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Update and insights into treatment options for chronic spontaneous urticaria Expert Rev. Clin. Immunol. 10(3), 397–403 (2014)
Nadine Marrouche* and Clive Grattan Department of Dermatology, Norfolk and Norwich University Hospital, Colney Lane, Norwich, NR4 7UY, UK *Author for correspondence: Tel.: +44 016 0328 8265 Fax: +44 016 0328 8601 [email protected]
Chronic spontaneous urticaria (CSU) is defined as itchy weals, angio-oedema, or both, arising spontaneously without external physical stimuli. Symptoms of the disease continue to develop for more than 6 weeks. It carries a high socioeconomic burden with considerable health care costs. Second generation H1-antihistamines are the mainstay of urticaria treatment and are the only licensed option. However, many patients are resistant to H1-antihistamine therapy. Omalizumab has proven to be an effective therapeutic option in patients with recalcitrant chronic urticaria. Ciclosporin appears to be more beneficial in patients with functional histamine releasing autoantibodies as a cause of their disease. This review article will highlight the major therapeutic options available today for the management of CSU knowing that good quality evidence for efficacy of many agents is scarce except for H1-antihistamines and omalizumab. KEYWORDS: autoimmune urticaria • chronic spontaneous urticaria • ciclosporin • H1-antihistamines • miltefosine • omalizumab • treatment
Chronic spontaneous urticaria (CSU) is defined as itchy weals, angio-edema or both, arising spontaneously without external physical stimuli. Symptoms continue to develop for more than 6 weeks [1]. The disease is characterized by unpredictable attacks often causing decreased social functioning and work productivity and significant sleep disruption [2,3]. It has a considerable impact on the quality of life which is similar to that seen in patients awaiting a coronary artery bypass [4,5]. With a prevalence of 1% in the general population, CSU clearly carries a high socioeconomic burden [6] with considerable healthcare costs [7]. This is compounded by the duration of the disease that is more than 1 year in up to 50% of patients [8].The guidelines for the management of urticaria propose a twofold approach starting with the identification and elimination of underlying causes and/or triggers like drugs [9]. In CSU, studies have demonstrated a clear association with autoimmune disease in up to 45% of patients [10,11] and, to a much lesser extent, non-organ-specific autoantibodies [12]. However this, along with routine laboratory testing, has no beneficial implications on patients’ management as yet [13]. As a second line of approach, the guidelines recommend informahealthcare.com
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treatment targeted at symptom relief [9]. Nonsedating (second-generation) H1-antihistamines are clearly the mainstay of urticaria treatment and are the only licensed option. More than 50% of patients do not respond to antihistamines at regular doses [6], so the guidelines recommend updosing the H1-antihistamine first then adding leukotriene-antagonists or H2-antihistamines or changing the H1-antihistamine if symptoms persist. However, many patients remain symptomatic despite the above and require alternative therapies. The updated international guidelines recommend adding ciclosporin or omalizumab as third-line treatment options. In addition, a short course of systemic steroids is suggested for exacerbations of CSU [1]. The latter patients appear to benefit from referral to tertiary care centers [14]. Antihistamines H1-antihistamines
It is widely recognized that mast cells play a pivotal role in the pathophysiology of urticaria. The mediators released from these cells, mainly histamine, result in the prototypical symptoms that ensue. The classical weal and flare is caused by vasodilatation and extravasation of fluids leading to tissue edema, whereas
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activation of sensory nerves results in pruritus [15,16]. As such, antihistamines remain the mainstay of urticaria treatment. H1-antihistamines are inverse agonists of the H1-receptor, binding and stabilizing it in the inactive conformation [17]. Antihistamines have been used in the treatment of urticaria for over half a century now. The longest clinical experience is with the firstgeneration antihistamines, which are still widely used for the treatment of all types of urticaria. However, current guidelines recommend against their use in the routine management of chronic urticaria [9]. Indeed, first-generation antihistamines have demonstrated a wide array of potentially dangerous adverse effects ranging from daytime somnolence and drowsiness to impaired concentration and decreased memory and learning ability [18]. Most of these adverse effects are thought to be caused by the effect of first-generation H1-antihistamines on the sleepwake cycle. It has been demonstrated that these agents increase the latency to the onset of rapid eye movement sleep and reduce its duration at night with hangover effects on the next morning [19,20]. Second-generation H1-antihistamines, compared with their first-generation counterparts, appear to be largely free from these side effects mainly because of better peripheral H1-receptor selectivity and decreased ability to cross the blood– brain barrier [21]. In addition to their role as histamine inverse agonists, a number of second-generation antihistamines have demonstrated some anti-inflammatory and immunomodulatory properties, which may be important in addressing the late-phase allergic reaction of urticaria [17,22]. Among second-generation H1-antihistamines, fexofenadine has been studied the most but there are limited data comparing the various agents against one another in the treatment of CSU [23]. Comparative studies of cetirizine in the treatment of chronic urticaria show comparable clinical efficacy with loratadine and levocetirizine with one study showing a therapeutic advantage over fexofenadine [24–26]. The efficacy of levocetirizine was compared with that of loratadine in two randomized controlled trials. Both showed superiority of levocetirizine in treatment of CSU [27,28]. Newer secondgeneration antihistamines, like rupatadine, are proving to be at least as effective as older molecules [22]. The range of secondgeneration antihistamines is wider than discussed above, but the aim of this review is to cover concepts pertinent to antihistamines in general, using some specific molecules as examples. Overall, the number and quality of the comparative studies are insufficient to make strong recommendations supporting one antihistamine over another. Many patients with CSU do not benefit from standard dosing of H1-antihistamines. Recent guidelines for management of urticaria have suggested using second-generation H1-antihistamines in doses up to fourfold higher than recommended [9]. These recommendations are largely based on expert opinion, but evidence to endorse this practice is increasing [28]. However, the results of updosing studies of different second-generation H1-antihistamines are sometimes inconsistent and the amount and quality of the data are not adequate to perform a meta-analysis. Despite the lack of good scientific evidence, higher doses of second-generation H1-antihistamines are still a safer option to other alternative 398
treatments in patients refractory to standard doses H1-antihistamines and are generally favored in routine practice [29]. A recent study based on a patients’ survey has shown that up to 75% of CSU patients have better symptomatic relief at updosing the H1-antihistamines with no reported increase in frequency of side effects [30]. Alternatively, it may be appropriate to consider alternative second-generation H1-antihistamines in case the patient fails to respond to one specific agent. Another interesting clinical question that remains to be answered with good quality evidence is whether on-demand rather than continuous treatment with H1-antihistamines is an efficacious modality of treatment. The rationale for such a therapeutic approach stems from the nature of CSU, which is often characterized by a fluctuating pattern changing significantly from day to day. Two recent studies on desloratadine have tried to answer this question and so far it appears that the on-demand approach is of very little benefit [31,32]. H2-antihistamines & leukotriene receptor antagonists
H2 receptor antagonists and leukotriene antagonists are often used as add-on therapies to H1-antihistamines in the treatment of CSU. Their efficacy remains uncertain as well as designed controlled studies in combination with currently available second-generation H1-antihistamines have not been done [33–36]. Among these agents, montelukast appears to benefit a specific subpopulation of patients with CSU and intolerance to food additives and/or salicylic acid [37]. Omalizumab
The introduction of omalizumab to the management of CSU is an example of the successful translation of molecular biological technology to medical practice. Omalizumab is a recombinant humanized anti-IgE antibody that binds to the C3 domain of the IgE heavy chain where IgE binds to its high-affinity receptor FceRI. It has been largely studied in the field of asthma and is currently approved for the treatment of both adult and pediatric (children; >6-year-old) patients with moderate-to-severe asthma [38]. Omalizumab has also proven to be an effective therapeutic option in patients with recalcitrant chronic urticaria. The original evidence stemmed from several case series/small trials [39–43]. The first study that investigated optimal dosing of omalizumab in chronic urticaria was a Phase II trial conducted by Saini et al. in 2011. The group demonstrated that a single fixed dose of 300 or 600 mg of the drug (unlike in asthma where the dose is calculated according to weight) is a rapid and effective therapeutic option in patients who are symptomatic despite treatment with H1-antihistamines [44]. Although many studies inferred that omalizumab is beneficial in CSU with a likely autoimmune etiology [40,45], other studies have demonstrated the efficacy of omalizumab in CSU irrespective of autoimmune status [44]. In fact, a recent prospective study showed that omalizumab is an effective treatment for CSU patients with negative autoantibodies assays against either IgE or its high-affinity receptor that are resistant to antihistamines [46]. These findings suggest that omalizumab is Expert Rev. Clin. Immunol. 10(3), (2014)
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Update & insights into treatment options for CSU
likely to mediate its therapeutic effects in urticaria through a multitude of mechanisms. Omalizumab results in a significant and rapid reduction in serum levels of free IgE [47]. This may lead to non-specific desensitization of mast cells in the skin and thus explain the rapid therapeutic response seen in clinical practice. In addition, omalizumab has been shown to downregulate not only IgE receptors on effector cells, including mast cells and basophils, but also dendritic cells [48,49]. The latter effect suggests that blocking IgE can inhibit more chronic aspects of allergic inflammation involving T-cell activation. Moreover, omalizumab is thought to mediate some of its anti-inflammatory action by inducing apoptosis of eosinophils [50]. Clearly though, the precise mechanisms by which omalizumab acts require further investigation. In the meantime, licensing studies for omalizumab in the treatment of CSU are ongoing. The results of the first of three Phase III clinical trials have been reported. In this trial, it was shown that during the initial 12 weeks of the study, omalizumab at doses of 150 and 300 mg significantly diminished the symptoms and signs of CSU in patients who remained symptomatic despite the use of approved doses of H1-antihistamines. Side effects were more likely to be reported in patients treated with the highest dose [51]. Similar beneficial results were more recently reported in patients treated with 300 mg/month or placebo for chronic spontaneous/idiopathic urticaria not responding to standard combination therapy [52]. There are several important questions regarding the use of omalizumab for the treatment of CSU that remain to be answered. Well-designed studies are needed to determine the patient profile most suitable for omalizumab treatment, the optimal duration of therapy and rates of long-term remission. In addition, potential long-term side effects of omalizumab in the treatment of CSU require further investigation. Other biologics
Omalizumab is by far the most studied biologic agent in urticaria to date. However, a few other biologics have been tested in individual case reports. A rapid resolution of symptoms was reported in a case of recalcitrant chronic autoimmune urticaria treated with anti-CD20 monoclonal antibody therapy (rituximab) in two reports [53,54] but not another [55]. The response is thought to be related to targeting IgG autoantibodies producing B lymphocytes, which are functional and pathologic in autoimmune urticaria. Other biologics, like anti-TNF-a and anti-IL-1 agents, have been reported to treat other forms of urticaria [56,57]. Ciclosporin
Ciclosporin has immunomodulatory properties. It is known to interfere with the activity of T lymphocytes including downregulation of T-cell-dependent antibody formation. This is of relevance in CSU as functional factors including pathogenic histamine-releasing autoantibodies have been identified in the sera of up to 40% of patients [58–60]. Indeed, treatment of CSU patients with ciclosporin was shown to reduce histaminereleasing autoantibodies and autologous serum skin test response rates [61]. In the same study, it was demonstrated that patients with a positive basophil histamine release assay informahealthcare.com
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(BHRA) were more likely to respond to ciclosporin than those with a negative BHRA. The latter finding was recently confirmed in a larger number of patients with chronic urticaria [62]. The BHRA thus appears to be a useful predictive biomarker for a good response to ciclosporin in CSU patients who prove to be resistant to H1-antihistamines therapy. However, the effect of ciclosporin on the reduction of functional autoantibodies does not explain the early therapeutic response to ciclosporin seen in some patients. Other factors are likely playing a role such as inhibition of de novo synthesis of prostaglandins and stabilization of histamine release, which have been demonstrated both in vitro and in vivo on human basophils and skin mast cells pretreated with ciclosporin and stimulated with anti-IgE [63–66]. In addition, ciclosporin appears to have other anti-inflammatory effects. Experiments in mice suggest that ciclosporin can suppress neutrophil infiltration induced by mast cell degranulation by inhibiting IgE-dependent TNF-a secretion from skin mast cells and reducing responsiveness of target cells to TNF-a [67]. In addition, ciclosporin also inhibits the release of cytokines from eosinophils, which often infiltrate urticaria lesions [68]. From a clinical perspective, ciclosporin has proved its efficacy in the treatment of CSU in more than 20 original studies over the past two decades. Fradin et al. were the first to report on the successful use of ciclosporin in three patients suffering from severe chronic urticaria. However, the therapy was discontinued in all patients as the high dose administered (6 mg/kg) caused major adverse effects [69]. Subsequently, ciclosporin was used in many trials at lower doses (2–5 mg/kg) with sustained benefit but improved tolerability, especially at the lower doses [61,70–73]. Most of these studies reported comparable response rates and used ciclosporin for 1–3 months. In many of them however, urticaria relapsed upon drug discontinuation. A more recent study reported on the efficacy and safety of long-term ciclosporin therapy. Treatment was started at 3 mg/kg of ciclosporin for 3 months in all patients, but a small group eventually continued at a very low dose (1–1.5 mg/kg) for longer periods between 5 and 10 years. In this group, treatment continued on being effective but more importantly, no increased incidence of side effects was noted [74]. Overall, based on current evidence, a 3-month ciclosporin therapy at a starting dose of 3–4 mg/kg daily (with dosing adjusted according to clinical response and adverse events) is likely to produce a good response and lowest relapse rates. However, the optimal dose and duration of treatment still need to be established. Other immunosuppressive agents
Patients with recalcitrant CSU, who fail to respond to higher doses of antihistamines, often require immunosuppressive therapy. Ciclosporin has been the most studied among diseasesuppressive agents. Methotrexate has been investigated in a case series of steroid-dependent chronic urticaria where patients failed to respond to antihistamines and other second-line agents, except prednisolone. It proved to be well tolerated and beneficial. It is thought to act as a non-specific anti399
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inflammatory and immunosuppressive agent as the clinical response did not correlate with the presence of functional autoantibodies [75]. Mycophenolate mofetil is another effective therapeutic option in patients who poorly respond to conventional treatments [76]. Other potentially useful agents include dapsone, colchicine, hydroxychloroquine and sulfasalazine; however, most of these drugs have been reported to be beneficial in small open series or controlled clinical studies, but wellconducted and large studies are needed to determine the value of the above agents in the treatment of CSU. Unmet needs
The management of CSU remains largely unsatisfactory in the absence of a cure for the disease. Most current treatment is targeted at symptoms and H1-antihistamines are currently the only licensed therapy for CSU. However, it remains difficult to predict which antihistamine is best for a particular patient. As such, research should focus not only on comparative studies among different antihistamines, but also look into predictive models to assess the efficacy of these agents and potentially new similar drugs [77]. Although preformed histamine released from mast cells is believed to be the major mediator of urticaria symptoms, other molecules, including cytokines and chemokines, also seem to play a pathological role [78]. This might be one of the reasons why antihistamines are not effective in up to a half of CSU patients. The pharmaceutical industry needs to keep developing agents based on better understanding of mechanisms involved in the disease. Miltefosine, a lipid raft modulator, is a good illustration of this concept. Miltefosine has been approved for the treatment of cutaneous metastases in breast cancer and visceral leishmaniasis [79,80]. Miltefosine interacts with cell membrane lipid rafts, interfering with many cell membrane functions like cellular transport [81,82]. In addition, miltefosine has been shown to inhibit mast cell activation and mediator release both in vitro and in vivo [83]. Topical application of miltefosine has demonstrated promising results in mast cell-mediated conditions like cutaneous mastocytosis [84]. More recently, the efficacy and safety of miltefosine were explored in the treatment of CSU patients who did not respond to standard-dose antihistamines. The drug resulted in a significant decrease in weal numbers. The authors hypothesized that miltefosine, as a lipid raft modulator, inhibits mast cell degranulation and mediator release, which are the most downstream events of the pathogenesis of CSU [85]. It is widely accepted that up to 40% of patients with CSU have an autoimmune basis for their disease in which functional IgG antibodies play a pathological role. This is the rationale for the use of immunosuppressive agents in the treatment of this condition. However, most of these agents act in non-specific ways in controlling CSU symptoms. There is a need for more targeted therapy in this regard, as it is well known that the mast cell is not the sole cellular player in urticaria. Indeed, skin biopsies taken from CSU lesions reveal infiltrations by numerous inflammatory cells including neutrophils, eosinophils, basophils and undifferentiated T cells [86]. These cells are not likely to be innocent bystanders. 400
For instance, eosinophils have been shown to play a crucial role in perpetuating CSU by releasing major basic protein [87]. Moreover, there is a need for the determination of both clinical and laboratory parameters that can serve as prognostic factors for CSU. It was shown in a recent systematic review that plasma levels of prothrombin fragment 1 + 2, D-dimer and C-reactive protein may predict CSU severity [88]. Conclusion
The physical and mental impairment caused by CSU underscores the need for rapid and effective therapy. Although management of urticaria is well covered in consensus documents, management decisions should be tailored to each patient based not only on proper risk/benefit assessment, but also the patient’s preferences. Despite major advancements made in understanding the pathogenesis of CSU, currently available treatment options remain unsatisfactory for some patients. The need for new pharmacotherapeutic options remains. Expert commentary
The presentation of CSU may range from relatively mild to very severe for different individuals and during different periods of the disease course. Fortunately, H1-antihistamines may be highly effective for the itch of urticaria and help to suppress some of the visible manifestations (weals, redness and angioedema) while the disease is active, but do not influence the course of the illness. In other words, they may relieve symptoms but are not disease-modifying. There is no certainty that any of the currently available treatments for CSU turn off the illness, although there is some evidence from studies of ciclosporin that immunomodulatory drugs may have this effect for some patients with functional histamine-releasing autoantibodies as a cause of their disease. Recent studies of anti-IgE (omalizumab) have shown that it may work even when other treatments have failed but the reasons for this are still uncertain. The optimal dose and treatment duration of omalizumab still need defining for individual patients and its relatively high cost is limiting its use in many countries. There are currently no predictive biomarkers for response, but there is a likelihood that these will emerge with experience and careful study of clinical and investigational markers. Five-year view
The next 5 years should see the emergence of more focused individualized treatment protocols based on better understanding of the cellular and biochemical events that occur from onset through to resolution of CSU and the clinical behavior of the illness. Understanding susceptibility genes and environmental triggers should help to predict onset and relapse of symptoms. As more mediator and cellular-specific treatments emerge, it is likely that the current concept of an endogenous mast cell activation process causing primarily histamine-driven symptomatology will become more complex and the range of opportunities for targeted disease suppression will increase to the benefit of patients. Expert Rev. Clin. Immunol. 10(3), (2014)
Update & insights into treatment options for CSU
Financial & competing interests disclosure
C Grattan is on the advisory bodies for Novartis, GSK and CSL Behring. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial
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conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Chronic spontaneous urticaria is defined as itchy weals, angioedema or both, arising spontaneously without external physical stimuli and lasting for more than 6 weeks.
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• It is a common disease that can be debilitating and carries a high socioeconomic burden. • Most of the current treatment options are targeted at symptoms and are not disease-modifying. • Second-generation H1-antihistamines are the mainstay of urticaria treatment and are the only licensed option but are not effective for all patients. • Omalizumab has proven to be an effective therapeutic option in patients with recalcitrant chronic urticaria. • Ciclosporin appears to be more beneficial in patients with functional histamine-releasing autoantibodies as a cause of their disease. • Future research should focus on better understanding of the cellular and biochemical events involved in the pathophysiology of the disease and development of drugs targeting disease suppression.
References
7.
Papers of special note have been highlighted as: • of interest •• of considerable interest 1.
••
2.
3.
4.
5.
6.
Maurer M, Magerl M, Metz M, Zuberbier T. Revisions to the international guidelines on the diagnosis and therapy of chronic urticaria. J Dtsch Dermatol Ges 2013;11(10):971-8 An important article summarizing the revisions to the international guidelines on the diagnosis and treatment of chronic urticaria, which were discussed at the 4th International Consensus Meeting (URTICARIA 2012). Baiardini I, Giardini A, Pasquali M, et al. Quality of life and patients’ satisfaction in chronic urticaria and respiratory allergy. Allergy 2003;58(7):621-3 Maurer M, Ortonne JP, Zuberbier T. Chronic urticaria: a patient survey on quality-of-life, treatment usage and doctor-patient relation. Allergy 2009;64(4): 581-8 O’Donnell B, Lawlor F, Simpson J, et al. The impact of chronic urticaria on the quality of life. Br J Dermatol 1997;136(2): 197-201 Grob J, Revuz J, Ortonne J, et al. Comparative study of the impact of chronic urticaria, psoriasis and atopic dermatitis on the quality of life. Br J Dermatol 2005; 152(2):289-95 Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy 2011;66(3):317-30
informahealthcare.com
8.
9.
10.
Delong L, Culler S, Saini S, et al. Annual direct and indirect health care costs of chronic idiopathic urticaria: a cost analysis of 50 nonimmunosuppressed patients. Arch Dermatol 2008;144(1):35-9
15.
Maurer M, Metz M, Magerl M, et al. Autoreactive urticaria and autoimmune urticaria. Hautarzt 2004;55(4):350-6
16.
Kozel MM, Mekkes JR, Bossuyt PM, Bos JD. Natural course of physical and chronic urticaria and angioedema in 220 patients. J Am Acad Dermatol 2001; 45(3):378-91
Hakim-Rad K, Metz M, Maurer M. Mast cells: makers and breakers of allergic inflammation. Curr Opin Allergy Clin Immunol 2009;9(5):427-30
17.
Zuberbier T, Asero R, Bindslev-Jensen C, et al. EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy 2009;64(10):1427-43
Leurs R, Church MK, Taglialatela M. H1-antihistamines: inverse agonism, antiinflammatory actions and cardiac effects. Clin Exp Allergy 2002;32(4):489-98
18.
Leznoff A, Josse R, Denburg J. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol 1983;119(8):636-40
Church MK, Maurer M, Simons FE, et al. Risk of first-generation H(1)-antihistamines: a GA(2)LEN position paper. Allergy 2010; 65(4):459-66
19.
Boyle J, Eriksson M, Stanley N, et al. Allergy medication in Japanese volunteers: treatment effect of single doses on nocturnal sleep architecture and next day residual effects. Curr Med Res Opin 2006;22(7): 1343-51
20.
Rojas-Zamorano JA, Esqueda-Leon E, Jimenez-Anguiano A, et al. The H1 histamine receptor blocker, chlorpheniramine, completely prevents the increase in REM sleep induced by immobilization stress in rats. Pharmacol Biochem Behav 2009;91(3):291-4
11.
Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy 2009; 39(6):777-87
12.
Confino-Cohen R, Chodick G, Shalev V, et al. Chronic urticaria and autoimmunity: associations found in a large population study. J Allergy Clin Immunol 2012;129(5): 1307-13
13.
Tarbox JA, Gutta RC, Radojicic C, Lang DM. Utility of routine laboratory testing in management of chronic urticaria/ angioedema. Ann Allergy Asthma Immunol 2011;107(3):239-43
21.
Simons FE. Advances in H1-antihistamines. N Engl J Med 2004;351(21):2203-17
22.
Weller K, Schoepke N, Krause K, et al. Selected urticaria patients benefit from a referral to tertiary care centres – results of an expert survey. J Eur Acad Dermatol Venereol 2013;27(1):e8-16
Mullol J, Bousquet J, Bachert C, et al. Rupatadine in allergic rhinitis and chronic urticaria. Allergy 2008;63(Suppl 87):5-28
23.
Kavosh ER, Khan DA. Second-generation H1-antihistamines in chronic urticaria: an evidence-based review. Am J Clin Dermatol 2011;12(6):361-76
14.
401
Review 24.
25.
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 02/08/15 For personal use only.
26.
27.
28.
29.
Marrouche & Grattan
Guerra L, Vincenzi C, Marchesi E, et al. Loratadine and cetirizine in the treatment of chronic urticaria. J Eur Acad Dermatol Venereol 1994;3(2):148-52 Handa S, Dogra S, Kumar B. Comparative efficacy of cetirizine and fexofenadine in the treatment of chronic idiopathic urticaria. J Dermatolog Treat 2004;15(1):55-7 Garg G, Thami GP. Comparative efficacy of cetirizine and levocetirizine in chronic idiopathic urticaria. J Dermatolog Treat 2007;18(1):23-4
Staevska M, Popov TA, Kralimarkova T, et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to treat urticaria. J Allergy Clin Immunol 2010;125(3):676-82 Ferrer M, Sastre J, Ja´uregui I, et al. Effect of antihistamine up-dosing in chronic urticaria. J Investig Allergol Clin Immunol 2011;21(Suppl 3):34-9 A critical review of studies on updosing H1-antihistamines in chronic urticaria, highlighting the need for more robust evidence to support that practice.
30.
Weller K, Ziege C, Staubach P, et al. H1-antihistamine up-dosing in chronic spontaneous urticaria: patients’ perspective of effectiveness and side-effects: a retrospective survey study. PLoS One 2011;6(9):e23931
32.
33.
34.
Grob J, Auquier P, Dreyfus I, Ortonne J. How to prescribe antihistamines for chronic idiopathic urticaria: desloratadine daily vs PRN and quality of life. Allergy 2009;64(4): 605-12 Weller K, Ardelean E, Scholz E, et al. Can on demand non sedating antihistamines improve urticaria symptoms? A double-blind, randomized, single-dose study. Acta Derm Venereol 2013;93(2): 168-74 Erbagci Z. The leukotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria: a single-blind, placebo-controlled, crossover clinical study. J Allergy Clin Immunol 2002;110(3): 484-8 Sanada S, Tanaka T, Kameyoshi Y, Hide M. The effectiveness of montelukast for the treatment of anti-histamine-resistant chronic urticaria. Arch Dermatol Res 2005;297(3): 134-8
402
Wan KS. Efficacy of leukotriene receptor antagonist with an anti-H1 receptor antagonist for treatment of chronic idiopathic urticaria. J Dermatolog Treat 2009;20(4):194-7
An interesting study demonstrating the effectiveness of omalizumab in chronic spontaneous urticaria (CSU) patients with negative autoantibodies assays against either IgE or its high-affinity receptor, shedding light on new potential mechanisms involved in the pathophysiology of the disease.
47.
Casale TB, Bernstein IL, Busse WW, et al. Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis. J Allergy Clin Immunol 1997; 100(1):110-21
48.
MacGlashan D, Bochner BS, Adelman DC, et al. Down-regulation of FceRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997;158(3):1438-45
49.
MacGlashan D. Loss of receptors and IgE in vivo during treatment with anti-IgE antibody. J Allergy Clin Immunol 2004; 114(6):1472-4
50.
Noga O, Hanf G, Brachmann I, et al. Effect of omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma. J Allergy Clin Immunol 2006;117(6):1493-9
51.
Maurer M, Rose´n K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013;368(10):924-35
••
Magerl M, Staubach P, Altrichter S, et al. Effective treatment of therapy resistant chronic spontaneous urticaria with omalizumab. J Allergy Clin Immunol 2010; 126(3):665-6
First Phase III licensing study for omalizumab in the treatment of CSU to be reported.
52.
Groffik A, Mitzel-Kaoukhov H, Magerl M, et al. Omalizumab: an effective and safe treatment of therapy-resistant chronic spontaneous urticaria. Allergy 2011;66(2): 303-5
Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013;132(1):101-9
53.
Arkwright P. Anti-CD20 or anti-IgE therapy for severe chronic autoimmune urticaria. J Allergy Clin Immunol 2009; 123(2):510-11
54.
Chakravarty SD, Yee AF, Paget SA. Rituximab successfully treats refractory chronic autoimmune urticaria caused by IgE receptor autoantibodies. J Allergy Clin Immunol 2011;128(6):1354-5
55.
Mallipeddi R, Grattan CE. Lack of response of severe steroid-dependent chronic urticaria to rituximab. Clin Exp Dermatol 2007; 32(3):333-4
56.
Lenormand C, Lipsker D. Efficiency of interleukin-1 blockade in refractory delayed-pressure urticaria. Ann Intern Med 2012;157(8):599-600
Fedorowicz Z, van Zuuren EJ, Hu N. Histamine H2-receptor antagonists for urticaria. Cochrane Database Syst Rev 2012;3:CD008596
37.
Pacor ML, Di Lorenzo G, Corrocher R. Efficacy of leukotriene receptor antagonist in chronic urticaria. A double-blind, placebo-controlled comparison of treatment with montelukast and cetirizine in patients with chronic urticaria with intolerance to food additive and/or acetylsalicylic acid. Clin Exp Allergy 2011; 31(10):1607-14
38.
39.
EMA. Xolair summary of product characteristics. Available from: www.ema. europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/ 000606/WC500057298.pdf Spector SL, Tan RA. Effect of omalizumab on patients with chronic urticaria. Ann Allergy Asthma Immunol 2007;99(2):190-3
40.
Kaplan AP, Joseph K, Maykut RJ, et al. Treatment of chronic autoimmune urticaria with omalizumab. J Allergy Clin Immunol 2008;122(3):569-73
41.
Gober LM, Sterba PM, Eckman JA, Saini SS. Effect of Anti-IgE (omalizumab) in chronic idiopathic urticaria (CIU) patients. J Allergy Clin Immunol 2008; 121(2 Suppl 1):S147
42.
43.
44.
non-autoimmune urticaria. J Allergy Clin Immunol 2011;127(5):1300-2 •
36.
Potter PC, Kapp A, Maurer M, et al. Comparison of the efficacy of levocetirizine 5mg and desloratadine 5mg in chronic idiopathic urticaria patients. Allergy 2009; 64(4):596-604
•
31.
35.
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(3):567-73
45.
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(1):202-9
46.
Ferrer M, Gamboa P, Sanz M, et al. Omalizumab is effective in
Expert Rev. Clin. Immunol. 10(3), (2014)
Update & insights into treatment options for CSU
57.
58.
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 02/08/15 For personal use only.
59.
60.
61.
62.
•
63.
Krause K, Mahamed A, Weller K, et al. Efficacy and safety of canakinumab in urticarial vasculitis: an open-label study. J Allergy Clin Immunol 2013;132(3):751-4 Grattan CEH, Francis DM, Hide M, Greaves MW. Detection of circulating histamine releasing autoantibodies with functional properties of anti-IgE in chronic urticaria. Clin Exp Allergy 1991;21(6): 695-704 Hide M, Francis DM, Grattan CH, Greaves MW. Autoantibodies against the high affinity IgE receptor as a cause for histamine release in chronic urticaria. N Eng J Med 1993;328(22):1599-604 Sabroe RA, Fiebiger E, Francis DM, et al. Classification of anti-FceRI and anti-IgE autoantibodies in chronic idiopathic urticaria and correlation with disease severity. J Allergy Clin Immunol 2002; 110(3):492-9 Grattan CEH, O’Donnell BF, Francis DM, et al. Randomized double-blind study of cyclosporin in chronic ‘idiopathic’ urticaria. Br J Dermatol 2000;143(2):365-72 Iqbal K, Bhargava K, Skov PS, et al. A positive serum basophil histamine release assay is a marker for ciclosporinresponsiveness in patients with chronic spontaneous urticaria. Clin Transl Allergy 2012;2(1):19 Interesting study showing that the basophil histamine release assay may be a useful predictive biomarker for a good response to ciclosporin in patients with H1-antihistamine-unresponsive CSU. Cirillo R, Triggiani M, Siri L, et al. Cyclosporin A rapidly inhibits mediator release from human basophils presumably by interacting with cyclophilin. J Immunol 1990;144(10):3891-7
64.
Stellato C, de Paulis A, Ciccarelli A, et al. Anti-inflammatory effect of cyclosporin A on human skin mast cells. J Invest Dermatol 1992;98(5):800-4
65.
Casolaro V, Spadaro G, Patella V, Marone G. In vivo characterization of the anti-inflammatory effect of cyclosporin A on human basophils. J Immunol 1993;151(10): 5563-73
66.
Marsland AM, Soundararajan S, Joseph K, Kaplan AP. Effects of calcineurin inhibitors on an in vitro assay for chronic urticaria. Clin Exp Allergy 2005;35(5):554-9
67.
mast cell-leukocyte cytokine cascades. Multiple mechanisms of inhibition of IgEand mast cell-dependent cutaneous inflammation in the mouse. J Immunol 1995;154(3):1391-8
Review
leukotrienes in chronic urticaria. Int Arch Allergy Immunol 2002;129(3):254-60 79.
Leonard R, Hardy J, Van Tienhoven G, et al. Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 2001;19(21):4150-9
68.
Chapman I, Mazzoni L. Mechanisms of inhibition by cyclosporin A on pulmonary leukocyte accumulation. Trends Pharmacol Sci 1994;15(4):99-101
80.
69.
Fradin MS, Ellis CN, Goldfarb MT, Voorhees JJ. Oral cyclosporine for severe chronic idiopathic urticaria and angioedema. J Am Acad Dermatol 1991;25(6 Pt 1): 1065-7
Rahman M, Ahmed BN, Faiz MA, et al. Phase IV. Trial of Miltefosine in Adults and Children for Treatment of Visceral Leishmaniasis (Kala- Azar) in Bangladesh. Am J Trop Med Hyg 2011;85(1):66-9
81.
70.
Barlow RJ, Black AK, Greaves MW. Treatment of severe chronic urticaria with cyclosporine-A. Eur J Dermatol 1993;3(4): 273-5
Barratt G, Saint-Pierre-Chazalet M, Loiseau PM. Cellular transport and lipid interactions of miltefosine. Curr Drug Metab 2009;10(3):247-55
82.
71.
Toubi E, Blant A, Kessel A, Golan TD. Low-dose cyclosporin A in the treatment of severe chronic urticaria. Allergy 1997;52(3): 312-16
Silveira ESAM, Mazucato VM, Jamur MC, Oliver C. Lipid rafts in mast cell biology. J Lipids 2011;2011:752906
83.
Weller K, Artuc M, Jennings G, et al. Miltefosine inhibits human mast cell activation and mediator release both in vitro and in vivo. J Invest Dermatol 2009;129(2): 496-8
84.
Hartmann K, Siebenhaar F, Belloni B, et al. Effects of topical treatment with the raft modulator miltefosine and clobetasol in cutaneous mastocytosis: a randomized, double-blind, placebo-controlled trial. Br J Dermatol 2010;162(1):185-90
85.
Magerl M, Rother M, Bieber T, et al. Randomized, double-blind, placebo controlled study of safety and efficacy of miltefosine in antihistamine resistant chronic spontaneous urticaria. J Eur Acad Dermatol Venereol 2013;27(3):e363-9
86.
Ying S, Kikuchi Y, Meng Q, et al. TH1/ TH2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria: comparison with the allergen-induced late-phase cutaneous reaction. J Allergy Clin Immunol 2002;109(4):694-700
87.
Puccetti A, Bason C, Simeoni S, et al. In chronic idiopathic urticaria autoantibodies against Fc epsilonRII/CD23 induce histamine via eosinophil activation. Clin Exp Allergy 2005;35(12):1599-607
88.
Rabelo-Filardi R, Daltro-Oliveira R, Campos RA. Parameters associated with chronic spontaneous urticaria duration and severity: a systematic review. Int Arch Allergy Immunol 2013;161(3):197-204
72.
Vena GA, Cassano N, Colombo D, et al. Neo-I-30 study Group. Cyclosporin A in chronic idiopathic urticaria: a double blind, randomized, placebo-controlled trial. J Am Acad Dermatol 2006;55(4):705-9
73.
Serhat Inaloz H, Ozturk S, Akcali C, et al. Low-dose and short-term cyclosporine treatment in patients with chronic urticaria: a clinical and immunological evaluation. J Dermatol 2008;35(5):276-82
74.
Kessel A, Toubi E. Cyclosporine-A in severe chronic urticaria: the option for long-term therapy. Allergy 2010;65(11):1478-82
75.
Perez A, Woods A, Grattan CE. Methotrexate: a useful steroid-sparing agent in recalcitrant chronic urticaria. Br J Dermatol 2010;162(1):191-4
76.
Shahar E, Bergman R, Guttman-Yassky E, Pollack S. Treatment of severe chronic idiopathic urticaria with oral mycophenolate mofetil in patients not responding to antihistamines and/or corticosteroids. Int J Dermatol 2006;45(10):1224-7
77.
Church MK, Maurer M. H. 1)antihistamines and urticaria: how can we predict the best drug for our patient? Clin Exp Allergy 2012;42(10):1423-9
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Important review article exploring models of predicting effectiveness of H1-antihistamines in clinical practice.
78.
Ferrer M, Luquin E, Sanchez-Ibarrola A, et al. Secretion of cytokines, histamine and
Wershil BK, Furuta GT, Lavigne JA, et al. Dexamethasone or cyclosporin A suppresses
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Update and insights into treatment options for chronic spontaneous urticaria Expert Rev. Clin. Immunol. 10(3), 397–403 (2014)
Nadine Marrouche* and Clive Grattan Department of Dermatology, Norfolk and Norwich University Hospital, Colney Lane, Norwich, NR4 7UY, UK *Author for correspondence: Tel.: +44 016 0328 8265 Fax: +44 016 0328 8601 [email protected]
Chronic spontaneous urticaria (CSU) is defined as itchy weals, angio-oedema, or both, arising spontaneously without external physical stimuli. Symptoms of the disease continue to develop for more than 6 weeks. It carries a high socioeconomic burden with considerable health care costs. Second generation H1-antihistamines are the mainstay of urticaria treatment and are the only licensed option. However, many patients are resistant to H1-antihistamine therapy. Omalizumab has proven to be an effective therapeutic option in patients with recalcitrant chronic urticaria. Ciclosporin appears to be more beneficial in patients with functional histamine releasing autoantibodies as a cause of their disease. This review article will highlight the major therapeutic options available today for the management of CSU knowing that good quality evidence for efficacy of many agents is scarce except for H1-antihistamines and omalizumab. KEYWORDS: autoimmune urticaria • chronic spontaneous urticaria • ciclosporin • H1-antihistamines • miltefosine • omalizumab • treatment
Chronic spontaneous urticaria (CSU) is defined as itchy weals, angio-edema or both, arising spontaneously without external physical stimuli. Symptoms continue to develop for more than 6 weeks [1]. The disease is characterized by unpredictable attacks often causing decreased social functioning and work productivity and significant sleep disruption [2,3]. It has a considerable impact on the quality of life which is similar to that seen in patients awaiting a coronary artery bypass [4,5]. With a prevalence of 1% in the general population, CSU clearly carries a high socioeconomic burden [6] with considerable healthcare costs [7]. This is compounded by the duration of the disease that is more than 1 year in up to 50% of patients [8].The guidelines for the management of urticaria propose a twofold approach starting with the identification and elimination of underlying causes and/or triggers like drugs [9]. In CSU, studies have demonstrated a clear association with autoimmune disease in up to 45% of patients [10,11] and, to a much lesser extent, non-organ-specific autoantibodies [12]. However this, along with routine laboratory testing, has no beneficial implications on patients’ management as yet [13]. As a second line of approach, the guidelines recommend informahealthcare.com
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treatment targeted at symptom relief [9]. Nonsedating (second-generation) H1-antihistamines are clearly the mainstay of urticaria treatment and are the only licensed option. More than 50% of patients do not respond to antihistamines at regular doses [6], so the guidelines recommend updosing the H1-antihistamine first then adding leukotriene-antagonists or H2-antihistamines or changing the H1-antihistamine if symptoms persist. However, many patients remain symptomatic despite the above and require alternative therapies. The updated international guidelines recommend adding ciclosporin or omalizumab as third-line treatment options. In addition, a short course of systemic steroids is suggested for exacerbations of CSU [1]. The latter patients appear to benefit from referral to tertiary care centers [14]. Antihistamines H1-antihistamines
It is widely recognized that mast cells play a pivotal role in the pathophysiology of urticaria. The mediators released from these cells, mainly histamine, result in the prototypical symptoms that ensue. The classical weal and flare is caused by vasodilatation and extravasation of fluids leading to tissue edema, whereas
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activation of sensory nerves results in pruritus [15,16]. As such, antihistamines remain the mainstay of urticaria treatment. H1-antihistamines are inverse agonists of the H1-receptor, binding and stabilizing it in the inactive conformation [17]. Antihistamines have been used in the treatment of urticaria for over half a century now. The longest clinical experience is with the firstgeneration antihistamines, which are still widely used for the treatment of all types of urticaria. However, current guidelines recommend against their use in the routine management of chronic urticaria [9]. Indeed, first-generation antihistamines have demonstrated a wide array of potentially dangerous adverse effects ranging from daytime somnolence and drowsiness to impaired concentration and decreased memory and learning ability [18]. Most of these adverse effects are thought to be caused by the effect of first-generation H1-antihistamines on the sleepwake cycle. It has been demonstrated that these agents increase the latency to the onset of rapid eye movement sleep and reduce its duration at night with hangover effects on the next morning [19,20]. Second-generation H1-antihistamines, compared with their first-generation counterparts, appear to be largely free from these side effects mainly because of better peripheral H1-receptor selectivity and decreased ability to cross the blood– brain barrier [21]. In addition to their role as histamine inverse agonists, a number of second-generation antihistamines have demonstrated some anti-inflammatory and immunomodulatory properties, which may be important in addressing the late-phase allergic reaction of urticaria [17,22]. Among second-generation H1-antihistamines, fexofenadine has been studied the most but there are limited data comparing the various agents against one another in the treatment of CSU [23]. Comparative studies of cetirizine in the treatment of chronic urticaria show comparable clinical efficacy with loratadine and levocetirizine with one study showing a therapeutic advantage over fexofenadine [24–26]. The efficacy of levocetirizine was compared with that of loratadine in two randomized controlled trials. Both showed superiority of levocetirizine in treatment of CSU [27,28]. Newer secondgeneration antihistamines, like rupatadine, are proving to be at least as effective as older molecules [22]. The range of secondgeneration antihistamines is wider than discussed above, but the aim of this review is to cover concepts pertinent to antihistamines in general, using some specific molecules as examples. Overall, the number and quality of the comparative studies are insufficient to make strong recommendations supporting one antihistamine over another. Many patients with CSU do not benefit from standard dosing of H1-antihistamines. Recent guidelines for management of urticaria have suggested using second-generation H1-antihistamines in doses up to fourfold higher than recommended [9]. These recommendations are largely based on expert opinion, but evidence to endorse this practice is increasing [28]. However, the results of updosing studies of different second-generation H1-antihistamines are sometimes inconsistent and the amount and quality of the data are not adequate to perform a meta-analysis. Despite the lack of good scientific evidence, higher doses of second-generation H1-antihistamines are still a safer option to other alternative 398
treatments in patients refractory to standard doses H1-antihistamines and are generally favored in routine practice [29]. A recent study based on a patients’ survey has shown that up to 75% of CSU patients have better symptomatic relief at updosing the H1-antihistamines with no reported increase in frequency of side effects [30]. Alternatively, it may be appropriate to consider alternative second-generation H1-antihistamines in case the patient fails to respond to one specific agent. Another interesting clinical question that remains to be answered with good quality evidence is whether on-demand rather than continuous treatment with H1-antihistamines is an efficacious modality of treatment. The rationale for such a therapeutic approach stems from the nature of CSU, which is often characterized by a fluctuating pattern changing significantly from day to day. Two recent studies on desloratadine have tried to answer this question and so far it appears that the on-demand approach is of very little benefit [31,32]. H2-antihistamines & leukotriene receptor antagonists
H2 receptor antagonists and leukotriene antagonists are often used as add-on therapies to H1-antihistamines in the treatment of CSU. Their efficacy remains uncertain as well as designed controlled studies in combination with currently available second-generation H1-antihistamines have not been done [33–36]. Among these agents, montelukast appears to benefit a specific subpopulation of patients with CSU and intolerance to food additives and/or salicylic acid [37]. Omalizumab
The introduction of omalizumab to the management of CSU is an example of the successful translation of molecular biological technology to medical practice. Omalizumab is a recombinant humanized anti-IgE antibody that binds to the C3 domain of the IgE heavy chain where IgE binds to its high-affinity receptor FceRI. It has been largely studied in the field of asthma and is currently approved for the treatment of both adult and pediatric (children; >6-year-old) patients with moderate-to-severe asthma [38]. Omalizumab has also proven to be an effective therapeutic option in patients with recalcitrant chronic urticaria. The original evidence stemmed from several case series/small trials [39–43]. The first study that investigated optimal dosing of omalizumab in chronic urticaria was a Phase II trial conducted by Saini et al. in 2011. The group demonstrated that a single fixed dose of 300 or 600 mg of the drug (unlike in asthma where the dose is calculated according to weight) is a rapid and effective therapeutic option in patients who are symptomatic despite treatment with H1-antihistamines [44]. Although many studies inferred that omalizumab is beneficial in CSU with a likely autoimmune etiology [40,45], other studies have demonstrated the efficacy of omalizumab in CSU irrespective of autoimmune status [44]. In fact, a recent prospective study showed that omalizumab is an effective treatment for CSU patients with negative autoantibodies assays against either IgE or its high-affinity receptor that are resistant to antihistamines [46]. These findings suggest that omalizumab is Expert Rev. Clin. Immunol. 10(3), (2014)
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likely to mediate its therapeutic effects in urticaria through a multitude of mechanisms. Omalizumab results in a significant and rapid reduction in serum levels of free IgE [47]. This may lead to non-specific desensitization of mast cells in the skin and thus explain the rapid therapeutic response seen in clinical practice. In addition, omalizumab has been shown to downregulate not only IgE receptors on effector cells, including mast cells and basophils, but also dendritic cells [48,49]. The latter effect suggests that blocking IgE can inhibit more chronic aspects of allergic inflammation involving T-cell activation. Moreover, omalizumab is thought to mediate some of its anti-inflammatory action by inducing apoptosis of eosinophils [50]. Clearly though, the precise mechanisms by which omalizumab acts require further investigation. In the meantime, licensing studies for omalizumab in the treatment of CSU are ongoing. The results of the first of three Phase III clinical trials have been reported. In this trial, it was shown that during the initial 12 weeks of the study, omalizumab at doses of 150 and 300 mg significantly diminished the symptoms and signs of CSU in patients who remained symptomatic despite the use of approved doses of H1-antihistamines. Side effects were more likely to be reported in patients treated with the highest dose [51]. Similar beneficial results were more recently reported in patients treated with 300 mg/month or placebo for chronic spontaneous/idiopathic urticaria not responding to standard combination therapy [52]. There are several important questions regarding the use of omalizumab for the treatment of CSU that remain to be answered. Well-designed studies are needed to determine the patient profile most suitable for omalizumab treatment, the optimal duration of therapy and rates of long-term remission. In addition, potential long-term side effects of omalizumab in the treatment of CSU require further investigation. Other biologics
Omalizumab is by far the most studied biologic agent in urticaria to date. However, a few other biologics have been tested in individual case reports. A rapid resolution of symptoms was reported in a case of recalcitrant chronic autoimmune urticaria treated with anti-CD20 monoclonal antibody therapy (rituximab) in two reports [53,54] but not another [55]. The response is thought to be related to targeting IgG autoantibodies producing B lymphocytes, which are functional and pathologic in autoimmune urticaria. Other biologics, like anti-TNF-a and anti-IL-1 agents, have been reported to treat other forms of urticaria [56,57]. Ciclosporin
Ciclosporin has immunomodulatory properties. It is known to interfere with the activity of T lymphocytes including downregulation of T-cell-dependent antibody formation. This is of relevance in CSU as functional factors including pathogenic histamine-releasing autoantibodies have been identified in the sera of up to 40% of patients [58–60]. Indeed, treatment of CSU patients with ciclosporin was shown to reduce histaminereleasing autoantibodies and autologous serum skin test response rates [61]. In the same study, it was demonstrated that patients with a positive basophil histamine release assay informahealthcare.com
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(BHRA) were more likely to respond to ciclosporin than those with a negative BHRA. The latter finding was recently confirmed in a larger number of patients with chronic urticaria [62]. The BHRA thus appears to be a useful predictive biomarker for a good response to ciclosporin in CSU patients who prove to be resistant to H1-antihistamines therapy. However, the effect of ciclosporin on the reduction of functional autoantibodies does not explain the early therapeutic response to ciclosporin seen in some patients. Other factors are likely playing a role such as inhibition of de novo synthesis of prostaglandins and stabilization of histamine release, which have been demonstrated both in vitro and in vivo on human basophils and skin mast cells pretreated with ciclosporin and stimulated with anti-IgE [63–66]. In addition, ciclosporin appears to have other anti-inflammatory effects. Experiments in mice suggest that ciclosporin can suppress neutrophil infiltration induced by mast cell degranulation by inhibiting IgE-dependent TNF-a secretion from skin mast cells and reducing responsiveness of target cells to TNF-a [67]. In addition, ciclosporin also inhibits the release of cytokines from eosinophils, which often infiltrate urticaria lesions [68]. From a clinical perspective, ciclosporin has proved its efficacy in the treatment of CSU in more than 20 original studies over the past two decades. Fradin et al. were the first to report on the successful use of ciclosporin in three patients suffering from severe chronic urticaria. However, the therapy was discontinued in all patients as the high dose administered (6 mg/kg) caused major adverse effects [69]. Subsequently, ciclosporin was used in many trials at lower doses (2–5 mg/kg) with sustained benefit but improved tolerability, especially at the lower doses [61,70–73]. Most of these studies reported comparable response rates and used ciclosporin for 1–3 months. In many of them however, urticaria relapsed upon drug discontinuation. A more recent study reported on the efficacy and safety of long-term ciclosporin therapy. Treatment was started at 3 mg/kg of ciclosporin for 3 months in all patients, but a small group eventually continued at a very low dose (1–1.5 mg/kg) for longer periods between 5 and 10 years. In this group, treatment continued on being effective but more importantly, no increased incidence of side effects was noted [74]. Overall, based on current evidence, a 3-month ciclosporin therapy at a starting dose of 3–4 mg/kg daily (with dosing adjusted according to clinical response and adverse events) is likely to produce a good response and lowest relapse rates. However, the optimal dose and duration of treatment still need to be established. Other immunosuppressive agents
Patients with recalcitrant CSU, who fail to respond to higher doses of antihistamines, often require immunosuppressive therapy. Ciclosporin has been the most studied among diseasesuppressive agents. Methotrexate has been investigated in a case series of steroid-dependent chronic urticaria where patients failed to respond to antihistamines and other second-line agents, except prednisolone. It proved to be well tolerated and beneficial. It is thought to act as a non-specific anti399
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inflammatory and immunosuppressive agent as the clinical response did not correlate with the presence of functional autoantibodies [75]. Mycophenolate mofetil is another effective therapeutic option in patients who poorly respond to conventional treatments [76]. Other potentially useful agents include dapsone, colchicine, hydroxychloroquine and sulfasalazine; however, most of these drugs have been reported to be beneficial in small open series or controlled clinical studies, but wellconducted and large studies are needed to determine the value of the above agents in the treatment of CSU. Unmet needs
The management of CSU remains largely unsatisfactory in the absence of a cure for the disease. Most current treatment is targeted at symptoms and H1-antihistamines are currently the only licensed therapy for CSU. However, it remains difficult to predict which antihistamine is best for a particular patient. As such, research should focus not only on comparative studies among different antihistamines, but also look into predictive models to assess the efficacy of these agents and potentially new similar drugs [77]. Although preformed histamine released from mast cells is believed to be the major mediator of urticaria symptoms, other molecules, including cytokines and chemokines, also seem to play a pathological role [78]. This might be one of the reasons why antihistamines are not effective in up to a half of CSU patients. The pharmaceutical industry needs to keep developing agents based on better understanding of mechanisms involved in the disease. Miltefosine, a lipid raft modulator, is a good illustration of this concept. Miltefosine has been approved for the treatment of cutaneous metastases in breast cancer and visceral leishmaniasis [79,80]. Miltefosine interacts with cell membrane lipid rafts, interfering with many cell membrane functions like cellular transport [81,82]. In addition, miltefosine has been shown to inhibit mast cell activation and mediator release both in vitro and in vivo [83]. Topical application of miltefosine has demonstrated promising results in mast cell-mediated conditions like cutaneous mastocytosis [84]. More recently, the efficacy and safety of miltefosine were explored in the treatment of CSU patients who did not respond to standard-dose antihistamines. The drug resulted in a significant decrease in weal numbers. The authors hypothesized that miltefosine, as a lipid raft modulator, inhibits mast cell degranulation and mediator release, which are the most downstream events of the pathogenesis of CSU [85]. It is widely accepted that up to 40% of patients with CSU have an autoimmune basis for their disease in which functional IgG antibodies play a pathological role. This is the rationale for the use of immunosuppressive agents in the treatment of this condition. However, most of these agents act in non-specific ways in controlling CSU symptoms. There is a need for more targeted therapy in this regard, as it is well known that the mast cell is not the sole cellular player in urticaria. Indeed, skin biopsies taken from CSU lesions reveal infiltrations by numerous inflammatory cells including neutrophils, eosinophils, basophils and undifferentiated T cells [86]. These cells are not likely to be innocent bystanders. 400
For instance, eosinophils have been shown to play a crucial role in perpetuating CSU by releasing major basic protein [87]. Moreover, there is a need for the determination of both clinical and laboratory parameters that can serve as prognostic factors for CSU. It was shown in a recent systematic review that plasma levels of prothrombin fragment 1 + 2, D-dimer and C-reactive protein may predict CSU severity [88]. Conclusion
The physical and mental impairment caused by CSU underscores the need for rapid and effective therapy. Although management of urticaria is well covered in consensus documents, management decisions should be tailored to each patient based not only on proper risk/benefit assessment, but also the patient’s preferences. Despite major advancements made in understanding the pathogenesis of CSU, currently available treatment options remain unsatisfactory for some patients. The need for new pharmacotherapeutic options remains. Expert commentary
The presentation of CSU may range from relatively mild to very severe for different individuals and during different periods of the disease course. Fortunately, H1-antihistamines may be highly effective for the itch of urticaria and help to suppress some of the visible manifestations (weals, redness and angioedema) while the disease is active, but do not influence the course of the illness. In other words, they may relieve symptoms but are not disease-modifying. There is no certainty that any of the currently available treatments for CSU turn off the illness, although there is some evidence from studies of ciclosporin that immunomodulatory drugs may have this effect for some patients with functional histamine-releasing autoantibodies as a cause of their disease. Recent studies of anti-IgE (omalizumab) have shown that it may work even when other treatments have failed but the reasons for this are still uncertain. The optimal dose and treatment duration of omalizumab still need defining for individual patients and its relatively high cost is limiting its use in many countries. There are currently no predictive biomarkers for response, but there is a likelihood that these will emerge with experience and careful study of clinical and investigational markers. Five-year view
The next 5 years should see the emergence of more focused individualized treatment protocols based on better understanding of the cellular and biochemical events that occur from onset through to resolution of CSU and the clinical behavior of the illness. Understanding susceptibility genes and environmental triggers should help to predict onset and relapse of symptoms. As more mediator and cellular-specific treatments emerge, it is likely that the current concept of an endogenous mast cell activation process causing primarily histamine-driven symptomatology will become more complex and the range of opportunities for targeted disease suppression will increase to the benefit of patients. Expert Rev. Clin. Immunol. 10(3), (2014)
Update & insights into treatment options for CSU
Financial & competing interests disclosure
C Grattan is on the advisory bodies for Novartis, GSK and CSL Behring. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial
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conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Chronic spontaneous urticaria is defined as itchy weals, angioedema or both, arising spontaneously without external physical stimuli and lasting for more than 6 weeks.
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• It is a common disease that can be debilitating and carries a high socioeconomic burden. • Most of the current treatment options are targeted at symptoms and are not disease-modifying. • Second-generation H1-antihistamines are the mainstay of urticaria treatment and are the only licensed option but are not effective for all patients. • Omalizumab has proven to be an effective therapeutic option in patients with recalcitrant chronic urticaria. • Ciclosporin appears to be more beneficial in patients with functional histamine-releasing autoantibodies as a cause of their disease. • Future research should focus on better understanding of the cellular and biochemical events involved in the pathophysiology of the disease and development of drugs targeting disease suppression.
References
7.
Papers of special note have been highlighted as: • of interest •• of considerable interest 1.
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2.
3.
4.
5.
6.
Maurer M, Magerl M, Metz M, Zuberbier T. Revisions to the international guidelines on the diagnosis and therapy of chronic urticaria. J Dtsch Dermatol Ges 2013;11(10):971-8 An important article summarizing the revisions to the international guidelines on the diagnosis and treatment of chronic urticaria, which were discussed at the 4th International Consensus Meeting (URTICARIA 2012). Baiardini I, Giardini A, Pasquali M, et al. Quality of life and patients’ satisfaction in chronic urticaria and respiratory allergy. Allergy 2003;58(7):621-3 Maurer M, Ortonne JP, Zuberbier T. Chronic urticaria: a patient survey on quality-of-life, treatment usage and doctor-patient relation. Allergy 2009;64(4): 581-8 O’Donnell B, Lawlor F, Simpson J, et al. The impact of chronic urticaria on the quality of life. Br J Dermatol 1997;136(2): 197-201 Grob J, Revuz J, Ortonne J, et al. Comparative study of the impact of chronic urticaria, psoriasis and atopic dermatitis on the quality of life. Br J Dermatol 2005; 152(2):289-95 Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy 2011;66(3):317-30
informahealthcare.com
8.
9.
10.
Delong L, Culler S, Saini S, et al. Annual direct and indirect health care costs of chronic idiopathic urticaria: a cost analysis of 50 nonimmunosuppressed patients. Arch Dermatol 2008;144(1):35-9
15.
Maurer M, Metz M, Magerl M, et al. Autoreactive urticaria and autoimmune urticaria. Hautarzt 2004;55(4):350-6
16.
Kozel MM, Mekkes JR, Bossuyt PM, Bos JD. Natural course of physical and chronic urticaria and angioedema in 220 patients. J Am Acad Dermatol 2001; 45(3):378-91
Hakim-Rad K, Metz M, Maurer M. Mast cells: makers and breakers of allergic inflammation. Curr Opin Allergy Clin Immunol 2009;9(5):427-30
17.
Zuberbier T, Asero R, Bindslev-Jensen C, et al. EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy 2009;64(10):1427-43
Leurs R, Church MK, Taglialatela M. H1-antihistamines: inverse agonism, antiinflammatory actions and cardiac effects. Clin Exp Allergy 2002;32(4):489-98
18.
Leznoff A, Josse R, Denburg J. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol 1983;119(8):636-40
Church MK, Maurer M, Simons FE, et al. Risk of first-generation H(1)-antihistamines: a GA(2)LEN position paper. Allergy 2010; 65(4):459-66
19.
Boyle J, Eriksson M, Stanley N, et al. Allergy medication in Japanese volunteers: treatment effect of single doses on nocturnal sleep architecture and next day residual effects. Curr Med Res Opin 2006;22(7): 1343-51
20.
Rojas-Zamorano JA, Esqueda-Leon E, Jimenez-Anguiano A, et al. The H1 histamine receptor blocker, chlorpheniramine, completely prevents the increase in REM sleep induced by immobilization stress in rats. Pharmacol Biochem Behav 2009;91(3):291-4
11.
Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy 2009; 39(6):777-87
12.
Confino-Cohen R, Chodick G, Shalev V, et al. Chronic urticaria and autoimmunity: associations found in a large population study. J Allergy Clin Immunol 2012;129(5): 1307-13
13.
Tarbox JA, Gutta RC, Radojicic C, Lang DM. Utility of routine laboratory testing in management of chronic urticaria/ angioedema. Ann Allergy Asthma Immunol 2011;107(3):239-43
21.
Simons FE. Advances in H1-antihistamines. N Engl J Med 2004;351(21):2203-17
22.
Weller K, Schoepke N, Krause K, et al. Selected urticaria patients benefit from a referral to tertiary care centres – results of an expert survey. J Eur Acad Dermatol Venereol 2013;27(1):e8-16
Mullol J, Bousquet J, Bachert C, et al. Rupatadine in allergic rhinitis and chronic urticaria. Allergy 2008;63(Suppl 87):5-28
23.
Kavosh ER, Khan DA. Second-generation H1-antihistamines in chronic urticaria: an evidence-based review. Am J Clin Dermatol 2011;12(6):361-76
14.
401
Review 24.
25.
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 02/08/15 For personal use only.
26.
27.
28.
29.
Marrouche & Grattan
Guerra L, Vincenzi C, Marchesi E, et al. Loratadine and cetirizine in the treatment of chronic urticaria. J Eur Acad Dermatol Venereol 1994;3(2):148-52 Handa S, Dogra S, Kumar B. Comparative efficacy of cetirizine and fexofenadine in the treatment of chronic idiopathic urticaria. J Dermatolog Treat 2004;15(1):55-7 Garg G, Thami GP. Comparative efficacy of cetirizine and levocetirizine in chronic idiopathic urticaria. J Dermatolog Treat 2007;18(1):23-4
Staevska M, Popov TA, Kralimarkova T, et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to treat urticaria. J Allergy Clin Immunol 2010;125(3):676-82 Ferrer M, Sastre J, Ja´uregui I, et al. Effect of antihistamine up-dosing in chronic urticaria. J Investig Allergol Clin Immunol 2011;21(Suppl 3):34-9 A critical review of studies on updosing H1-antihistamines in chronic urticaria, highlighting the need for more robust evidence to support that practice.
30.
Weller K, Ziege C, Staubach P, et al. H1-antihistamine up-dosing in chronic spontaneous urticaria: patients’ perspective of effectiveness and side-effects: a retrospective survey study. PLoS One 2011;6(9):e23931
32.
33.
34.
Grob J, Auquier P, Dreyfus I, Ortonne J. How to prescribe antihistamines for chronic idiopathic urticaria: desloratadine daily vs PRN and quality of life. Allergy 2009;64(4): 605-12 Weller K, Ardelean E, Scholz E, et al. Can on demand non sedating antihistamines improve urticaria symptoms? A double-blind, randomized, single-dose study. Acta Derm Venereol 2013;93(2): 168-74 Erbagci Z. The leukotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria: a single-blind, placebo-controlled, crossover clinical study. J Allergy Clin Immunol 2002;110(3): 484-8 Sanada S, Tanaka T, Kameyoshi Y, Hide M. The effectiveness of montelukast for the treatment of anti-histamine-resistant chronic urticaria. Arch Dermatol Res 2005;297(3): 134-8
402
Wan KS. Efficacy of leukotriene receptor antagonist with an anti-H1 receptor antagonist for treatment of chronic idiopathic urticaria. J Dermatolog Treat 2009;20(4):194-7
An interesting study demonstrating the effectiveness of omalizumab in chronic spontaneous urticaria (CSU) patients with negative autoantibodies assays against either IgE or its high-affinity receptor, shedding light on new potential mechanisms involved in the pathophysiology of the disease.
47.
Casale TB, Bernstein IL, Busse WW, et al. Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis. J Allergy Clin Immunol 1997; 100(1):110-21
48.
MacGlashan D, Bochner BS, Adelman DC, et al. Down-regulation of FceRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997;158(3):1438-45
49.
MacGlashan D. Loss of receptors and IgE in vivo during treatment with anti-IgE antibody. J Allergy Clin Immunol 2004; 114(6):1472-4
50.
Noga O, Hanf G, Brachmann I, et al. Effect of omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma. J Allergy Clin Immunol 2006;117(6):1493-9
51.
Maurer M, Rose´n K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013;368(10):924-35
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Magerl M, Staubach P, Altrichter S, et al. Effective treatment of therapy resistant chronic spontaneous urticaria with omalizumab. J Allergy Clin Immunol 2010; 126(3):665-6
First Phase III licensing study for omalizumab in the treatment of CSU to be reported.
52.
Groffik A, Mitzel-Kaoukhov H, Magerl M, et al. Omalizumab: an effective and safe treatment of therapy-resistant chronic spontaneous urticaria. Allergy 2011;66(2): 303-5
Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013;132(1):101-9
53.
Arkwright P. Anti-CD20 or anti-IgE therapy for severe chronic autoimmune urticaria. J Allergy Clin Immunol 2009; 123(2):510-11
54.
Chakravarty SD, Yee AF, Paget SA. Rituximab successfully treats refractory chronic autoimmune urticaria caused by IgE receptor autoantibodies. J Allergy Clin Immunol 2011;128(6):1354-5
55.
Mallipeddi R, Grattan CE. Lack of response of severe steroid-dependent chronic urticaria to rituximab. Clin Exp Dermatol 2007; 32(3):333-4
56.
Lenormand C, Lipsker D. Efficiency of interleukin-1 blockade in refractory delayed-pressure urticaria. Ann Intern Med 2012;157(8):599-600
Fedorowicz Z, van Zuuren EJ, Hu N. Histamine H2-receptor antagonists for urticaria. Cochrane Database Syst Rev 2012;3:CD008596
37.
Pacor ML, Di Lorenzo G, Corrocher R. Efficacy of leukotriene receptor antagonist in chronic urticaria. A double-blind, placebo-controlled comparison of treatment with montelukast and cetirizine in patients with chronic urticaria with intolerance to food additive and/or acetylsalicylic acid. Clin Exp Allergy 2011; 31(10):1607-14
38.
39.
EMA. Xolair summary of product characteristics. Available from: www.ema. europa.eu/docs/en_GB/document_library/ EPAR_-_Product_Information/human/ 000606/WC500057298.pdf Spector SL, Tan RA. Effect of omalizumab on patients with chronic urticaria. Ann Allergy Asthma Immunol 2007;99(2):190-3
40.
Kaplan AP, Joseph K, Maykut RJ, et al. Treatment of chronic autoimmune urticaria with omalizumab. J Allergy Clin Immunol 2008;122(3):569-73
41.
Gober LM, Sterba PM, Eckman JA, Saini SS. Effect of Anti-IgE (omalizumab) in chronic idiopathic urticaria (CIU) patients. J Allergy Clin Immunol 2008; 121(2 Suppl 1):S147
42.
43.
44.
non-autoimmune urticaria. J Allergy Clin Immunol 2011;127(5):1300-2 •
36.
Potter PC, Kapp A, Maurer M, et al. Comparison of the efficacy of levocetirizine 5mg and desloratadine 5mg in chronic idiopathic urticaria patients. Allergy 2009; 64(4):596-604
•
31.
35.
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(3):567-73
45.
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(1):202-9
46.
Ferrer M, Gamboa P, Sanz M, et al. Omalizumab is effective in
Expert Rev. Clin. Immunol. 10(3), (2014)
Update & insights into treatment options for CSU
57.
58.
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 02/08/15 For personal use only.
59.
60.
61.
62.
•
63.
Krause K, Mahamed A, Weller K, et al. Efficacy and safety of canakinumab in urticarial vasculitis: an open-label study. J Allergy Clin Immunol 2013;132(3):751-4 Grattan CEH, Francis DM, Hide M, Greaves MW. Detection of circulating histamine releasing autoantibodies with functional properties of anti-IgE in chronic urticaria. Clin Exp Allergy 1991;21(6): 695-704 Hide M, Francis DM, Grattan CH, Greaves MW. Autoantibodies against the high affinity IgE receptor as a cause for histamine release in chronic urticaria. N Eng J Med 1993;328(22):1599-604 Sabroe RA, Fiebiger E, Francis DM, et al. Classification of anti-FceRI and anti-IgE autoantibodies in chronic idiopathic urticaria and correlation with disease severity. J Allergy Clin Immunol 2002; 110(3):492-9 Grattan CEH, O’Donnell BF, Francis DM, et al. Randomized double-blind study of cyclosporin in chronic ‘idiopathic’ urticaria. Br J Dermatol 2000;143(2):365-72 Iqbal K, Bhargava K, Skov PS, et al. A positive serum basophil histamine release assay is a marker for ciclosporinresponsiveness in patients with chronic spontaneous urticaria. Clin Transl Allergy 2012;2(1):19 Interesting study showing that the basophil histamine release assay may be a useful predictive biomarker for a good response to ciclosporin in patients with H1-antihistamine-unresponsive CSU. Cirillo R, Triggiani M, Siri L, et al. Cyclosporin A rapidly inhibits mediator release from human basophils presumably by interacting with cyclophilin. J Immunol 1990;144(10):3891-7
64.
Stellato C, de Paulis A, Ciccarelli A, et al. Anti-inflammatory effect of cyclosporin A on human skin mast cells. J Invest Dermatol 1992;98(5):800-4
65.
Casolaro V, Spadaro G, Patella V, Marone G. In vivo characterization of the anti-inflammatory effect of cyclosporin A on human basophils. J Immunol 1993;151(10): 5563-73
66.
Marsland AM, Soundararajan S, Joseph K, Kaplan AP. Effects of calcineurin inhibitors on an in vitro assay for chronic urticaria. Clin Exp Allergy 2005;35(5):554-9
67.
mast cell-leukocyte cytokine cascades. Multiple mechanisms of inhibition of IgEand mast cell-dependent cutaneous inflammation in the mouse. J Immunol 1995;154(3):1391-8
Review
leukotrienes in chronic urticaria. Int Arch Allergy Immunol 2002;129(3):254-60 79.
Leonard R, Hardy J, Van Tienhoven G, et al. Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 2001;19(21):4150-9
68.
Chapman I, Mazzoni L. Mechanisms of inhibition by cyclosporin A on pulmonary leukocyte accumulation. Trends Pharmacol Sci 1994;15(4):99-101
80.
69.
Fradin MS, Ellis CN, Goldfarb MT, Voorhees JJ. Oral cyclosporine for severe chronic idiopathic urticaria and angioedema. J Am Acad Dermatol 1991;25(6 Pt 1): 1065-7
Rahman M, Ahmed BN, Faiz MA, et al. Phase IV. Trial of Miltefosine in Adults and Children for Treatment of Visceral Leishmaniasis (Kala- Azar) in Bangladesh. Am J Trop Med Hyg 2011;85(1):66-9
81.
70.
Barlow RJ, Black AK, Greaves MW. Treatment of severe chronic urticaria with cyclosporine-A. Eur J Dermatol 1993;3(4): 273-5
Barratt G, Saint-Pierre-Chazalet M, Loiseau PM. Cellular transport and lipid interactions of miltefosine. Curr Drug Metab 2009;10(3):247-55
82.
71.
Toubi E, Blant A, Kessel A, Golan TD. Low-dose cyclosporin A in the treatment of severe chronic urticaria. Allergy 1997;52(3): 312-16
Silveira ESAM, Mazucato VM, Jamur MC, Oliver C. Lipid rafts in mast cell biology. J Lipids 2011;2011:752906
83.
Weller K, Artuc M, Jennings G, et al. Miltefosine inhibits human mast cell activation and mediator release both in vitro and in vivo. J Invest Dermatol 2009;129(2): 496-8
84.
Hartmann K, Siebenhaar F, Belloni B, et al. Effects of topical treatment with the raft modulator miltefosine and clobetasol in cutaneous mastocytosis: a randomized, double-blind, placebo-controlled trial. Br J Dermatol 2010;162(1):185-90
85.
Magerl M, Rother M, Bieber T, et al. Randomized, double-blind, placebo controlled study of safety and efficacy of miltefosine in antihistamine resistant chronic spontaneous urticaria. J Eur Acad Dermatol Venereol 2013;27(3):e363-9
86.
Ying S, Kikuchi Y, Meng Q, et al. TH1/ TH2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria: comparison with the allergen-induced late-phase cutaneous reaction. J Allergy Clin Immunol 2002;109(4):694-700
87.
Puccetti A, Bason C, Simeoni S, et al. In chronic idiopathic urticaria autoantibodies against Fc epsilonRII/CD23 induce histamine via eosinophil activation. Clin Exp Allergy 2005;35(12):1599-607
88.
Rabelo-Filardi R, Daltro-Oliveira R, Campos RA. Parameters associated with chronic spontaneous urticaria duration and severity: a systematic review. Int Arch Allergy Immunol 2013;161(3):197-204
72.
Vena GA, Cassano N, Colombo D, et al. Neo-I-30 study Group. Cyclosporin A in chronic idiopathic urticaria: a double blind, randomized, placebo-controlled trial. J Am Acad Dermatol 2006;55(4):705-9
73.
Serhat Inaloz H, Ozturk S, Akcali C, et al. Low-dose and short-term cyclosporine treatment in patients with chronic urticaria: a clinical and immunological evaluation. J Dermatol 2008;35(5):276-82
74.
Kessel A, Toubi E. Cyclosporine-A in severe chronic urticaria: the option for long-term therapy. Allergy 2010;65(11):1478-82
75.
Perez A, Woods A, Grattan CE. Methotrexate: a useful steroid-sparing agent in recalcitrant chronic urticaria. Br J Dermatol 2010;162(1):191-4
76.
Shahar E, Bergman R, Guttman-Yassky E, Pollack S. Treatment of severe chronic idiopathic urticaria with oral mycophenolate mofetil in patients not responding to antihistamines and/or corticosteroids. Int J Dermatol 2006;45(10):1224-7
77.
Church MK, Maurer M. H. 1)antihistamines and urticaria: how can we predict the best drug for our patient? Clin Exp Allergy 2012;42(10):1423-9
••
Important review article exploring models of predicting effectiveness of H1-antihistamines in clinical practice.
78.
Ferrer M, Luquin E, Sanchez-Ibarrola A, et al. Secretion of cytokines, histamine and
Wershil BK, Furuta GT, Lavigne JA, et al. Dexamethasone or cyclosporin A suppresses
informahealthcare.com
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