Effects of H1 antihistamine therapy on the cytokine profile in chronic urticaria

Introduction Chronic urticaria (CU) is defined by the presence of recurrent urticarial lesions, transient, pruritic and erythematous, for a period of at least 6 weeks. The diagnosis of urticaria integrates a heterogeneous group of diseases emerging as a result of a great variety of causes (Zuberbier et al 2009). All types and subtypes share a distinctive pattern of skin reactions manifested by urticarial lesions and angioedema. Urticaria is one of the most common 20 skin diseases, known since antiquity. It is estimated that about 3% of the population of Western Europe suffer from chronic urticarial (Kapplan et al 2009). Even though CU is an easily recognizable disease, which is generally not life threatening, except for rare cases when it is accompanied by severe symptoms of angioedema, it severely affects patients’ lives at a level comparable to that of patients suffering from coronary artery disease awaiting surgery for triple bypass (O’Donnell et al 1997). A significant percentage of all cases of chronic urticaria is represented by chronic autoimmune urticaria, whose name is given by the pathogenic mechanism of production, being mediated by specific anti-FcεRI and/or anti-IgE autoantibodies (Konstantinou et al 2013). In a previous study, we showed that immuno-inflammatory changes occurring in chronic urticaria are a combination of mixed Th1/Th2 as well as Th17 lymphocyte response (Crisan et al 2014). Even if we could not confirm a unique pathogenic mechanism common to all forms of urticaria, it is considered that the mastocyte is the central cell in the pathogenesis of this disease. Mast cells are involved in the early stages of inflammation, generating and releasing a series of cytokines involved in the generation and maintenance of an immune response, such as IL-1β, IL-6, TNF-α or IFN-γ. IL-1β is an interleukin which plays a key role in the immune response, stimulating the proliferation and differentiation of T lymphocytes. Anti-interleukin-1 therapy (Anakinra or ILIRa) has proven to be effective in auto-inflammatory syndromes including chronic urticaria as a manifestation (Kapplan 2012). IL-2, with a similar function as IL-1β, may also have an antiinflammatory function, however, by its ability to induce the proliferation of regulatory LyT. TNF-α secreted mainly by activated macrophages, triggers acute phase response, together with IL-1β. In chronic autoimmune urticaria anti-TNF alpha therapy was effective in 60% of patients who had not previously responded to anti-H1 therapy (Sand 2013). IL-6, dominant pro-inflammatory cytokine, is the most important stimulant of the synthesis of acute phase proteins (APP). However, after its pro-inflammatory action, IL-6 interrupts the inflammatory cascade by inhibiting the synthesis of IL-1β and TNF-α, along with the stimulation of IL-1 receptor antagonist (IL-1Ra) and IL-10. IFN-γ is a type II interferon, with antiviral and immunomodulatory, antibacterial, antitumor function. IFN-γ has the effect of stimulating monocytes/macrophages Abstract. Aim: to assess the variation in pro and anti-inflammatory cytokines: IL-1β, IL-2, IL-4, IL-6, IL-10, IFN γ, TNF-α, IL-17 and IL-31 under treatment with second-generation H1 antihistamines, Levocetirizine and Desloratadine. Materials and methods: patients diagnosed with chronic urticaria without background therapy with H1 antihistamines or cortisone in the past three months were included in the study. Patient evaluation included medical history and a specific questionnaire for assessing disease severity. They were regularly followed up for up to 3 months in order to adjust the treatment. Blood samples, required for cytokine assay (IL-1β, IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α, IL-17 and IL-31) were collected at baseline and 3 months after initiation of treatment. Results: Disease control was achieved in all patients 3 months after initiation of therapy, but patients had different treatment regimens. A percentage of 71.1% of patients responded favorably to treatment with second-generation H1 antihistamines (Desloratadine and Levocetirizine), but at various doses. Pro-inflammatory cytokines decreased significantly under treatment, while IL-10, an anti-inflammatory cytokine, had no significant variations. When comparing the two studied antihistamines, Desloratadine and Levocetirizine, there was no significant difference between the two in terms of reduced cytokine levels, except for IL-1, which decreased significantly more in the group of patients treated with Desloratadine. Conclusions: in most cases, H1 antihistamines provided chronic urticaria symptom control. H1 antihistamines significantly reduce plasma levels of IL-1β, IL-2, IL-4 IL-6, IFN-γ, TNF-α, IL IL-17 and IL-31, but not IL-10 levels. Patients treated with Desloratadine had a greater decrease in IL-1β than those treated with Levocetirizine.