Chronic spontaneous urticaria (CSU), formerly known as chronic idiopathic urticaria, is an autoimmune skin disorder. It is characterized by persistent and/or recurrent daily attacks of fleeting itchy wheals, erythema and/or angioedema that lasts for ≥6 weeks [1] . Histologically, wheals are oedema in the upper dermis while angioedema is in the lower part of the dermis [2] . It is a disabling skin disease that impairs quality of life and affects several domains of health-related quality of life, such as activities of daily living, sleep, emotional and psychological well-being, and work productivity. While chronic urticaria affects 0.5% - 1% of the general population worldwide, CSU accounts for more than two-thirds of those cases [3] . It should be differentiated from a) inducible urticaria associated with local or systemic exposure to allergens or Angiotensin-converting enzyme inhibitors, b) vasculitis, and c) systemic autoimmune diseases [2] . CSU develops after mast cell activation followed by degranulation and release of histamine as the main mediator of symptoms alongside other cytokines and neuropeptides. The release of histamine from mast cells is a classic type I immediate reaction, yet mediated by autoantigens. Hence, and according to the EAACI/GA2LEN/WAO guidelines, a) second-generation non-sedating H1-antihistamines (AH2) used in quadruple doses are the first-line therapy and b) Omalizumab (Om) is for refractory cases [2] . Om is a monoclonal anti-IgE antibody that prevents IgE from binding to the FcεR1 receptor on mast cells and basophils, thereby inhibiting the release of inflammatory mediators [4] . Another less common cause of mast cell activation is the cross-binding of the Fc-receptors or the IgE molecules by IgG or IgM auto-antibodies, known as a type IIb reaction. Intracellularly the signal from the cross-binding is mediated through the Bruton tyrosine kinase pathway that activates nuclear factor kappa-light-chain-enhancer, nuclear factor of activated T cells, and activator protein-1 [2] . In the latter type, the response to AH2 and Om is limited [5] . In both types of CSU, high-dose Corticosteroids (C) are indicated in acute disease flare yet, due to their multiple long-term side effects, they should be tapered down and discontinued after remission by biological agents [6] . It should be noted that CSU does not lead to permanent organ damage, and it ultimately resolves in the majority of patients, with or without treatment within 2 - 5 years [1] . Unfortunately, the limited efficacy of anti-histamines II (AHII), multiple side effects of C as well as the cost and the parenteral mode of admiration biological agents are limiting factors in the treatment of such chronic and disabling disease. Hence, we conducted our study to assess the efficacy of hydroxychloroquine (HCQ) as an oral, inexpensive and relatively safe immunomodulator in the management of such disease.

In the past 5-years, a total of 16 patients with CSU, were treated in this prospective study. Patients were included if they had: a) severe CSU, b) duration ≤ 6 months to ensure previous treatment and clinical history, c) negative serology for autoimmune diseases, d) C-refractory disease i.e. previous treatments limited only to short-courses of AH2 and C yet with frequent remissions and relapses or C-dependency on C-dose reduction. CSU was defined by persistent and/or recurrent daily attacks of fleeting itchy wheals, erythema and/or angioedema that lasted ≥6 weeks.

A total of 16 patients fulfilled the clinical criteria for inclusion in the study, of whom 8 had recurrent angioneurotic oedema ( Figure 1 & Figure 2 ). Patient’s demographical profiles, UAS7 scores on entry and subsequent follow-up at 1 month then 2 years are summarized in Table 1 . Eight (50%) patients were females. All were adults with (age at 44 ± 7 years). Their duration of CSU prior to our treatment was 5 ± 1 months and their disease was severe at a UAS7 score of 30 ± 3.

CSU does not lead to permanent organ damage, and it ultimately resolves in the majority of patients, with or without treatment, within a few years. Hence, it is a) difficult to assess the impact of therapy versus its natural history, and b) long-term therapy with expensive drugs or those with serious adverse side effects is not warranted. In our study, all patients had definite and severe CSU that did not remit, with conventional therapy, for >6 months and hence, indicated long-term treatment. Hence, a) drugs with long-term side effects C, Calcineurin-inhibitors, Mycophenolate, dapsone, Sulfasalazine and costly one (Om) were avoided [10] [11] . In our study, HCQ was used, as a disease-modifying agent, for a minimum of 2 years based on its low cost as well as its documented efficacy and safety profile in rheumatological disorders [12] . Compared to Om, its monthly cost is $149 versus $2446 [13] . Interestingly, our patients, with severe disease, had shown definite and rapid responses to our induction therapy with C-HCQ combination within 1 month similar to that achieved by Om [11] . Moreover, we proved that HCQ can be used safely as a sole maintenance therapy in C-refractory cases. In our study, we selected C-refractory cases and avoided, the rare, steroid-resistant cases that may require more aggressive immunosuppressive therapy [2] [14] . In our study, we confirmed the clinical response to HCQ (UAS7) with impressive improvements in both: a) serum total IgE level and b) CRP. The first plays a significant role in the immune system’s response to allergens and parasites. Its initial high level correlates with response in type I CSU while those with low initial level reflect more of type II CSU [15] . On the other hand, CRP is an acute-phase reactant that is elevated in the presence of inflammation [16] . The mechanism of action of HCQ entails impairment of lysosome function in humans as well as plasmodia. Altering the pH of the lysosomes reduces low-affinity self-antigen presentation in autoimmune diseases and interferes with the ability of plasmodia to proteolyze hemoglobin for their energy requirements. Presently, it is being evaluated in bone marrow transplant patients to treat graft-versus-host disease as an immunosuppressive agent since it blocks T-cell activation in vitro via interfering with T-cell receptor-CD3 complex (TCR). The latter mediates recognition of antigenic peptides bound to MHC molecules, whereas the CD3 molecules transduce activation signals to the T cell [17] . In a concentration-dependent manner, HCQ inhibited anti-TCR-induced up-regulation of CD69 expression, a distal TCR signaling event. Proximal TCR signals, including inductive protein tyrosine phosphorylation, tyrosine phosphorylation of phospholipase C gamma1, and total inositol phosphate production, were unaffected by HCQ. Moreover, anti-TCR-crosslinking-induced calcium mobilization was significantly inhibited by HCQ, particularly at the highest concentrations tested (100 micromole/L) in both T-cell lines and primary T cells. Furthermore, HCQ, in a dose-dependent fashion, also reduced a B-cell antigen receptor calcium signal, indicating this effect may be a general property of HCQ. Inhibition of the calcium signal correlated directly with a reduction in the size of thapsigargin-sensitive intracellular calcium stores in HCQ-treated cells. Together, these findings suggest that disruption of TCR-crosslinking-dependent calcium signaling provides an additional mechanism to explain the immunomodulatory properties of HCQ [18] .

HCQ is a safe and cost-effective treatment in C-refractory CSU.

Prof/Kamel El-Reshaid conceived the study, participated in its design, and drafted the manuscript. Dr. Shaima Al-Bader and Dr. Abdulla Al-Refaee participated in the study design, follow-up of patients and data collection and tabulated the data. All authors read and approved the final manuscript.

The data provided in the current review are available from the references.