**3. Current therapies for CSU**

The introduction of the non-sedative anti-histamines replacing the first generation (sedative) one was a giant step forward in the treatment of CSU. At a later date, H1-antihistamine up-dosing was established and shown to be safe and of better efficacy. However, even when up-dosing was increased fourfold, the rate of non-responders remained high, thereby suggesting that additional treatments were needed [23]. As early as 1991, targeting T-cells by cyclosporine A (CsA) was shown to be highly effective in severe cases of CSU [24]. Later on, we demonstrated that low doses of CsA (2–3 mg/ml) given for three months were both extremely beneficial and had a low prevalence of side-effects. In some patients, we could demonstrate a long-lasting full remission, while in others it was even curative [25]. The efficacy of CsA was established by many double-blind, randomized studies. Symptom scores significantly improved in the CsA group over with placebo. CsA was well tolerated at daily doses of 3 mg/kg. Side effects such as hypertension and increased serum creatinine were rare [26]. In addition, the efficacy and safety of CsA in CSU was evaluated by a meta-analysis of eighteen studies. A low-dose (2–3 mg/kg/d) was considered to be both beneficial and safe, and adverse events appear to be dose dependent and occur more frequently in patients that have been treated with moderate doses (4–5 mg/kg/d) [27]. In a recent study, the prediction of beneficial response to CsA treatment, was assessed using, positive ASST, plasma D-dimer levels, IL-2, IL-5 levels and total IgE level. Decreased plasma D-dimer levels, and decreased serum IL-2 and IL-5were reported to be correlated with clinical improvement after CsA treatment [28]. While cyclosporine A is still used in cases with severe CSU, the fear of side effects, mainly in those with mild hypertension or diabetes, has limited its usage, allowing omalizumab (an IgG-anti-IgE monoclonal antibody), approved for the treatment of anti-histamine-refractory CSU in 2014 to become the preferable option in treating CSU. In the European

Academy of Allergology and Clinical Immunology, Global Allergy and Asthma European Network, European Dermatology Forum, and World Allergy (EAACI/ GA2LEN/EDF/WAO) guidelines for the treatment of CSU, it is recommended that omalizumab should be added to off-label doses of anti-histamines when CSU is inadequately controlled [29, 30]. Cyclosporine A remains the final option for those considered to be omalizumab failures. The main mechanism through which omalizumab acts, is its ability to bind soluble IgE and the down regulation of FcεRI expression on skin mast cells. This is followed by decreased mast cell activation and degranulation. In this respect, higher levels of FcεRI expression, predict a faster response to omalizumab. In addition higher levels of total serum IgE were shown to be associated with a greater responsiveness to omalizumab [31]. While it is well accepted that a complete response to the standard dose of omalizumab (300 mg/ month) is observed in about 59% of patients, 15% of treated patients still remain resistant to this dose of omalizumab [32]. In many studies, up dosing of omalizumab to 450 mg/month was shown to achieve better clinical respnses with a good safety profile [33]. Options of higher doses of cyclosporine A or the combination of omalizumab and cyclosporine A were also reported in few case reports in severe and refractory to all of the above mentioned approaches. Un-met needs and the requirement for new treatments in still refractory CSU are the subject of many on-going clinical trials in which targeting new relevant pathways is assessed.
