 39. Arkwright PD. Anti-CD20 or anti-IgE therapy for severe chronic autoimmune urticaria. J Allergy Clin Immunol 2009; 123:510–511. 40. Chakravarty SD, Yee AF, Paget SA. Rituximab successfully treats refractory chronic autoimmune urticaria caused by IgE receptor autoantibodies. J Allergy Clin Immunol 2011; 128:1354–1355. 41. Mallipeddi R, Grattan CE. Lack of response of severe steroid-dependent chronic urticaria to rituximab. Clin Exp Dermatol 2007; 32:333–334. 42. Wilson LH, Eliason MJ, Leiferman KM, et al. Treatment of refractory chronic urticaria with tumor necrosis factor-alfa inhibitors. J Am Acad Dermatol 2009; 64:1221–1222. 43. Schultz-Larsen F, Hanifin J. Epidemiology of atopic dermatitis. Immunol Allergy Clin North Am 2002; 22:1–24. 44. Rudzki E, Samochocki Z, Litewska D, et al. Clinical features of atopic dermatitis and a family history of atopy. Allergy 1991; 46:125–128. 45. Garmhausen D, Hagemann T, Bieber T, et al. Characterization of different courses of atopic dermatitis in adolescent and adult patients. Allergy 2013; 68:498–506. 46. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management && of atopic dermatitis. J Am Acad Dermatol 2014. [Epub ahead of print] This guideline addresses important clinical questions that arise in atopic dermatitis management and care, providing recommendations based on the available evidence. 47. Novak N, Simon D. Atopic dermatitis– from new pathophysiologic insights to individualized therapy. Allergy 2011; 66:830–839. 48. Bieber T. Atopic dermatitis: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 2012; 67:1475–1482. 49. Vigo PG, Girgis KR, Pfuetze BL, et al. Efficacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol 2006; 55:168–170. 50. Lane JE, Cheyney JM, Lane TN, et al. Treatment of recalcitrant atopic dermatitis with omalizumab. J Am Acad Dermatol 2006; 54:68–72. 51. Krathen RA, Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis. J Am Acad Dermatol 2005; 53:338–340. 52. Heil PM, Maurer D, Klein B, et al. Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course-a randomized, placebocontrolled and double blind pilot study. J Dtsch Dermatol Ges 2010; 8:990– 998. 53. Kim DH, Park KY, Kim BJ, et al. Anti-immunoglobulin E in the treatment of refractory atopic dermatitis. Clin Exp Dermatol 2013; 38:446–450. 54. Belloni B, Ziai M, Lim A, et al. Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. J Allergy Clin Immunol 2007; 120:1223– 1225. 55. Lim A, Luderschmidt S, Weidinger A, et al. The IgE repertoire in PBMCs of atopic patients is characterized by individual rearrangements without VH bias. J Allergy Clin Immunol 2007; 120:696–706. 56. Velling P, Skowasch D, Pabst S, et al. Improvement of quality of life in patients with concomitant allergic asthma and atopic dermatitis: one year follow-up of omalizumab therapy. Eur J Med Res 2011; 16:407–410. 57. Hotze M, Baurecht H, Rodriguez E, et al. Increased efficacy of omalizumab in & atopic dermatitis patients with wild-type filaggrin status and higher serum levels of phosphatidylcholines. Allergy 2014; 69:132–135. A pilot study which shows for the first time that atopic dermatitis patients who respond to omalizumab are characterized by the absence of filaggrin mutations and altered lipid metabolite profiles with high levels of various glycerophospholipids. 58. Toledo F, Silvestre JF, Munoz C. Combined therapy with low-dose omalizumab and intravenous immunoglobulin for severe atopic dermatitis. Report of four cases. J Eur Acad Dermatol Venereol 2012; 26:1325–1327.
1528-4050 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-allergy.com
415
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Skin allergy 59. Simon D, Hosli S, Kostylina G, et al. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol 2008; 121:122–128. 60. Sediva A, Kayserova J, Vernerova E, et al. Anti-CD20 (rituximab) treatment for atopic eczema. J Allergy Clin Immunol 2008; 121:1515–1516. 61. Sa´nchez-Ramo´n S, Eguı´luz-Gracia I, Rodrı´guez-Mazariego ME, et al. Sequential combined therapy with omalizumab and rituximab: a new approach to severe atopic dermatitis. J Investig Allergol Clin Immunol 2013; 23:190–196. 62. Oldhoff JM, Darsow U, Werfel T, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy 2005; 60:693–696.
416
www.co-allergy.com
63. Jacobi A, Antoni C, Manger B, et al. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol 2005; 52:522–526. 64. Navarini AA, French LE, Hofbauer GF. Interrupting IL-6-receptor signaling improves atopic dermatitis but associates with bacterial superinfection. J Allergy Clin Immunol 2011; 128:1128–1130. 65. Ohsawa Y, Hirasawa N. The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via antipruritic and anti-inflammatory effects in NC/Nga mice. Allergy 2012; 67:1014–1022. 66. Jalilian C, Jevtic A. The management of toxic epidermal necrolysis. Australas J Dermatol 2012; 53:165–171.
Volume 14 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The use of biologicals in cutaneous allergies – present and future Michael P. Makris a,c, Evangelia Papadavid b, and Torsten Zuberbier c
Purpose of review Up-to-date biologicals in cutaneous allergies play – unfortunately – only a minor role. However, this situation might change. Recently, omalizumab was licensed for chronic urticaria; this article reviews recent advances in the use of biologicals in cutaneous allergies. Recent findings Interestingly, the mechanism of omalizumab appears to be different in urticaria and allergic asthma for which the drug has been licensed previously. In urticaria dosage is not dependent on serum IgE-levels and response is seen very often after only 12 h. Other indications in cutaneous allergy in which biologicals have been investigated, at least in case reports or small studies, are TNF-a-antagonists and rituximab in chronic urticaria, omalizumab, rituximab and TNF-a-antagonists in atopic dermatitis as well as mepolizumab in this disease. However, all these studies appear to show a benefit for individual patients but not a clear breakthrough for the whole group of patients involved. This, however, might also be one of the future approaches that sub-groups of patients who have different responses to biologicals may be identified, as apparently different cytokine patterns are predominantly involved in the individual patient. Summary In conclusion, although currently only one biological is approved in chronic urticaria, there is hope that a rapid better understanding of individual disease factors will support the development of other novel drugs in this field. Keywords atopic dermatitis, chronic urticaria, omalizumab, rituximab, TNF-a-antagonist
INTRODUCTION Biologicals are now a mainstay of modern therapy in many fields of medicine. In dermatology especially in the field of psoriasis, autoimmune diseases, and neoplasia of the skin, biologicals have already been licensed for several years. Especially in the field of psoriasis and psoriasis arthritis, biologicals have changed the quality of life and disease progression of patients considerably ensuring that invalidism still observed only 20 years ago in psoriasis arthritis is now only a ghost of the past. A similar success story can be hoped for those patients suffering from severe cutaneous allergies like urticaria in which with the licensing of omalizumab again the dream of Paul Ehrlich, who conceived antibody-based therapy calling the magic bullets, appears to come true. This review summarizes the current literature on the use of biologicals in cutaneous allergies, although it is limited to urticaria and atopic dermatitis, as these drugs have not been used in any other case of cutaneous allergic disease extensively.
GROWING EVIDENCE: CHRONIC SPONTANEOUS URTICARIA IS HIGHLY HETEROGENEOUS Chronic spontaneous urticaria (CSU) is a skin disorder characterized by spontaneous appearance of wheals, angioedema, or both for at least 6 weeks because of known or unknown causes [1 ]. CSU has an estimated prevalence of 0.5–1%, with predominance in females, and a heavy impact on the quality of life [2,3]. &&
a
Allergy Unit ‘D. Kalogeromitros’, b2nd Dpt. Of Dermatology and Venereology, University of Athens Medical School, University General Hospital ‘Attikon’, Athens, Greece and cDpt. of Dermatology and Allergy, Allergy Centre Charite´, Charite´ - Universita¨tsmedizin Berlin, Berlin, Germany Correspondence to Michael P. Makris, MD, PhD, University General Hospital ‘Attikon’, Rimini 1, Athens, Xaidari, PC 12462, Greece. Tel: +30 2105832450; e-mail: [email protected], mmakris. [email protected] Curr Opin Allergy Clin Immunol 2014, 14:409–416 DOI:10.1097/ACI.0000000000000096
1528-4050 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-allergy.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Skin allergy
KEY POINTS Omalizumab represents the first biological that was approved for treatment of chronic spontaneous urticaria. In atopic dermatitis the response to biologicals might depend on the disease phenotype and vary between individuals. The ongoing understanding of the pathophysiology of allergic cutaneous diseases might help to distinguish the patients that would benefit from use of biological.
The cause of CSU is unknown in approximately 50% of the cases, although studies during the last 2 decades identified the presence of anti-immunoglobulin (Ig)E and/or anti-FcRI IgG autoantibodies in a subgroup of patients, suggesting a possible underlying autoimmune mechanism [4 ]. In addition, it has been reported that patients with active chronic urticaria have abnormal basophil function, including suppression of the high-affinity IgE receptor (FceRI) pathway (related to altered expression of Src homology-2 containing inositol phosphatase), blood basopenia, and recruitment of basophils to skin lesion sites. In remission, these abnormalities revert toward normal [5]. Current European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network/European Dermatology Forum/ World Allergy Organization guidelines state that the aim of treatment for all types of urticaria is to achieve complete symptom relief. All scientific panels of experts organized their documents as a stepwise treatment to be adapted from one patient to another, based on the severity of the disease and on the response to therapy [1 ,6 ]. Second-generation antihistamines (bilastine, rupatadine, ebastine, cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, mizolastine) are unquestionably the cornerstone of treatment of CSU. The response rate to high-dose antihistamines is 40–50%; thus, alternative approaches for treatment have been sought for decades. Recent advances in the knowledge of CSU pathophysiology have provided the rationale for the use of immunomodulatory drugs and biologic agents in CSU [7]. &
&&
&&
Omalizumab: the facts Omalizumab, a recombinant humanized IgG1 noncomplement fixing monoclonal antibody that binds to the high-affinity receptor-binding domain (Ce3) on the Fc portion of free IgE, was the first 410
www.co-allergy.com
monoclonal antibody approved for patients with allergic disorders. Omalizumab is administered subcutaneously and is absorbed slowly; reaching peak serum concentrations after 7–8 days, it binds to IgE in a reversible reaction to form tiny, biologically inert complexes with a molecular mass and stoichiometry varying from 1 : 2, through 1 : 1, to 2 : 1 depending on the molar ratio of omalizumab and total IgE. Omalizumab is cleared via Fcg interaction in the reticuloendothelial system and has a half-life of around 26 days [8]. Its mechanism of action for asthma is well understood; complete reduction of free IgE within hours after administration combined with downregulation of expression of the high-affinity IgE receptor on basophils within 2 weeks and mast cells after 8 weeks abolishes the allergic response at its initial phase [9]. On the contrary, the mechanism by which omalizumab exerts its action in urticaria requires further investigation. The fact that it is effective in a wide spectrum of urticarias with different underlying pathogenic mechanisms raises the suspicion that it may exercise its action through different mechanisms or through an inhibitory message that leads to rapid and nonspecific desensitization of cutaneous mast cells. In addition, the subsequent down-regulation of the IgE receptor may help to sustain the response. However, recent studies have identified an unexpected effect occurring during treatment with omalizumab. Two clinical studies [10,11] have shown that peripheral blood basophils respond better to stimulation with a panspecific cross-linking anti-IgE antibody during omalizumab treatment. Saini et al. [12 ] extended their studies showing that the change in maximum release is not only a repeatable feature of basophil responsiveness, but also that a marked change in the intrinsic sensitivity of the basophil occurs. One interpretation of the various results is that omalizumab alters a process that serves to variably suppress the natural sensitivity and responsiveness of basophils. The clinical efficacy of omalizumab in CSU has been reported in numerous observational studies. Initially, in most case reports and case series the dose schedule was formed according to the Food Drug Administration approved label for asthma according to total serum IgE concentration and body weight [13–18]. As data from randomized controlled trials accumulated, the more recent observational studies [19,20] adopted the therapeutical strategy of ‘one size fits all’, administering a fixed dose of 150 mg or 300 mg in most cases, every 4 or 2 weeks. Interestingly enough, in some retrospective studies [17,18] given that dose-ranging studies were not available at the start of the administration, both therapeutic &
Volume 14 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The use of biologicals in cutaneous allergies Makris et al.
strategies were used depending on the time point of omalizumab onset. These studies [13–20] have clearly shown robust efficacy of omalizumab in refractory chronic urticaria patients. Occasionally, some fails have also been reported [21]. An interesting finding in these observational studies was the response time; in contrast to benefit in asthmatic subjects, salutary response to CSU patients was observed within 24 h in most cases and within days in the remaining. These studies provided the impetus for planning and conducting randomized controlled trials to evaluate efficacy and safety of omalizumab in patients with refractory CSU. The first proof-of-concept study was conducted by Kaplan et al. [22] in autoimmune urticaria not controlled by antihistamines. They included 12 patients with positive autologous serum skin and histamine release tests, who received omalizumab following 4 weeks of treatment with placebo, and showed significant improvement in clinical scores (complete resolution in seven cases), a significant decrease in consumption of drugs used for symptomatic relief, and improvement in quality of life, with only one patient not responding to treatment. A phase II, prospective, double-blind, placebocontrolled, dose-ranging study enrolled 90 adult patients with chronic idiopathic urticaria (CIU) who remained symptomatic despite H1-antihistamine therapy to evaluate efficacy and safety. Participants received a single dose of 75 300, or 600 mg of omalizumab or placebo and finally it was demonstrated that single-dose 300 or 600 mg provides rapid and effective treatment of CIU. Regarding safety, no new safety issues or concerns were released [23]. A second randomized, double-blind, placebocontrolled study was performed in 49 adult CSU patients with autoantibodies against thyroperoxidase. Patients were treated with 75–375 mg dose determined by using the approved asthma dosing table for 24 weeks. Complete protection from wheal development was observed in 19 (70.4%) patients in the omalizumab group compared with only 1 (4.5%) patient in the placebo group. The rate of adverse event was similar in both groups [24]. A recent multicenter, randomized, double-blind, phase III study evaluated the efficacy and safety of omalizumab in a large population of patients with moderate-to-severe CIU, who remained symptomatic despite antihistamine therapy at the licensed doses; 323 patients received three doses of 75 mg, 150 mg, or 300 mg, or placebo at 4-week intervals, followed by a 16-week observation period. At week 12, the mean change from baseline in weekly itch severity score was 5.1 5.6 in the placebo group, 5.9 6.5 in the 75 mg group (P ¼ 0.46), 8.1 6.4
in the 150 mg group (P ¼ 0.001), and 9.8 6.0 in the 300 mg group (P, 0.001). These results lead to a calculated number needed to treat for being hive free and itch free in association with receiving omalizumab at doses of 150 or 300 mg for 12 weeks of 5.9 and 2.6, respectively. The rate of serious adverse events observed in individuals randomized to 300 mg, which included melena, nephrolithiasis, and urticaria, was higher (6%) than the rates observed in those randomized to 150 mg (1%), 75 mg (1%), or placebo (3%); however, a number of the adverse events in this study [25 ] were observed during the follow up period when omalizumab administration had been suspended similarly across the groups. Another, phase III multicenter study evaluated the safety and efficacy of 24 weeks of treatment (six subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo) in patients with persistent CIU or CSU despite treatment with H1-antihistamines at up to four times the approved dose plus H2-antihistamines, leukotriene receptor antagonists, or both. Of 480 patients screened, 336 were randomized to treatment; at week 12, the mean change from baseline in weekly itch severity score was 28.6 [95% confidence interval (CI), 29.3 to 27.8] in the omalizumab group compared with 24.0 (95% CI, 25.3 to 22.7) in the placebo group (P < 0.001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24. The safety profile was consistent with omalizumab in patients with allergic asthma whereas headache and upper respiratory tract infections were the most frequently reported adverse effects [26 ]. The results of this study are of great importance as the population belongs in the subgroup of patients with poorly controlled CUA despite combination pharmacotherapy. In addition, patients enrolled in randomized controlled studies of omalizumab for CSA or CIU had a high disease burden, with a mean Urticaria Activity Score (UAS-7) of 31. On the basis of its design features, these randomised studies enhance the strength of evidence supporting the efficacy of omalizumab for patients with CSA or CIU. Conclusively, given the high cost of omalizumab, it will be prudent to consider omalizumab only in those refractory patients who have failed traditional first or second-line therapies [27]. With regard to safety, omalizumab was confirmed to be exceedingly safe as shown from studies in patients with both severe allergic asthma and chronic urticaria. &&
&&
Omalizumab: the queries Unambiguously, the most important issue that has been raised about omalizumab administration in CSU patients is to identify possible clinical or
1528-4050 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-allergy.com
411
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Skin allergy
laboratory markers that are related to the responsiveness to treatment. Although initially it was speculated that omalizumab might fit better for autoimmune urticaria, based on first studies [22,23] in this subgroup of patients, we now know that this is not true. Neither demographics (age, sex) and clinical course (duration, severity), nor laboratory findings (autologous serum and/or plasma skin test, histamine releasing activity, autoantibodies to IgE or FcERI, biomarkers) can predict salutary response to omalizumab [18]. In addition, it is well shown from both observational [14,15,17] and randomized studies [23,24, 25 ,26 ] that like asthma, patients with CSU experienced recrudescence of symptoms after stopping omalizumab therapy. Contrary to allergic asthma that is a chronic, usually lifelong, inflammatory disease, the natural course of CSU is unpredictable and may last from a few months to many years. So, it is of great clinical interest to identify optimal strategies for suspending omalizumab. Some preliminary observational studies [20,28] try to address this issue. Additionally, initial reports about successful retreatment with omalizumab after disease relapse have already appeared in the literature [29]. Hopefully, further understanding of the mechanism by which omalizumab is efficacious in CSU might provide clues for the subgroup of patients that will respond to treatment as well as the dosing and discontinuation schedule. &&
&&
Omalizumab in physical urticarias Physical or inducible according to the recent guidelines, urticarias [1 ] comprise up to 25% of chronic urticarias and occur more frequently in young adults. Although trigger avoidance and symptomatic treatment are the key therapeutic concepts for physical urticarias, in a large proportion of cases these therapeutic strategies are ineffective [30]. Randomized trials addressing the efficacy of omalizumab in physical urticarias have not been published; numerous case reports described improvement of varying degrees in different types of physical urticarias, including cholinergic [31], cold urticaria [32], delayed pressure urticaria [33], symptomatic dermographism [34], and solar urticaria [35]. Ineffectiveness has also been reported [36]. The feedback from these cases is strongly positive, eliciting enthusiasm for the expansion of omalizumab administration in refractory cases of physical urticarias. &&
Other biologicals in treatment of chronic spontaneous urticaria Although omalizumab accounts for the vast majority of biologic agents tested for efficacy in urticaria, other approaches have also appeared. 412
www.co-allergy.com
Rituximab, a chimeric monoclonal antibody that binds specifically to the CD20 antigen present on the surface of B cells, produces B-cell depletion via induction of apoptosis. Although approved only for Hodgkin lymphoma and rheumatoid arthritis [37], rituximab has been successfully used for several autoimmune diseases [38]. Three case reports are published; in two of them it was effective in two patients with evidence of autoimmune urticaria [39,40] whereas in another with a steroid-dependent patient, it failed to control the disease [41]. Wilson et al. [42] reported a case series of six patients who were recalcitrant to all other immunosuppressive therapies, and had dramatic improvement with different TNF-inhibitors (infliximab, etarnecept, and adalimumab) that lasted for several years.
ATOPIC DERMATITIS: CURRENT PERSPECTIVE Atopic dermatitis is the most common recurrent inflammatory skin disorder affecting more than 10% of children and 1–3% of adults [43]. Acute atopic dermatitis is characterized by erythematous and exudative lesions, whereas in chronic form lichenification, thickened skin and hyperpigmentation represent the main features of the disease [44]. As in other atopic diseases, atopic dermatitis is commonly associated with raised serum IgE whereas sensitizations to common inhalant and food allergens are also frequent. However, the role and the importance of IgE in the pathogenic mechanism of atopic dermatitis are, at present, unresolved [45]. Treatment of atopic dermatitis depends on the clinical severity. A wide range of topical agents, including bland emollients, torical steroids, and the calcineurin inhibitors tacrolimus and pimecrolimus are the main therapeutic options in mild-tomoderate atopic dermatitis. In addition, systemic modalities such as antibiotics, systemic corticosteroids, ciclosporin, methotrexate, mycophenolate mofetil, and others are mainly recommended for moderate-to-severe disease and especially in chronic atopic dermatitis, or for patients whose dermatitis causes significant psychosocial impact [46 ]. As our understanding of immune dysregulation of atopic dermatitis increases, new immunomodulatory drugs are emerging. In addition, the high degree of heterogeneity of underlying pathogenic mechanisms, triggers and clinical presentation in atopic dermatitis necessitates the stratification of patients and the selection of targeted treatment approaches [47,48]. &&
Volume 14 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The use of biologicals in cutaneous allergies Makris et al.
Omalizumab in atopic dermatitis: a choice for selected patients? Omalizumab, among various other conditions apart from asthma and spontaneous urticaria, has also been investigated in atopic dermatitis. However limited data exist to determine its efficacy in atopic dermatitis; a number of case series delivered conflicting results [49–51]. Heil et al. conducted one double-blind, placebo-controlled study for 16–20 week atopic dermatitis patients with omalizumab administered subcutaneously. They have shown that omalizumab reduced free serum IgE, lowered surface IgE and FceRI expression on different peripheral blood mononuclear cells, reduced the saturation of FceRI with IgE, increased the number of free FceRI, and lowered the number of IgEþ, but not of FceRIþ cells in skin but did not show clinical improvement in atopic dermatitis [52]. Kim et al. studied for a 6-month period, ten East Asian adult patients with atopic dermatitis who received anti-IgE treatment for persistent asthma with a fixed schedule of eight cycles of omalizumab 300 mg, administered subcutaneously at intervals of 2 weeks. There was a steady improvement in the objective SCORing Atopic Dermatitis (SCORAD), with significantly lower scores observed at the 6-month evaluation. At 2 months after the end of treatment no patient had worsening of the atopic dermatitis (increase of > 25% in SCORAD), and once a clinical improvement occurred, none of the patients experienced worsening of their eczema symptoms while on omalizumab. Noteworthy, those patients had serum IgE-levels of 5000 IU/ml or higher, far exceeding the approved limit for omalizumab treatment. Consequently, they were treated with omalizumab at a much lower dosage than that required for the complete removal of IgE from the circulation [53]. These results are in accordance with previous preliminary experience in 11 adult patients that regardless of their IgE values were treated with a fixed schedule of 10 cycles of 150 mg omalizumab subcutaneously in 2-week intervals. Six out of 11 showed very good or satisfying clinical response, suggesting that the effect of omalizumab in these patients seems to be a regulatory mechanism rather than simple blocking of IgE [54]. Notably, molecular changes such as a switch to reduced IgE IgG mRNA production initially seemed to be good indicators of which patients will have clinical response [55] but failed to identify all patients without clinical improvement [54]. In addition, this marker was not confirmed in larger cohorts. In a case series of subjects with seasonal allergic rhinitis (SAR) with (IgE 3528 2723 IU/ml) and without (IgE 212 224 IU/ml) atopic dermatitis, it
was reported that in the subgroup with SAR or atopic dermatitis, the atopic dermatitis-related quality of life (DLQl) following 2 months of omalizumab treatment had significantly improved and that effective oral corticosteroid use was better (9/9) than in the subjects with SAR only (9/13) [56]. Furthermore, Hotze et al. [57 ] have recently published a prospective 28-week open-label trial on 20 adults with moderate-to-severe atopic dermatitis aiming to evaluate the efficacy of omalizumab in atopic dermatitis and to identify markers associated with treatment response . In brief, all patients, regardless of their total IgE values, were treated with a fixed schedule of 14 cycles of 150 mg omalizumab in 2-week intervals. Patients who did not achieve a reduction in SCORAD at least 25% after seven applications received 300 mg from visit eight onwards. Of the 20 patients who completed the study, four patients showed a very good clinical response (SCORAD reduction 50%) and four patients responded with satisfying results (SCORAD reduction 25–50%), whereas five patients showed no relevant clinical changes (reduction or increase in SCORAD < 25%), and seven patients experienced a deterioration of the disease (SCORAD increase). Of note, none of the seven patients carrying a filaggrin mutation responded to therapy, whereas all eight responders were non-filaggrin-mutation carriers (P ¼ 0.05, Fisher’s test), indicating that patients with a primary skin barrier deficiency are less likely to benefit from an immunomodulatory therapy with anti-IgE. Additionally, targeted metabolite quantification in fasting serum showed significantly higher baseline levels of three glycerophospholipids as well as lower total sphingomyelin/total phosphatidylcholine ratio in responders when compared with nonresponders. In a small case series, administration of omalizumab in combination with IVIg has been applied to patients with severe atopic dermatitis resulting in drastic clinical improvement and long-term effects [58]. In general, the successful trials had longer treatment periods. Although it is well known that free IgE is extensively and very rapidly suppressed after omalizumab administration, it takes up to 3 months before this suppression has an effect on eczema symptoms. Thus, the treatment as well as the follow up period must be sufficiently long to allow an effect to be seen. In addition, recent data suggest that metabolic profiling can potentially assist the classification of patients and the prediction of treatment response. Large, randomized, double-blind, placebocontrolled, multicenter trials are warranted to adequately assess the efficacy of omalizumab in atopic
1528-4050 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-allergy.com
413
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Skin allergy
dermatitis and to determine the clinical phenotypes that might benefit more than others. To our knowledge, there are no ongoing studies in clinicaltrials. gov addressing these issues.
Anti-CD20 (rituximab) in atopic dermatitis Six patients with severe angioedema that received two i.v. applications of rituximab, each 1000 mg, 2 weeks apart resulted in a rapid reduction in skin inflammation in all patients with a sustained effect over 5 months in five of six patients, although specific IgE-levels were not affected [59]. On the contrary, in two cases affected by very severe atopic dermatitis, rituximab failed to show clinical effectiveness [60]. Interestingly enough, a recent pilot study proposes a sequential therapeutic strategy with two monoclonal antibodies, omalizumab and rituximab (anti-CD20), in selected individuals with atopic dermatitis. The authors report six cases of severe atopic dermatitis refractory to conventional therapy that underwent sequential switch therapy with omalizumab and rituximab. With the proposed switch therapy, four out of six patients achieved a dramatic clinical improvement [61]. However, safety and costeffectiveness studies are essential prerequisites before using such combination treatments with biologicals.
Anti interleukin-5 and atopic dermatitis Bearing in mind that eosinophils play a major role in the pathogenesis of atopic dermatitis a randomized, placebo-controlled parallel-group study was performed in 40 adult patients with moderate-to-severe atopic dermatitis, to evaluate the effect of a shortterm therapy with an anti-IL-5 antibody (mepolizumab; 2 750 mg). Unfortunately, despite a significant decrease in peripheral blood eosinophils, two single doses of 750 mg mepolizumab did not result in clinical success in atopic dermatitis patients [62]. Other studies have not been performed so far.
As far as our knowledge in the mechanisms of atopic dermatitis deepens, new molecules are potential therapeutic targets like IL-4, IL-13 and their receptors as well as histamine receptor 4 [65]. A randomized, double-blind, placebo-controlled, parallel-group study investigating the efficacy, safety, serum concentration, and biomarker profile of an anti-IL-4 antibody, dupilumab administered to adults with moderate-to-severe atopic dermatitis is registered in clinicaltrials.gov.
OTHER CUTANEOUS ALLERGIES In other cutaneous allergies biologicals have not been extensively used nor have case reports been published. However, there is one exception. This is toxic epidermal necrolysis in which anti-TNF-aantagonists have been discussed in the literature [66]. Because of the extremely rare incidence of the disease however randomized larger trials are missing.
CONCLUSION Although companies for a long time have concentrated on developing biologicals in the field of dermatological diseases like psoriasis, now apparently interest is growing also to look at cutaneous allergies. With the licensing of omalizumab in urticaria a huge step forward has been made. Especially as again like in psoriasis, this biological is able to prove in double-blind placebo-controlled trials an enormous efficacy to control this disease and a very high number of total responders. It can be hoped for that this trend is ongoing with current research concepts targeting cytokines involved, for example, in atopic dermatitis new biologicals will hopefully be available within the next 5 years. Acknowledgements This study was not funded by any grant or other sources.
Other biological agents in atopic dermatitis Although anti-TNF-a antibody has been shown to significantly decrease atopic dermatitis severity and pruritus, the effect proved to be transient and disease relapse occurred shortly [63]. In addition, inadequate effects or even severe exacerbations of atopic dermatitis upon anti-TNF-a therapy have been also reported. Inhibition of IL-6 signaling theoretically has potential to dampen inflammation at the level of CD4þ T-Helper 2 and T-Helper 17 polarization. A preliminary report of blocking the IL-6 receptor by the mAb tocilizumab in three patients affected with severe atopic dermatitis however, led to adverse severe infections [64]. 414
www.co-allergy.com
Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA2LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014; 69:868–887. This guideline is the result of a systematic literature review using the ‘Grading of Recommendations Assessment, Development and Evaluation’ methodology and a structured consensus conference. It clearly outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.
&&
Volume 14 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The use of biologicals in cutaneous allergies Makris et al. 2. Greaves MW, Tan KT. Chronic urticaria: recent advances. Clin Rev Allergy Immunol 2007; 33:134–143. 3. O’Donnell BF, Lawlor F, Simpson J, et al. The impact of chronic urticaria on the quality of life. Br J Dermatol 1997; 136:197–201. 4. Konstantinou GN, Asero R, Ferrer M, et al. EAACI task force position paper: & evidence for autoimmune urticaria and proposal for defining diagnostic criteria. Allergy 2013; 68:27–36. A position article of Dermatology section of the European Academy of Allergy and Clinical Immunology about autoimmune urticaria. A systematic in depth review of published data with consensus and recommendations from the experts’ panel. 5. Vonakis BM, Saini SS. New concepts in chronic urticaria. Curr Opin Immunol 2008; 20:709–716. 6. Bernstein JA, Lang DM, Khan DA. The diagnosis and management of acute && and chronic urticaria: 2014 update. J Allergy Clin Immunol 2014; 133:1270– 1277. The urticaria practice parameter workgroup using a systematic literature review in conjunction with consensus expert opinion and workgroup-identified supplementary documents developed practice parameters that provide a comprehensive approach for the assessment and management of urticaria with or without concomitant angioedema. 7. Asero R, Tedeschi A, Cugno M. Treatment of Chronic Urticaria. Immunol Allergy Clin N Am 2014; 34:105–116. 8. Babu KS, Polosa R, Morjaria JB. Anti-IgE–emerging opportunities for omalizumab. Expert Opin Biol Ther 2013; 13:765–777. 9. Eckman JA, Sterba PM, Kelly D, et al. Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge. J Allergy Clin Immunol 2010; 125:889–895. 10. Zaidi AK, Saini SS, Macglashan DW Jr. Regulation of Syk kinase and FcRb expression in human basophils during treatment with omalizumab. J Allergy Clin Immunol 2010; 125:902–908; e7. 11. MacGlashan DW Jr, Savage J, Wood RA, et al. Suppression of the basophil response to allergen during treatment with omalizumab is dependent on two competing factors. J Allergy Clin Immunol 2012; 130:1130–1135. 12. Macglashan DW, Saini SS. Omalizumab increases the intrinsic sensitivity of & human basophils to IgE-mediated stimulation. J Allergy Clin Immunol 2013; 132:906–911. A study that provides a better quantitative sense of the phenotypic change that occurs in basophils during omalizumab treatment, which has both mechanistic and clinical implications. 13. Young-Hee N, Joo-Hee K, Hyun Jung J, et al. Effects of omalizumab treatment in patients with refractory chronic urticaria. Allergy Asthma Immunol Res 2012; 4:357–361. 14. Buyukozturk S, Gelincik A, Demirturk M, et al. Omalizumab markedly improves urticaria activity scores and quality of life scores in chronic spontaneous urticaria patients: a real life survey. J Dermatol 2012; 39:439–442. 15. Groffik A, Mizel-Kaoukhov H, Magerl M, et al. Omalizumab: an effective and safe treatment of therapy resistant chronic spontaneous urticaria. Allergy 2011; 66:303–305. 16. Vestergaard C, Deleuran M. Two cases of severe refractory chronic idiopathic urticaria treated with omalizumab. Acta Derm Venereol 2010; 90:443–444. 17. Metz M, Ohanyan T, Church MK, et al. Omalizumab is an effective and rapidly acting therapy in difficult to treat chronic urticaria: a retrospective clinical analysis. J Dermatol Sci 2014; 73:57–62. 18. Viswanathan RK, Moss MH, Mathur SK. Retrospective analysis of the efficacy of omalizumab in chronic refractory urticaria. Allergy Asthma Proc 2013; 34:446–452. 19. Song CH, Stern S, Giruparajah M, et al. Long-term efficacy of fixed dose omalizumab for patients with severe chronic spontaneous urticaria. Ann Allergy Asthma Immunol 2013; 110:113–117. 20. Sussman G, Hebert J, Barron C, et al. Real-life experiences with omalizumab for the treatment of chronic urticaria. Ann Allergy Asthma Immunol 2014; 112:170–174. 21. Altman M, Naimi D. Omalizumab for chronic urticaria [letter]. N Engl J Med 2013; 368:2528–2530. 22. Kaplan AP, Joseph K, Maykut RJ, et al. Treatment of chronic autoimmune urticaria with omalizumab. J Allergy Clin Immunol 2008; 122:569–573. 23. Saini S, Rosen KE, Hsieh HJ, et al. A randomized, placebo-controlled, dose ranging study of single-dose omalizumab in patients with H1-antihistamine refractory chronic idiopathic urticaria. J Allergy Clin Immunol 2011; 128:567– 573. 24. Maurer M, Altrichter S, Bieber T, et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol 2011; 128:202–209. 25. Maurer M, Rosen K, Hsin-Ju HJ, et al. Omalizumab for the treatment of chronic && idiopathic or spontaneous urticaria. N Engl J Med 2013; 368:924–935. A phase-3, multicenter, randomized, double-blind study, which shows that omalizumab at doses of 150 mg and 300 mg significantly improved outcomes. 26. Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic && chronic idiopathic/spontaenous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013; 132:101–109. A phase-3, multicenter, randomized, double-blind study that proves efficacy and tolerability of omalizumab in patients with CIU or CSU who remain symptomatic despite receiving H1-antihistamines at up to four times the approved dose plus H2-antagonists, leucotriene receptor antagonists, or both.
27. Kaplan AP. Treatment of chronic spontaneous urticaria. Allergy Asthma Immunol Res 2012; 4:326–331. 28. Uysal P, Eller E, Mortz CG, et al. An algorithm for treating chronic urticaria with omalizumab: dose interval should be individalized. J Allergy Clin Immunol 2014; 133:914–915. 29. Metz M, Ohanyan T, Church MK, et al. Retreatment with omalizumab results in rapid remission in chronic spontaneous and inducible urticaria. JAMA Dermatol 2014; 150:288–290. 30. Abajian M, Mlynek A, Maurer M. Physical urticaria. Curr Allergy Asthma Rep 2012; 12:281–287. 31. Metz M, Bergmann P, Zuberbier T, et al. Successful treatment of cholinergic urticaria with anti-immunoglobulin E therapy. Allergy 2008; 63:247–249. 32. Brodska P, Schmid-Grendelmeier P. Treatment of severe cold contact urticaria with omalizumab: case reports. Case Rep Dermatol 2012; 4:275–280. 33. Bindslev-Jensen C, Skov PS. Efficacy of omalizumab in delayed pressure urticaria: a case report. Allergy 2010; 65:130–139. 34. Krause K, Ardelean E, Kessler B, et al. Antihistamine resistant urticaria factitia successfully treated with anti-immunoglobulin E therapy. Allergy 2010; 65:1494–1495. 35. Guzelbey O, Ardelean E, Magerl M, et al. Successful treatment of solar urticaria with anti-immunoglobulin E therapy. Allergy 2008; 63:1563–1565. 36. Sabroe RA. Failure of omalizumab in cholinergic urticaria. Clin Exp Dermatol 2009; 35:e127–e129. 37. Hauser SL, Waubant E, Arnold DL, et al., HERMES Trial Group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358:676–688. 38. Joly P, Mouquet H, Roujeau JC, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007; 357:545–552. 39. Arkwright PD. Anti-CD20 or anti-IgE therapy for severe chronic autoimmune urticaria. J Allergy Clin Immunol 2009; 123:510–511. 40. Chakravarty SD, Yee AF, Paget SA. Rituximab successfully treats refractory chronic autoimmune urticaria caused by IgE receptor autoantibodies. J Allergy Clin Immunol 2011; 128:1354–1355. 41. Mallipeddi R, Grattan CE. Lack of response of severe steroid-dependent chronic urticaria to rituximab. Clin Exp Dermatol 2007; 32:333–334. 42. Wilson LH, Eliason MJ, Leiferman KM, et al. Treatment of refractory chronic urticaria with tumor necrosis factor-alfa inhibitors. J Am Acad Dermatol 2009; 64:1221–1222. 43. Schultz-Larsen F, Hanifin J. Epidemiology of atopic dermatitis. Immunol Allergy Clin North Am 2002; 22:1–24. 44. Rudzki E, Samochocki Z, Litewska D, et al. Clinical features of atopic dermatitis and a family history of atopy. Allergy 1991; 46:125–128. 45. Garmhausen D, Hagemann T, Bieber T, et al. Characterization of different courses of atopic dermatitis in adolescent and adult patients. Allergy 2013; 68:498–506. 46. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management && of atopic dermatitis. J Am Acad Dermatol 2014. [Epub ahead of print] This guideline addresses important clinical questions that arise in atopic dermatitis management and care, providing recommendations based on the available evidence. 47. Novak N, Simon D. Atopic dermatitis– from new pathophysiologic insights to individualized therapy. Allergy 2011; 66:830–839. 48. Bieber T. Atopic dermatitis: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 2012; 67:1475–1482. 49. Vigo PG, Girgis KR, Pfuetze BL, et al. Efficacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol 2006; 55:168–170. 50. Lane JE, Cheyney JM, Lane TN, et al. Treatment of recalcitrant atopic dermatitis with omalizumab. J Am Acad Dermatol 2006; 54:68–72. 51. Krathen RA, Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis. J Am Acad Dermatol 2005; 53:338–340. 52. Heil PM, Maurer D, Klein B, et al. Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course-a randomized, placebocontrolled and double blind pilot study. J Dtsch Dermatol Ges 2010; 8:990– 998. 53. Kim DH, Park KY, Kim BJ, et al. Anti-immunoglobulin E in the treatment of refractory atopic dermatitis. Clin Exp Dermatol 2013; 38:446–450. 54. Belloni B, Ziai M, Lim A, et al. Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. J Allergy Clin Immunol 2007; 120:1223– 1225. 55. Lim A, Luderschmidt S, Weidinger A, et al. The IgE repertoire in PBMCs of atopic patients is characterized by individual rearrangements without VH bias. J Allergy Clin Immunol 2007; 120:696–706. 56. Velling P, Skowasch D, Pabst S, et al. Improvement of quality of life in patients with concomitant allergic asthma and atopic dermatitis: one year follow-up of omalizumab therapy. Eur J Med Res 2011; 16:407–410. 57. Hotze M, Baurecht H, Rodriguez E, et al. Increased efficacy of omalizumab in & atopic dermatitis patients with wild-type filaggrin status and higher serum levels of phosphatidylcholines. Allergy 2014; 69:132–135. A pilot study which shows for the first time that atopic dermatitis patients who respond to omalizumab are characterized by the absence of filaggrin mutations and altered lipid metabolite profiles with high levels of various glycerophospholipids. 58. Toledo F, Silvestre JF, Munoz C. Combined therapy with low-dose omalizumab and intravenous immunoglobulin for severe atopic dermatitis. Report of four cases. J Eur Acad Dermatol Venereol 2012; 26:1325–1327.
1528-4050 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-allergy.com
415
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Skin allergy 59. Simon D, Hosli S, Kostylina G, et al. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol 2008; 121:122–128. 60. Sediva A, Kayserova J, Vernerova E, et al. Anti-CD20 (rituximab) treatment for atopic eczema. J Allergy Clin Immunol 2008; 121:1515–1516. 61. Sa´nchez-Ramo´n S, Eguı´luz-Gracia I, Rodrı´guez-Mazariego ME, et al. Sequential combined therapy with omalizumab and rituximab: a new approach to severe atopic dermatitis. J Investig Allergol Clin Immunol 2013; 23:190–196. 62. Oldhoff JM, Darsow U, Werfel T, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy 2005; 60:693–696.
416
www.co-allergy.com
63. Jacobi A, Antoni C, Manger B, et al. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol 2005; 52:522–526. 64. Navarini AA, French LE, Hofbauer GF. Interrupting IL-6-receptor signaling improves atopic dermatitis but associates with bacterial superinfection. J Allergy Clin Immunol 2011; 128:1128–1130. 65. Ohsawa Y, Hirasawa N. The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via antipruritic and anti-inflammatory effects in NC/Nga mice. Allergy 2012; 67:1014–1022. 66. Jalilian C, Jevtic A. The management of toxic epidermal necrolysis. Australas J Dermatol 2012; 53:165–171.
Volume 14 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
