Hives are an allergic reaction to external and internal irritants. It looks like redness of certain areas of the skin, accompanied by rashes and blisters, reminiscent of a burn. It is often accompanied by itching, fever and other symptoms. In children, the disease is less common, but it has a more pronounced, recurrent form.
1.What is idiopathic urticaria?
Hives
is a skin reaction that most people have experienced at least once in their lives.
Most often, itching and skin rashes have specific causes (which can range from foods eaten and plant odors to liver disease, parasites or exposure to cold). Atypical diseases of unclear, purely individual origin are considered idiopathic. Thus, idiopathic urticaria
is itchy skin that has no specific cause.
Idiopathic urticaria can develop in a person of any age and social status, in any climate zone, and is one of the most common diseases. 25% of cases of causeless skin allergies become chronic.
There is no consensus on the causes of idiopathic urticaria, but most doctors are inclined to the hypothesis that antibodies are not working correctly, which for some reason begin to attack their own body and thereby disrupt its immune status.
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Histamine
The main cells involved in the development of the disease are mast cells and basophils, and the main mediator leading to the symptoms of most forms of urticaria is Histamine.
It is the production of histamine that causes visible signs of urticaria: local dilation of blood vessels, increased permeability of capillaries and small venules, leakage of plasma into the intercellular space.
Histamine is considered the main, if not the only, cause of itching. Therefore, antihistamines are usually effective in suppressing this symptom. In most patients, itching is most severe in the evening and/or at night, which is an important basis for daily prescription of medications.
2.Symptoms of urticaria
Usually urticaria appears quite clearly. These are, first of all, skin disorders:
- itching and swelling of the skin;
- watery blisters;
- small purple rashes.
In severe cases, when large areas of skin are affected, an exacerbation may be accompanied by general malaise, sleep disturbances, headaches, chills, and neurotic disorders
caused by itchy skin.
Most often, idiopathic urticaria differs from other skin allergies by prolonged exacerbations, which can last up to one and a half months
. However, starting with small spots and blisters, urticaria lesions can merge with each other, forming larger zones.
Severe skin itching, in addition to purely cosmetic problems, is the main, very unpleasant and unsafe symptom of this disease. Constant daytime irritation causes serious psycho-emotional trauma, sometimes forcing the patient to take sedatives. Involuntary scratching during sleep is no less dangerous, since it carries the risk of infection of the resulting wounds and scratches. When the blisters are injured, a clear liquid is usually released, and then a dry crust forms, which also itches.
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Chronic urticaria in children
Particular attention must be paid to the appearance of symptoms in children. It is in them that local lesions can quickly progress and take on a generalized form (spread throughout the body). At the same time, in 90-95% of cases it is almost impossible to identify the cause of the disease.
In children, chronic urticaria can last for years. At the same time, periods of remission tend to increase with age:
- in 50% remission occurs after 6 months;
- in 40% within 8 years;
- Just under 2% of all patients will suffer from recurrent manifestations of the disease for 25 years or more.
If your child has been diagnosed with chronic urticaria, hidden areas of the body should be examined periodically, because rashes most often appear in the armpits and groin.
With primary manifestations of urticaria in children, you should not rely on chance. You should undergo a full examination with him and identify the allergen2,3,5.
3. Diagnosis of rashes
Idiopathic urticaria can only be diagnosed by an allergist.
.
To do this, he prescribes a series of examinations, the purpose of which is to identify the connection of skin manifestations with specific factors and causes, the elimination of which could prevent the development or exacerbation of urticaria. The patient undergoes the following tests:
- general clinical blood test;
- biochemistry;
- HIV testing;
- blood for the Wasserman reaction;
- general urine analysis;
- blood and feces to identify parasites and helminths.
An important diagnostic step is a conversation with the patient
, during which the possible dependence of skin rashes on food, chemicals, stress, heredity, and medications taken is clarified.
Sometimes it is recommended to keep a symptomatic diary
, where each exacerbation of urticaria is recorded. In this case, the patient should try to remember any previous factors that could affect the state of the body, and also write them down. Sometimes only such records allow us to trace a certain pattern.
If a significant period of careful observation does not give a clear picture, there are no chronic diseases and exacerbations are unsystematic, then a diagnosis of “idiopathic allergy” is made.
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Chronic urticaria (CU) is hives that occur every day for more than 6 weeks. Chronic idiopathic urticaria, which has no obvious external cause, comprises the majority of cases of CU. It is believed that in more than half of all cases of chronic idiopathic urticaria, an autoimmune mechanism occurs due to antibodies to the high-affinity receptors (FcεRI) of immunoglobulin E. CU is believed to arise from the tendency of the patient's immune system to develop reactions against its own body. A strong association supporting this hypothesis has been found between CU and autoimmune diseases such as thyroid disease (autoimmune thyropathies), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome, celiac disease, and type 1 diabetes. Based on this, we consider the relationship between CU, autoimmune thyropathies and other autoimmune disorders, as well as implications from this statement that may have implications for therapeutic intervention in CU.
Introduction.
It is estimated that 25% of the population will develop urticaria during their lifetime. HC is urticaria that occurs daily for more than 6 weeks. CU usually lasts 1–5 years, but can last more than 5 years in approximately 14% of patients. \Individuals with chronic chronic disease report emotional distress, a feeling of isolation and fatigue from this disease, similar findings are observed in patients with coronary heart disease. This highlights the importance of treating CU while minimizing both the physical and mental impact of the disease. CU may arise from drugs, physical stimuli, be part of inflammatory or congenital diseases, or may be idiopathic in nature. Acetylsalicylic acid (ASA) or nonsteroidal anti-inflammatory drugs (NSAIDs) exacerbate CU, presumably by inhibiting the cyclooxygenase pathway by increasing leukotriene production. Physical urticaria (classically divided into heat, cold, solar, vibration, delayed pressure response, dermatographic, aquagenic, and cholinergic) occurs in response to external stimuli. Urticarial vasculitis is the appearance of urticarial rashes lasting more than 24 hours with histopathological changes in the vessels. Congenital CU syndromes include a spectrum of cryopyrinopathies such as familial cold autoinflammatory syndrome, Muckle-Wales syndrome, and neonatal multisystem inflammatory disease/chronic infantile neurological cutaneous-articular syndrome (NOMID/CINCA). Hives can be a symptom of many inflammatory diseases, such as Schnitzler's syndrome, Still's disease and Gleich's syndrome. Chronic idiopathic urticaria, unlike physical urticaria and intolerance to ASA or NSAIDs, has no obvious external cause. Chronic idiopathic urticaria is the most common type of urticaria, comprising up to 90% of all cases of urticaria. Chronic idiopathic urticaria is thought to affect 0.6 to 5% of the population. It is believed that more than half of cases of chronic idiopathic urticaria have an autoimmune mechanism. This is supported by the observation that 60% of patients with chronic idiopathic urticaria experience a wheal or flare reaction when autologous serum is administered intradermally when skin testing with autologous serum is performed. About 50% of patients with chronic idiopathic urticaria have specific IgG for the high-affinity IgE receptor (FcεRI). These autoantibodies activate skin mast cells, circulating basophils, and the complement system. Additional immunologic abnormalities that play a causative role in CC have been described and include IgG directed against IgE and low-affinity IgE receptors (FcεRII), antiendothelial antibodies, and C8 alpha-gamma deficiency in the complement system. Approximately 35% of patients with chronic idiopathic urticaria experience episodes of angioedema, and 25% have positive dermatographism. Like many autoimmune diseases, chronic idiopathic urticaria is more common among women than men, with a gender incidence of 2:1 to 4:1 reported by the authors. The variety of autoimmune conditions associated with chronic idiopathic urticaria include autoimmune thyropathies, celiac disease, and RA. The purpose of this review is to discuss the relationship of CU with autoimmune thyropathy and other autoimmune diseases, as well as the implications of this situation, which may be important for therapeutic intervention in CU.
Autoimmune thyropathy and CC.
Autoimmune thyropathy is the most commonly reported autoimmune condition in patients with CU. In the literature, the frequency of autoimmune lesions of the thyroid gland in patients with CU varies from 6.5% to 57%. Patients with coexisting autoimmune pathology and urticaria have a longer duration of urticaria, in contrast to those who do not have it. Patients with both CC and autoimmune pathology have an increased risk of developing angioedema. Leznoff and Sussmann reported that the triad of autoimmune thyropathy, CU, and angioedema occurs in 15% of those with CU. The risk of developing angioedema in patients with autoimmune thyropathy and CU is estimated to be 16.2 times higher than in patients with CU without thyropathy. In a recent large study of 12,778 patients with CU, Cofino-Cohen et al. it was found that 9.8% of patients had hypothyroidism, compared with 0.6% in the control group. Hypothyroidism was the most frequently identified autoimmune thyroidopathy in patients with CU. Women were more likely to have a combination of hypothyroidism and chronic hyperthyroidism than men. Patients with hyperthyroidism and CU comprised 2.7% of the study population, compared with 0.09% in the control group. In most patients, autoimmune thyropathy was identified in the next 10 years after the diagnosis of CU. This means that autoimmune thyropathy developed after the first manifestation of CU. In the same study, antithyroid antibodies were a significantly more common finding in patients with CU compared with controls. Among patients with CU who clinically had no signs of damage to the thyroid gland, antibodies to thyroid peroxidase were detected on average in 2.7%, antibodies to thyroglobulin - in 0.6%. Aamir et al. also noted a connection between antithyroid antibodies and CC, because The level of antibodies to thyroglobulin and microsomes was significantly increased among patients with CU and hypothyroidism. The development of autoimmune thyropathy is often considered a marker of autoimmunity. Autoimmune thyropathy is associated with a variety of autoimmune diseases, including in addition to CU, pernicious anemia, celiac disease, type 1 diabetes and SLE. Although the specific mechanism between the development of autoimmune thyropathy and CU has not yet been clearly established, it is widely believed that both diseases occur due to the tendency patient to the development of autoimmune reactions. It has been hypothesized that autoimmune thyropathy may worsen urticaria and angioedema by activating the complement system. Blanchin et al. demonstrated that thyroid peroxidase contains a domain that binds complement protein C4, activates it to C4a, and activates complement via the classical pathway. Kirpatrick noted that C4a levels are reduced in treated autoimmune thyropathy, leading to remission of CU. Based on this, a theory has been put forward that autoimmune thyropathy and CU can coexist due to the patient’s tendency to autoimmune reactions, and that autoimmune thyropathy can further aggravate the course of urticaria and angioedema through direct mechanisms of complement activation.
Other autoimmune diseases and chronic urticaria.
In addition to autoimmune thyropathy, many autoimmune diseases have been studied for association with CU. Confino-Cohen et al. showed that 12.5% of patients have another autoimmune disease, 2.1% have 2 diseases, 0.1% have 3 diseases, and a few patients have 4 or 5 diseases. Among patients with chronic hyperthyroidism and hypothyroidism, RA was the most common. The incidence of RA was 13.25 times higher among patients with CU than in the control group. Ryhal et al. showed that the main laboratory marker of RA, rheumatoid factor, was significantly elevated in patients with CU. Patients with CU of both sexes have an increased risk of developing type 1 diabetes. Among women with CU, the incidence of Sjögren's syndrome, celiac disease, or SLE was significantly higher than in controls. Most patients were diagnosed with an additional autoimmune disease within 10 years of CU diagnosis, highlighting that the diseases developed sequentially and were not incidentally discovered at the time of CU diagnosis. The association between celiac disease and CU has been previously discussed in the pediatric population. Asero et al. CC and Raynaud's phenomenon with positive anticentromere antibodies have been described. Other autoimmune diseases such as vitiligo and pernicious anemia have also been associated with CU. CU has been shown to have a genetic link to the human leukocyte antigen alleles HLA-DR4 and HLA-DQ8. HLA-DR4 is significantly associated with RA, HLA-DQ8 – with celiac disease and type 1 diabetes. Complement deficiency is associated with autoimmune diseases such as Sjögren's syndrome, RA, and SLE, as evidenced by the report of Park et al. about the development of CC, spondyloarthropathy and the presence of antinuclear antibodies in a 9-year-old boy with C8α-γ deficiency. CU was described in a 10-year-old boy with a strong autoimmune phenotype. The full list of diseases included total alopecia, vitiligo, psoriasis, Graves' disease, chronic hyperplasia, the autoimmune form of Lambert-Eaton myasthenic syndrome, and IgA deficiency. This patient had HLA genes that were found in the expanded haplotype 8.1 (ancestral haplotype), which is associated with the development of many autoimmune conditions. These cases clearly show that CU can occur as a manifestation of a combination of autoimmune diseases.
Treatment.
Treatment guidelines for CU were based on the GRADE approach. The second generation of non-sedating histamine type 1 receptor blockers is the 1st line of treatment for patients with CU. If the effect is not achieved within 2 weeks, a 2nd line of therapy is used, which consists of a 4-fold increase in the dose of antihistamines from the standard dose. Patients should be informed that symptoms of sedation and drug interactions may occur with increasing dosage. Cetirizine, desloratodine, fexofenadine and bilastine have been identified as the safest antihistamines when the dosage is increased. In 50% of observed patients, symptoms persist when using monotherapy with antihistamines. The 3rd line of therapy includes replacing antihistamines or combining them with leukotriene receptor antagonists. Leukotriene receptor antagonists are indicated for the improvement of patients with intolerance to ASA or NSAIDs in urticaria, with a positive skin test with autologous serum, or in urticaria with food hypersensitivity, but not in chronic idiopathic urticaria. A short 3-7 day course of systemic steroids can be used in conjunction with 3rd line therapy. If the 3rd line of therapy is unsuccessful, proceed to the 4th line of therapy, including the use of cyclosporine A, type 2 histamine receptor blockers, dapsone or omalizumab. The most effective in the 4th line of therapy for CC is omalizumab, monoclonal antibodies against IgE, used for treatment of severe forms of asthma. Mauer et al. published a randomized, double-blind study evaluating the effectiveness of omalizumab among patients with CU who had failed first-line therapy and showed a significant reduction in CU symptoms. Omalizumab reduced free IgE and levels of high-affinity IgE receptors on mast cells and basophils (cells thought to be responsible for the development of blisters in CU). The literature reports additional treatment for patients who fail 4th line therapy, which includes mycophenolate mofetil, methotrexate, tacrolimus, sulfasalazine and intravenous immunoglobulin. Treatment of concomitant autoimmune thyropathy has been reported to induce remission of CU. Kirkpatrick conducted a study in CU patients with apparent clinical or serological autoimmune thyropathy. In addition, first-line therapy with antihistamines was ineffective among these patients. It was demonstrated that levothyroxine induced remission of angioedema and urticaria in all 6 patients with autoimmune thyropathy and CU. Rumbryt reported obtaining clinical remission of CU in 7 out of 10 euthyroid patients with antithyroid antibodies by administering thyroxine, but when CU relapsed, therapy was discontinued. These studies suggest that treatment with levothyroxine may play a role in remission of CU in patients with CU and clinically diagnosed autoimmune thyropathy. However, Magen et al. recently compared patients with CU and autoimmune thyropathy treated with levothyroxine with patients with CU and euthyroid status (control). Patients treated with levothyroxine showed clinical improvement in urticaria, but no similar improvement was observed in the control group. This led to the conclusion that improvement in clinical symptoms in CU occurred spontaneously, regardless of treatment. Controversial data in the literature regarding the importance of treating autoimmune thyropathy in CU indicates the need for additional extensive research to establish the role of levothyroxine in patients with CU. The use of NSAIDs demonstrated a worsening of CU in an average of 20% of patients with a primary diagnosis of CU. NSAIDs are widely used to treat pain and inflammation associated with RA, inflammatory spondylopathies, and lupus arthritis. Autoimmune inflammatory arthropathies, especially RA, have been shown to be more common in patients with CU than in the general population. Therefore, exacerbation of CU symptoms due to NSAID use should be closely monitored in patients with CU and autoimmune arthropathies. Zembowitcz et al. demonstrated that selective COX-2 inhibitors do not cause urticaria in patients with CU, as is the case with NSAIDs. According to this, it is assumed that selective COX-2 inhibitors are preferable to NSAIDs in terms of preventing exacerbation of CC. It was previously assumed that Helicobacter pylori (H. pylori) may be an etiological factor in CU. This was supported by reports demonstrating a high incidence of H. pylori among patients with CU and improvement in clinical symptoms following eradication. But this assumption was questionable, since a number of authors did not find differences in the production of antibodies in patients with H. pylori and CC and the control group. Additional evidence was also demonstrated that eradication did not affect clinical recovery in CU. This discrepancy in the literature occurs due to differences in detection methods, resistance to therapy, and the possible return of H. pylori soon after treatment. Adding further confusion is recent evidence suggesting that eradication may be a trigger for CC. Shakouri et al. performed a review of the literature regarding H. pylori eradication and CU using the GRADE system, and concluded that the evidence for treatment was weak and more studies are needed to establish whether H. pylori eradication is beneficial for patients with CU.
Conclusion.
HC is urticaria with daily rash lasting more than 6 weeks. It is currently believed that up to 50% of cases of CU are caused by autoimmune mechanisms. The most commonly detected antibodies are those with high affinity for IgE receptors, which activate mast cells, basophils and the complement system, leading to blistering and worsening of the rash. It is assumed that CU occurs when the patient is predisposed to autoimmune diseases. Consistent with this hypothesis, other autoimmune diseases are also observed in patients with CU. Autoimmune thyroidopathy, hyperthyroidism in particular, is the most common concomitant autoimmune disease. Moreover, autoimmune thyropathy can directly aggravate the severity of CU by activating the complement system. Other autoimmune diseases that most often occur in patients with chronic urticaria are RA, SLE, vitiligo, pernicious anemia, celiac disease, and Sjögren's syndrome. In practice, CU may be part of a larger autoimmune phenotype. These connections are supported by the theory that patients who develop CU have an intrinsic predisposition to develop autoimmune reactions. According to the literature, treatment of autoimmune thyropathy has different effects on CU: induction of remission and no effect on the clinical course of CU. The treatment of autoimmune diseases, especially autoimmune thyropathy, in patients with CU is considered important, but further research is needed to justify this treatment in CU.
