Research Progress in Chronic Autoimmune Urticaria

Shan Zhang,Xu Yao?,Xue-Yuan Yang?

Department of Allergy and Rheumatology Immunology,Hospital for Skin Diseases(Institute of Dermatology),Chinese Academy of Medical Sciences and Peking Union Medical College,Nanjing,Jiangsu 210042,China.

Introduction

Urticaria,more commonly known as the sudden development of transient hives(wheals),angioedema,or both,is a prevalent disorder that affects 15%-25%of the general population at some point during their lifetimes.1The condition tends to be more common in adults than in children,and more common in women than in men with a peak occurrence in the third to fifth decades of life.This condition is marked by the onset of pruritic wheals,which manifest as well-circumscribed areas of nonpitting edema with blanched centers and raised borders that involve only the superficial portions of the dermis and are seen in conjunction with surrounding erythema of the skin.1

Chronic urticaria(CU),an immune-mediated inflammatory disease,is defined as the spontaneous or inducible appearance of hives,angioedema,or both lasting at least 6 weeks and presenting with numerous subtypes,all of which greatly impair patients’quality of life.2CU is observed much less frequently in children(prevalence of 0.1%-3.0%)than in adults.3Depending on whether the skin lesions appear spontaneously or are induced by a specific trigger, CU is classified as either chronic spontaneous urticaria(CSU)or chronic inducible urticaria. The EAACI/GA2LEN/EDF/WAO guideline for the definition,classification,diagnosis,and management of urticaria defines CSU as the spontaneous appearance of wheals,angioedema,or both lasting for ＞6 weeks and induced by either known or unknown causes.One known cause is autoreactivity;that is,the presence of mast cellactivating autoantibodies.4A nationwide epidemiological study revealed an annual prevalence of CSU ranging from 0.02%in 2002 to 0.38%in 2013 and an incidence of 0.10 to 1.50 per 1,000 person-years in Italy.For both the prevalence and incidence rates, female patients outnumbered male patients(0.48%vs.0.23%and 1.6 vs.0.8 per 1,000 person-years,respectively).5In more than 50% of children with CU, the CU is classified as spontaneous.Evidence supports an autoimmune pathogenesis in 30%to 40%of adults with CSU.During the last few decades,several observations have supported the role of autoimmunity in the pathogenesis of a substantial proportion of both adults and children with CSU.In fact,30%-40%of patients with CSU have been considered to have chronic autoimmune urticaria (CAU). CAU is defined by the detection of histamine-releasing immunoglobulin G(IgG)autoantibodies to the high-affinity IgE receptor FcRI or,less frequently,to IgE,regardless of the presence of another autoimmune comorbidity.In fact,CAU is often an isolated disease with a distinctive prognosis and therapy.3

Pathogenesis of CAU

The role of oncostatin M receptor gene

Oncostatin M(OSM),a member of the interleukin(IL)-6 family of cytokines, plays important roles in skin inflammatory responses as a potential keratinocyte activator.6OSM is synthesized by various inflammatory cells,such as activated T cells,neutrophils,eosinophils,and macrophages.6-7The oncostatin M receptor(OSMR)gene can mediate the biological functions of OSM.Human OSM can bind to either the type I receptor complex consisting of gp130 and the leukemia inhibitory factor receptor(gp130/LIFRβ)or the type II receptor complex consisting of gp130 and the OSMR(gp130/OSMRβ).Some studies have examined therapies based on the OSMR for the treatment of various cancers such as cervical squamous cell carcinoma and lung adenocarcinoma as well as skin diseases such as familial primary localized cutaneous amyloidosis.7A recent study showed that mRNA expression of the OSMR was elevated in CAUaffected skin tissues in an animal model,indicating that the OSMR plays a vital role in CAU.In that study,OSMRpositive cells were primarily located in the superficial and middle dermis, surrounding the blood vessels and appendages in CAU-affected skin tissues,with positive granules largely located inside the epithelial cells.Moreover,it is well accepted that inflammatory factors are increased in CAU-affected skin tissues.In line with this,Kay et al.8showed that CSU-affected skin contains a higher concentration of vascular markers together with eosinophil and neutrophil infiltration, which might contribute to tissue edema. Low-level increases in eosinophils and microvascular markers persist in uninvolved skin as well.8In a comparison of CAU-affected tissues with no transfection versus transfection with blank plasmids, the CAU-affected tissues transfected with OSMR-silencing RNA showed a lower inflammatory factor content.Additionally,as shown by this study,CAUaffected mice tissues transfected with OSMR-siRNA exhibited a significantly shorter duration of pruritus and lower number of eosinophils.These findings indicate that OSMR silencing relieves the pathological reaction in CAU and decreases the number of eosinophils.9

Recent studies have shown that the OSMR leads to the stimulation of various cytokines and inflammatory substances by activating the Janus kinase/signal transducer and activator of transcription(JAK-STAT)pathway.7,9-10Low expression of OSMRβ has been consistently shown to decrease atherogenesis by inactivating the JAK2/STAT3 signaling pathway in macrophages.Luo et al.9also found that OSMR silencing inhibits the expression of JAK/STAT3 signaling pathway-related genes(JAK2,STAT3,ISG15,CRK,and IRF9).A previous study showed that both type I and type II OSMR activated JAK1,JAK2,and TYK2 receptor-associated tyrosine kinases.The OSMR protein is reportedly capable of heterodimerizing with IL-6 signal transducer(gp130)to produce type II OSMR,and when the receptor complexes are taken in,JAK can be activated,followed by further activation of STAT3.The aforementioned findings and evidence suggest that OSMR gene silencing can suppress the JAK/STAT3 signaling pathway.

In conclusion, OSMR gene silencing significantly decreases the content of inflammatory factors and number of eosinophils,reduces the mRNA and protein expression of JAK/STAT3 signaling pathway-related genes,enhances cell proliferation and migration,and inhibits apoptosis of epithelial cells.This suggests that OSMR gene silencing can restrain the development of CAU by blocking the JAK/STAT3 signaling pathway.9

The role of the neuroendocrine system

Previous studies have proposed a role of psychological stress in patients with CU,and we summarized it in Figure 1.This involves a two-way interaction in which CU heightens psychological distress,and chronic stress may in turn be a trigger of CU.Rosin et al.11showed that the stress scores(Presumptive Stressful Life Events score and Daily Hassles and Uplifts Scale score)were significantly higher in cases than in controls and demonstrated a significant positive correlation with the urticaria activity score, thus implicating stressful life events in the pathogenesis of CU and disease exacerbations.Chronic stress can enhance the central tone of the hypothalamicpituitary-adrenal(HPA)axis and increase the secretion of corticotropin-releasing hormone (CRH). But longtime stimuli result in HPA axis fatigue,which causes hypocortisolism.In this study,the number of patients with hypocortisolism was significantly higher in those with autoimmune urticaria.

In addition,stress also results in secretion of IL-18,a pleiotropic cytokine with immune-modulatory and proinflammatory properties from the anterior pituitary and adrenals during activation of the HPA axis.IL-18 acts as a modulator of the HPA axis along with cortisol,setting up a negative feedback mechanism by inhibiting CRH secretion.However,long-term exposure to stress shifts the cytokine milieu toward increased production of proinflammatory cytokines such as IL-6 and IL-18. The increased levels of IL-18 fail to exert an inhibitory effect on CRH because of HPA axis fatigue,thereby further increasing the CRH production.CRH has been demonstrated to have proinflammatory properties by causing mast cell degranulation and increasing vascular permeability in vivo in rat skin.Moreover,recent human studies have reported the existence of a peripheral HPA axis equivalent to the central HPA axis in the skin,with epidermal and hair follicle keratinocytes,sebocytes,and mast cells secreting CRH and expressing CRH-R1 in response to stress.Keratinocytes also secrete IL-18 during stress,inducing severe cutaneous inflammation.Thus,the skin HPA axis may have its own regulatory feedback mechanism through interaction with inflammatory cytokines.12-13Previous studies have revealed overproduction of IL-18 and markers of systemic inflammation(including C-reactive protein and IL-6)in CU,especially in autoimmuneurticaria,correlatingwithdiseaseseverity.12,14-16The chronic inflammation in CU that is associated with increased secretion of IL-6 and IL-18 from keratinocytes,especially in autoimmune urticaria and chronic stress,establish a positive feedback mechanism that contributes to HPA axis fatigue and thereby worsens the hypocortisolism.

Diagnosis of CAU

The EAACI/GA2LEN/EDF/WAO guideline agrees that CAU is a distinctive disease entity,but more evidence is required to fully meet Witebsky criteria(a series of criteria developed by Ernst Witebsky that are used to determine if a condition can be considered autoimmune).The guideline recommends the diagnosis of CAU based on a combination of a positive bioassay,positive autoreactivity,and positive immunoassay.The details and referenced methodologies are presented below.4

Proposed gold standard for diagnosis of CAU

1.Positive bioassay(basophil histamine release assay or basophil activation marker expression)to demonstrate functionality in vitro

2.Positive autoreactivity[by means of a positive autologous serum skin test(ASST)]to demonstrate relevance in vivo to mast cell degranulation and vasopermeability;

3.Positive immunoassay for specific IgG autoantibodies to FceRIa and/or anti-IgE(western blot or enzyme-linked immunosorbent assay)to demonstrate antibody specificity.

Type I and II autoimmunity, both of which occur through activation of mast cells to release histamine,are thought to be among the most important factors in the etiology and pathogenesis of CSU according to previous studies.A recent review assessed the existing evidence in support of a role for type I and II autoimmunity in CSU with the help of Hill criteria of causality.The authors concluded that type I and II autoimmunity are likely to be relevant in CSU subpopulations rather than in the same patients,although some patients might exhibit IgE antibodies and IgG-anti-IgE/FcεRI.17In line with another study,some patients with CAU have low levels of IgE and thus respond to omalizumab slowly. Patients with a positive basophil activation test(BAT)and/or ASST also show slower responses to omalizumab.18

Currently,the only generally available tests to screen for autoantibodies to either IgE or FceR1(the high-affinity IgE receptor)are the ASST and BAT.The ASST is a nonspecific screening test that evaluates the presence of serum histamine-releasing factors of any type,not just histamine-releasing autoantibodies. Conversely, the BAT assesses histamine release or upregulation of activation markers of donor basophils in response to stimulation with the serum of patients with CSU.The BAT can help to coassess disease activity in patients with urticaria as well as to diagnose autoimmune urticaria.Furthermore,the BAT can be used as a marker for responsiveness to cyclosporine A or omalizumab.4A combination of CD123 and CCR3 markers is recommended for basophil identification,while CD123 alone may be used as an alternative.To detect basophil activation, either CD203c alone on IL-3 unprimed basophils or both CD203c and CD63 on IL-3 primed basophils is recommended,while CD63 alone on IL-3 primed basophils may be used as an alternative.19

Figure 1.Schematic diagram explaining the association among chronic stress,chronic inflammation,and the hypothalamic-pituitaryadrenocortical(HPA)axis.ACTH:adrenocorticotropic hormone;CRH:corticotropin-releasing hormone;IL:interleukin.

Therapy of CAU

1.Omalizumab:Anti-IgE is becoming increasingly recognized as an effective and rapidly acting therapy in patients with antihistamine-resistant difficult-to-treat CU;notably,however,it is currently being used offlabel for this condition.Many retrospective analyses have clearly indicated that omalizumab is highly effective, affording complete relief in more than three-quarters of patients;is rapidly acting,often within 1 day;and is safe.20Furthermore,one treatment is usually sufficient to determine whether a patient is likely to respond to therapy,and subsequent doses may be decreased or increased to achieve the minimal effective dose.20

Omalizmab may exert its beneficial effects in patients with CAU in three possible ways (Fig. 2). First,omalizumab sequesters monomeric IgE to reduce its priming effect on mast cells.This is particularly relevant if highly cytokinergic IgE is involved in the pathogenesis of urticaria.Second,in patients with IgG autoantibodies to IgE or FcεRI,the depletion of mast cell-bound IgE by omalizumab and the subsequent downregulation of FcεRI on mast cells and basophils lead to their decreased state of hyperexcitability.Third,in patients with IgE autoantibodies to autoallergens,the inhibition of IgE binding to FcεRI by omalizumab and the downregulation of FcεRI represent a central mechanism of omalizumab.Furthermore,accumulated omalizumab-IgE immune complexes sequester endogenous autoantigens,such as thyroid peroxidase and Doublestranded DNA,with which IgE reacts.In addition to these effects,the binding of omalizumab to IgE on B lymphocytes and memory cells reduces the continual generation of IgE-producing plasma cells and hence IgE synthesis.The overall effect of omalizumab is that the IgE-FcεRI-mast cell axis is downgraded and the threshold for activation of mast cells to undergo degranulation by various factors is increased. This decrease in mast cell sensitivity and potency and thus increase in mast cell stability causes the mast cells to undergo less degranulation and secrete smaller amounts of pharmacologic mediators,thus decreasing the manifestation of urticarial symptoms. Additionally, the decreased release of inflammatory cytokines and mediators from basophils in the vasculature as a result of omalizumab treatment reduces the inflammatory manifestation in the skin.Such an effect might be important during the initial period of omalizumab treatment,because the downregulation of FcεRI presented on basophils surface is faster than that on mast cells.21

Figure 2.Possible mechanisms underlying how omalizumab exerts its beneficial effects in patients with CAU.CAU:chronic autoimmune urticaria,TPO:Thyroperoxidase.

2.Immunomodulators:Given the autoimmune basis of CAU,immunosuppressive agents are needed for its treatment.Generally,immunosuppressive agents are either too costly or have serious adverse effects.Lowdose cyclosporine is often considered in severe unremitting cases of CAU.The T-cell-mediated action of cyclosporine is widely accepted in immunosuppression;inhibition of basophil activity and mast cells has also been reported.Potential renal impairment effects of cyclosporine and hypertension are often encountered.Some prior studies showed that azathioprine22and sulfasalazine23seem to address both of these issues.Azathioprine can impair γ-globulin synthesis and impair T-lymphocyte function and T-cell components such as IL-2,which are the probable mechanisms of action of azathioprine in patients with CAU.Moreover,the statistical analysis in one study revealed that the patients who had received azathioprine for the initial 8 weeks had significantly better suppression of symptoms than the placebo group;this was true throughout the follow-up period.Thus, azathioprine not only had immunomodulatory properties during the treatment period but also had a lasting therapeutic effect.22The efficacy and safety of sulfasalazine in patients with CSU are comparable with those of cyclosporine. In the absence of reliable markers to identify which patients will be responsive to the existing array of therapies for refractory CSU,sulfasalazine represents a safe and effective therapeutic option.However,existing research indicates that sulfasalazine is associated with serious adverse effects; therefore, monitoring of laboratory values is critical to ensure patient safety.23

Prospects

In recent years,novel and promising research findings of CAU have been constantly revealed in numerous studies.These achievements not only update our understanding of the pathogenesis of CAU,but also extend the prospect of therapy for CAU. Considering the complexity and limitations of the BAT and ASST for diagnosis of CAU,even more simplified methods are needed to improve the diagnostic efficiency and acceptance level.Clinicians are faced with many treatment options,so it is necessary for them to consider optimization and further investigation of the dosing,timing,and combination strategies.