Review paper
Autoimmune urticaria

Introduction

According to the contemporary definition proposed by EAACI/GA2LEN/EDF/WAO, urticaria is a highly heterogeneous group of diseases with a common clinical manifestation of an urticarial wheal (flare-type skin reaction) with or without angioedema [1]. Urticarial wheals are flat, edematous and palpable patches; porcelain or white to pale red in color; of various size and shape. They appear rapidly and usually persist up to 24 hours, without any secondary type of lesions left behind. Skin eruptions are often accompanied by pruritus and/or burning sensation of the skin [2]. There is no predilection being observed in urticaria, therefore any skin region may be involved in the process.

From the histological standpoint, a classical urticarial wheal is characterized by the swelling of the upper layers of the dermis and the widening of blood postcapillary and lymphatic vessels. If the process is located in the deeper layers of the dermis and/or involves the subcutaneous

tissue, angioedema (Quincke’s edema) is diagnosed. Angioedematous swelling usually involves the face (eyelids, lips) and genital areas. A combination of urticarial wheals and angioedema is being detected in approximately 50% of all cases, while in 40% and 10% – isolated wheals or angioedema, respectively, are being observed [3]. The disease may occur regardless of the age with a significant predominance of the female gender (M : F – 4 : 1) [4]. Several different classifications of urticaria which relate to various spectra of causative factors have been proposed. But first of all duration of the disease seems to be of the main importance. 6 weeks’ duration of recurrent urticarial flares has been established to be a borderline between the acute and chronic variants of the disease. Importantly,

20–30% of patients with acute urticaria will suffer further on, from the chronic form of disease. From the etiological standpoint, acute urticaria is mainly associated with allergy to drugs and/or alimentary allergens as well as to acute infections (viral and bacterial in origin). On the other hand, in the case of chronic urticaria, a complex, multifactorial etiological background should be suspected and investigated. Table 1 presents one of the contemporary classifications of urticaria and Fig. 1 summarizes the proposal of the general diagnostic approach [1].

It has been estimated that in about 75% of cases, causative factors of the chronic type of the disease remain unknown and chronic spontaneous urticaria, also known as chronic idiopathic urticaria (CIU) should be diagnosed. Current data indicate that in 25-60% of patients with CIU, auto-reactive processes are identified (autoreactive spontaneous chronic urticaria) [5-7].

History of the concept of autoimmunity in urticaria

The concept of autoimmune urticaria (AU) is relatively new while the first reports on the involvement of circulating histamine-releasing factors were published in the 1960s. In 1962, Rorsman stated that the degranulation response of leukocytes is the responsible antigen-antibody type of reaction [8]. In 1986, Grattan et al. observed a specific erythematous and wheal-type reaction as a result of an intradermal injection of autologous serum in patients suffering from urticaria [9]. Soon afterwards, Gruber et al. identified a non-functional type of IgG and IgE (causing no degranulation of basophils) in patients with chronic urticaria and cold-induced urticaria [10]. In 1991, Grattan et al. reported on IgE autoantibodies, and two years later, the same team discovered that IgG autoantibodies directed against IgE molecule and a high affinity IgE receptor (FcRI) are major mediators of inflammation and, consequently, the cause of spreading urticarial wheals in chronic urticaria [11, 12]. This finding was confirmed by other investigators [13, 14]. Additionally, in the 1980s, Leznoff et al. found that more than 14% of patients with chronic urticaria showed signs and/or symptoms of autoimmunity within the thyroid gland. On the basis of these characteristic autoantibodies, autoimmune urticaria has been further classified into two subgroups:

1) autoimmune urticaria associated with IgG antibodies, directed against the  chain of the receptor with a high affinity to the Fc portion of immunoglobulin E (FcRI) or against the immunoglobulin E (IgE);

2) autoimmune urticaria associated with the presence of autoantibodies against thyroid antigens:

• anti-thyroglobulin antibodies (anti-TG),

• anti-thyroperoxidase antibodies (anti-TPO),

• anti-thyrotropin receptor (anti-TSH-R).

Mechanism of autoreactivity

It seems that IgE antibodies on the surface of mast cells and basophils, bind a specific antigen such as IgG anti-IgE, which leads to the formation of cross-connections between adjacent FcRI receptors, resulting in the cascade of reactions finally leading to the release of histamine and other mediators of inflammation. The mechanism of degranulation induced by anti-FcRI is similar. The difference is related to the cross-coupled receptors without the involvement of adjacent IgE [15]. In addition to the autoantibodies (mainly IgG1 and IgG3), complement activation and release of anaphylatoxin C5a, which in turn causes mast cell degranulation seems to play an important role. It has been observed that serum IgG autoantibodies of urticarial patients present the ability to stimulate histamine release from cutaneous mast cells only in the presence of a complement. Thus, degranulation of these cells with FcRI is additionally strengthened by the activation of complement components [16]. The question what the “true” role of autoantibodies in the course of chronic urticaria is still remains not clearly answered. It needs to be clarified whether we are dealing with an epiphenomenon or a classical type of autoreactivity in selected cases of CIU. Kandeel et al. found that sera of patients with Hashimoto thyroiditis may induce degranulation of basophils in the absence of anti-FcRI. However, they failed to identify the causative factor for this reaction [17]. Rottem drew attention to the possible involvement of anti-IgE class TPO autoantibodies, which may stimulate degranulation of mast cells after exposure to specific circulating antigens. These antigens may be released as a result of thyroid damage related to the autoimmunological process involving the thyroid gland [18]. It seems that such an association of autoimmune thyroiditis with chronic urticaria confirms the basis for evaluation of thyroid autoantibodies in the diagnosis of CIU [19]. Skin reactions in response to IgG-depleted plasma drew attention to the possible role of plasma components in the formation of urticarial wheals. In addition, increased plasma levels of D-dimers, clotting factor VIIa, prothrombin fragment 1 + 2, recorded in patients with chronic urticaria may be considered as evidence for extrinsic coagulation cascades activation [20]. The impact of Helicobacter pylori (H. pylori) infection on the production of autoantibodies is another interesting issue. It seems that due to significant cell immunogenicity of bacterial polysaccharides, autoantibodies may arise in relation to specific antigenic mimicry. It has been also reported that H. pylori has the ability to induce expression of HLA-DR on gastrointestinal epithelial cells, providing them with characteristics of functionally active antigen presenting cells [21].

Diagnosis of autoimmune urticaria

Autologous serum skin test (ASST) is regarded to be of a great value in the primary assessment of patients’ autoreactivity. Skin reaction of erythematous and/or wheal-type in response to the autologous serum indicates the presence of autoantibodies, which may be responsible for the degranulation of mast cells [22]. First described by Grattan et al. in 1986 [9], ASST contemporarily is applied on a regular basis in the daily clinical practice. A surprisingly wide range of positive results of ASST in patients with chronic urticaria have been reported by different authors (from 4.1% to 76.5%), most probably due to different criteria used for as­sessment. In terms of methodology, blood sample for analysis is obtained from the clot and then centrifuged for 10 min (450-500 g). An intradermal injection of 0.05 ml of serum (forearm), 0.05 ml of 0.9% NaCl (negative control) and 0.05 ml of histamine (positive control) complete the whole testing procedure. After 30 minutes, results of ASST should be evaluated. There are certain differences in terms of evaluation of final results of testing. According to some authors, a positive result should be recorded when the mean diameter of the wheal is at least 1.5 mm larger than the negative control. But there are other approaches considering 2, 3 and 5 mm (mean diameter) to be the minimal values for the positive reading [23-25]. Some authors question the specificity of ASST, pointing to the possibility of obtaining false positive results, in conjunction with the release of significant amounts of bradykinin and C5 during the coagulation process and C5 disruption. According to Asero et al., the autoreactivity detection rate is higher with the autologous plasma test (APST) in comparison to ASST [20, 26]. A positive reaction in APST seems to be related in particular to the function of certain coagulation factors as plasma levels of coagulation factors correlate with the severity of the disease, and this seems to be related to the time point of blood collection [27]. Basically two different anticoagulants are used in the process of plasma preparations for APST, i.e. edetate potassium or sodium citrate. The general methodology of APST does not differ from ASST described above [28]. In conclusion, it seems that further implementation of the APST test allows for a more detailed, while still initial diagnosis of AU. In addition, there are certain restrictions concerning skin autologous tests to be mentioned. From a technical standpoint, there is for example a definite need for the withdrawal of antihistamines for at least three days before the scheduled examination. Concerning logic and interpretation of results one should possibly prove the functional activity of autoantibodies which may simply coexist in the complex and chronic urticarial process. It is believed that the functional significance of these antibodies should be confirmed by performing a histamine release assay (BHRA – basophil histamine release assay), with specificity characterized with Western blot or ELISA [22]. However, due to high costs, availability of these methodologies in our daily practice is rather limited.

Patients suffering from AU present with lower serum levels of IgE in comparison to other types of the disease with negative autoantibodies and basopenia seems to be another characteristic phenomenon [8].

Infiltrations within skin lesions in AU are composed predominantly of granulocytes and it seems that histopathological differences between various types of the disease are of no significance [29].

Clinical manifestations of autoimmune urticaria

Patients with AU usually present higher severity of the urticarial process in terms of the number of urticarial wheals and intensity of itching/burning sensation. They often suffer additionally from other autoimmune diseases (vitiligo, insulin-dependent diabetes, rheumatoid arthritis, autoimmune hepatitis or autoimmune Hashimoto thyroiditis) [30]. Spadoni et al. have reported on cases of urticaria, as the first manifestation of juvenile systemic lupus erythematosus [31]. In terms of treatment, it seems that patients diagnosed with AU need higher doses of antihistamines and/or general modification of therapy, including alternative therapeutic modalities [32, 33].

Treatment of autoimmune urticaria

In the case of AU, classical treatment even using a new generation of antihistamines is often ineffective. Systemic corticosteroids are not indicated for prolonged treatment due to significant side effects and this group of medications is recommended only in case of emergency.

In patients with hypothyroidism in the course of autoimmune thyroiditis, L-thyroxine may be efficacious. Coexistence of AU, autoimmune thyroiditis, and arthritis with significant improvement in the clinical course of urticaria after treatment with L-thyroxine (75 mg daily) has been described by Milchert et al. [34]. Also Rumbyrt et al. published good treatment results in seven patients with chronic urticaria and autoimmune euthyroid thyroiditis, treated with daily doses of 25-100 mg of L-thyroxine. In the control group composed of patients with chronic urticaria, but with no thyroid autoimmunity, treatment with L-thyroxine was not successful [35]. Obviously, further investigations and DBPC clinical trials are necessary to prove this important therapeutical concept.

Cyclosporine A (CsA) is a good alternative for the treatment of severe cases of AU. Boubouka et al. have proven that even low doses of CsA may be effective. He started treatment with an initial dose of 1.5-2.5 mg/kg, then being reduced on a monthly basis in relation to the individual clinical course, for the global treatment period of 5 months in 30 patients. The daily dose of 0.55 mg/kg was the lowest to control the urticarial process. Twenty-three patients completed the study. After the first month of treatment, an improvement of 31% was noted, reaching 88% after the fifth month of treatment. Six months after the final study end-point, ASST has been repeated and negative results were recorded in 78.3% of patients who completed the study. At one-year follow-up, 20 patients were symptom-free and 3 had relapsed [36]. Efficacy of CsA in comparison with prednisolone has been studied by Lori et al. [37], and good evidence for alternative treatment in the case of contraindications for systemic steroids in severe AU has been provided.

Mofetil mycophenolate may be also considered for the treatment of AU patients. Doses ranging from 1000 to 6000 mg/day and mean treatment duration of 14 weeks have been investigated. A significant clinical improvement was ob­served in up to 91% of AU patients with dyspepsia being the most common side effect [38]. Biologicals are obviously of a great interest for the treatment of AU. Omalizumab for instance may reduce serum IgE levels as well as expression of Fc?RI on mast cells and basophils [39]. Therefore, it may be truly needed for those presenting for instance autologous as IgE directed against thyroid antigens. However, due to a wide panel of diverse biological contradictions to therapy, detailed and cautious recruitment for the biological treatment is absolutely necessary. A high price of biologicals is another crucial limitation on treatment of AU patients with this particular group of medications.

There are also other alternative therapeutical modalities available such as hydroxychloroquine [40] and plasmapheresis [41], intravenous immunoglobulins, methotrexate, tacrolimus, interferon, dapsone, and sulfasalazine. Of course, further investigations and stronger evidence for their clinical efficacy are necessary [42, 43]. Anticoagulants are also an interesting therapeutical approach but further trials are still needed [44, 45].

In conclusion, chronic spontaneous urticaria is one of the most frequent skin disorders, and often people have been suffering from it for many years. It strongly affects the daily quality of life of patients and therefore the frequency of psychiatric comorbidities is high. Autoimmune urticaria seems to be one of the most difficult to treat variants of CIU as the underlying cause of the disease still remains unclear. Diagnostic procedures such as ASST, APST and evaluation of autoantibodies are recommended for the first-line diagnosis. However, there is a strong need for new methodologies of higher specificity, sensitivity and describing functional characteristics of the autoreactive process in AU. High doses of non-sedating antihistamines are usually ineffective and alternative therapeutical approaches including immunosuppression are often recommended in order to improve care for a large proportion of AU patients.



The authors declare no conflict of interest.

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