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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Nowadays&#44; second generation of H1 antihistamine as the first line therapy is recommended by the recent management of urticaria guidelines with an increase in dosage 4 times higher when there is no improvement in the clinical symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">1</span></a> Despite the dosage enhancement&#44; chronic spontaneous urticaria &#40;CSU&#41; therapy still requires a complement agent to maximize its effect&#44; necessitating the use of adjuvant therapy to increase the effectiveness of the first line therapy&#46; Adjuvant therapy for CSU is needed&#44; especially for refractory patients receiving increased antihistamine doses&#46; This literature review will discuss further a variety of adjuvant therapy and their role in the management of CSU&#46; As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; the level of evidence &#40;LoE&#41; of the management is based on Oxford Centre for Evidence-Based Medicine 2011 for the therapeutic study and the simplified table of adjuvant therapy modalities can be seen in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Chronic spontaneous urticaria</span><p id="par0010" class="elsevierStylePara elsevierViewall">The goal of treating CSU is to resolve all symptoms through non-pharmacology approaches&#44; including identification and elimination of the urticaria causes&#44; avoiding trigger factors&#44; and tolerance induction&#59; then pharmacological therapy to prevent the release of mast cell mediators or the effect of mast cell mediators&#46; The pharmacological treatment should allow the lowest dose to alleviate the symptoms&#46; The treatment is adjustable&#44; corresponding to the degree of disease activity&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">2</span></a> As illustrated in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; EAACI&#47;GA2LEN&#47;EDF&#47;WAO guideline in 2022 recommends the second generation of H1 antihistamine to be the first line of therapy for CSU&#44; with the dosage enhancement up to 4 times higher if there is no improvement in the clinical symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">1</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Adjuvant therapy for chronic spontaneous urticaria</span><p id="par0015" class="elsevierStylePara elsevierViewall">Adjuvant therapy is an additional therapy that is given together with the first line therapy simultaneously with the purpose of increasing the therapy effectivity&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">3</span></a> Adjuvant therapy in CSU is needed primarily on patients with no response to the treatment or refractory towards increasing antihistamine doses&#46; The following sections will discuss several adjuvant therapies and their roles in CSU&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Biologic agent</span><p id="par0020" class="elsevierStylePara elsevierViewall">Biological agent comes from living things and is used to prevent&#44; diagnose&#44; or treat a disease&#46; The biologic agents used to treat chronic refractory urticaria are omalizumab&#44; rituximab&#44; intravenous immunoglobulin &#40;IVIG&#41;&#44; dan inhibitor TNF-&#945; &#40;infliximab&#44; adalimumab&#44; and etanercept&#41;&#59; all used alongside the standard antihistamine regimen&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">4</span></a></p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Omalizumab</span><p id="par0025" class="elsevierStylePara elsevierViewall">Omalizumab &#40;OMA&#41; is a recombinant monoclonal antibody that comes from a human and acts as an anti-IgE antibody&#44; preventing the binding of IgE to receptor cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">5&#44;6</span></a> The effectiveness of OMA is proven and well tolerated in patients with refractory CSU&#46; The EAACI&#47;GA2LEN&#47;EDF&#47;WAO guidelines in 2022 recommend OMA as the third-line therapy for patients with chronic refractory urticaria towards the increase of H1 antihistamine dosage&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">2</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The mechanism of action of OMA is not fully understood&#46; Kaplan et al&#46; have reported the mechanism of actions of OMA in the CSU treatment is by decreasing the free IgE and IgE receptors&#44; reducing the mast cell ability to release histamine&#44; restoring basopenia&#44; restoring the IgE receptors function in basophile&#44; reducing the activity of auto-antibody IgG towards IgE and its receptors&#44; reducing the abnormal IgE intrinsic activity&#44; reducing the auto-antibody IgE towards an antigen or an unknown auto-antigen&#44; and reducing abnormal coagulation which related to the disease activity through in vitro&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">7</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The effectivity of the OMA addition in the CSU treatment was reported in many phases II<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">8&#44;9</span></a> and phase III<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">10&#8211;12</span></a> clinical trials&#44; as well as meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">13</span></a> The three phase III clinical trials observed CSU&#47;CindU moderate&#8211;severe patients who did not respond to the standard treatment and other additional therapies were given OMA 75<span class="elsevierStyleHsp" style=""></span>mg&#44; 150<span class="elsevierStyleHsp" style=""></span>mg&#44; or 300<span class="elsevierStyleHsp" style=""></span>mg for 12&#8211;24 weeks&#44; and there was a decrease in the itch severity score &#40;ISS&#41; on the 12-week treatment&#46; Casale et al&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">14</span></a> have reported that there were more patients with urticaria activity score 7 &#40;UAS7&#41; &#8804;6 &#40;symptoms are well controlled&#41; or UAS7 0 &#40;symptoms are perfectly controlled&#41; when treated with OMA 300<span class="elsevierStyleHsp" style=""></span>mg compared to placebo&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">OMA is effective in the dosage of 150&#8211;300<span class="elsevierStyleHsp" style=""></span>mg per month&#46; The dosage and duration of the therapy may vary between countries&#46; Generally&#44; OMA is well tolerated&#44; and the most common side effects are nasopharyngitis&#44; sinusitis&#44; URTI&#44; headache&#44; and cough&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">14</span></a> The risk of anaphylactic may occur 2<span class="elsevierStyleHsp" style=""></span>h after the first administration of OMA&#59; thus&#44; careful observation is needed&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Rituximab</span><p id="par0045" class="elsevierStylePara elsevierViewall">Rituximab is a chimeric monoclonal antibody to CD20&#46; The mechanism of action of rituximab in CSU prevents the production of autoantibody&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">15</span></a> The rituximab treatment result varies widely&#46; A case report of a patient with pressure urticaria who failed in the first and second line of therapy had received rituximab 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week infusion 4 times&#59; however&#44; there was no improvement&#46; A case report of CSU and immunodeficiency treated by rituximab 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#44; 4 times&#44; showed a perfect recovery of urticaria symptoms within 1 week&#44; with remission of more than 1 year&#44; and later the symptoms will be easily treated by an antihistamine&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">16</span></a> Another case report of refractory autoimmune CSU was given rituximab per week &#40;4 times in dosage&#44; within 4 weeks&#41; along with the administration of methotrexate showed a perfect remission 6 weeks after the last administration&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">17</span></a> There was no randomized controlled trials &#40;RCT&#41; study of rituximab in CSU&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Inhibitor TNF-&#945;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Some TNF-&#945; inhibitors drugs such as etanercept&#44; infliximab&#44; and adalimumab were used to treat CSU or vasculitis urticaria based on the postulation that TNF may have important roles in some types of urticaria&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">18&#44;19</span></a> For example&#44; etanercept 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>25<span class="elsevierStyleHsp" style=""></span>mg&#47;week is useful to treat delayed pressure urticaria and psoriasis&#46; On the 5-day of treatment&#44; the urticaria was resolved and did not appear until the end of the therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">20</span></a> A case series of 6 patients with chronic idiopathic urticaria or vasculitis urticaria treated by inhibitor TNF-&#945; showed a dramatic clinical improvement in all patients&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">21</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Serious infections such as tuberculosis&#44; fungal infection&#44; lymphoma&#44; and malignancy were reported&#46; This drug is not recommended for CSU treatment due to its lack of evidence to support the safety and efficacy of the treatment&#46; Furthermore&#44; there is no clinical trial comparing this drug to OMA&#44; in which the safety and efficacy have been tested&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="el