A Prospective study to assess the association of serum levels of interleukin-9, C5a, apolipoprotein A-IV with disease severity and response to antihistamines in patients with chronic spontaneous urticaria.

“Urticaria is a mast cell derived disease which is characterized by short lived itchy wheals,

angioedema or bothâ€. It can either present as acute urticaria with onset of symptoms and disease

duration of less than 6 weeks or chronic urticaria where disease duration is equal or more than 6

weeks. Onset of chronic urticaria can be spontaneous or induced. It affects 10-30% of population

once or more in a lifetime. According to EAACI guidelines, first line symptomatic treatment

for the management of urticaria is 2nd generation non sedating antihistaminics. If standard dosing

is not effective, it is recommended to hike the dose upto 4 times. Few patients of urticaria tend to

be more severely affected, and does not even respond  to 4 fold increased dosage of

antihistaminics.  In these antihistamine refractory urticaria, other modalities used are

Omalizumab, cyclosporine,  azathioprine, methotrexate and phototherapy, plasmapheresis and

corticosteroids, IVIG.

 There is enough evidence to say that chronic urticaria is characterized by a systemic pro-

inflammatory state. There are two major mechanisms described for the pathogenesis of

chronic urticaria. One mechanism involves dysregulation in intracellular signaling pathways in

the mast cells and basophils which causes defects in trafficking or function of these cells. The

second mechanism is decribed by the development of circulating antibodies against FcεRI or IgE

on both mast cells and basophils.

IL-9 was initially considered a Th2-cytokine but now it is said to be a product of Th9 specialized

 subset  of CD4+ T helper cells. IL-9 is a pleiotropic cytokine. It has both direct and indirect

 effects on various cell types. IL-9 is a potent growth factor which promots the proliferation as

 well as differentiation of  mast cells. Patients with CSU patients showed markedly increased

 numbers of Th9 cells in peripheral blood, though levels were not as high as seen in acute

 urticaria. It indicates a high expression of IL-9 in peripheral blood because of the positive

 correlation between Th9 and IL-9.  Study by Feng et al suggested that IL-9 and IL-10

 contribute to the pathogenesis of Chronic Spontaneous Urticaria via activation of the JAK/STAT

 signalling pathway.

 Recent studies have suggested a vital role for apolipoproteins in the pathogenesis of various

 inflammatory diseases.  ApoA-IV is known to have an inhibitory effect on basophil histamine

 release, which indicates that it could be a potential  therapeutic target for allergic diseases. It is

 an endogenous antiâ€inflammatory protein which potently represses effector cell functions in

 eosinophils. Therefore, ApoAâ€IV if applied exogenously may characterize a fresh

 pharmacological approach for the treatment of allergic inflammation and other eosinophil driven

 disorders.

          A possible role for complement in pathogenesis of chronic urticaria is supported by lack of

 enhancement of serum pathogenic IgG if the serum is scarce in the second or fifth components of

 complement. Hence an anaphylatoxic complement fragment, most likely C5a, was considered to

 mediate the direct activation of basophils and mast cells. Kikuchi et al confirmed that cross-

 linking of the IgE receptor α subunit by pathogenic IgG in patients with CU leads to release of

 histamine, which is augmented by complement, and they verified that C5a is responsible for that

 augmentation.

 The proposed study aims to identify biomarkers by correlating their levels with disease

 activity and response to treatment. It could be useful to predict the future evolution and

 response to treatment or to monitor the activity of CSU and the efficacy of treatment.