Definition and clinical presentation
Urticaria is a disease with complex aetiology and pathogenesis. A common feature of all variants of urticaria is the clinical presentation, characterized by a sudden appearance of wheals on the skin.
The name of the disease comes from the Latin word urtica (hives) a common plant whose leaves trigger the development of characteristic itching oedematous lesions on the skin.
A wheal is a raised skin lesion, porcelain white or pink in colour, which develops and disappears within 24 hours without scarring.
The size of wheals varies – their diameter may reach from a few millimetres to several centimetres (urticaria gigantea). Sometimes, individual lesions may become confluent and form polycyclic shapes, which cover large skin areas (urticaria circinata). Often wheals spread peripherally: with central clearing, and the lesions persist at the rims (urticaria annularis).
A typical feature of urticaria is severe pruritus and a sensation of skin burning. These symptoms may appear even before the wheals, and scratching the skin can provoke the appearance of new lesions in some cases.
The appearance of wheals may be accompanied by symptoms of angioedema – in about 40% of patients diagnosed with urticaria. This oedema is characterized by a sudden appearance of a limited skin, subcutaneous tissue or mucous membrane oedema, which resolves within 24–72 hours. The appearance of oedema is associated with the sensation of pain, bursting or tension, without pruritus. Oedematous lesions may appear in various localizations, most often the lips or eyelids, occasionally the anogenital area. The oedema may affect the larynx, what can pose a life-threating risk for the patient.
The underlying cause of urticaria is and increased permeability of blood vessels induced by degranulation of mast cells (mastocytes) and the release of several proinflammatory mediators, predominanly histamine, leukotrienes, and prostaglandins.
The activity of chronic urticaria and its influence on patient well being and comfort is most often assessed with the use of the Urticaria Activity Score (UAS), which is based on evaluating the number of wheals and pruritus intensity in the range of 0 to 3 for every symptom (table 1). It is a simple and clear test based on a numeric scale that can be used both by physicians and patients. A modified UAS, a so-called UAS7, is also very useful as it analyses the intensity of urticarial symptoms for 7 consecutive days. The application of this score allows for objective assessment of the course of urticaria and efficacy of applied therapeutic methods.
Classification and causes of urticaria
There is a wide spectrum various types of chronic urticaria. Moreover, several types of urticaria may be concomitant in a patient.
Urticaria is most often divided on the basis of following criteria: symptom duration, aetiological factors, and pathogenetic mechanisms.
With regard to the disease duration, urticaria is divided into acute and chronic with an accepted time limit being set at 6 weeks after the first appearance of wheals.
Acute urticaria is a common disease. Over 25% of the general population experiences an episode of acute urticaria in their lifetime. This form affects both children and adults. It may vary in intensity and course. In some patients it is mild, transient, while in severe cases it be a harbinger of life-threatening anaphylactic reactions. Food, drugs, infectious factors, hymenoptera venom, and plant pollen most often cause acute urticaria.
Chronic urticaria, in which symptoms persist continuously or with recurrences and remissions for
a period longer than 6 weeks, affects about 1% of the general population. Because of frequent diagnostic and therapeutic difficulties, this type constitutes a considerable challenge in everyday dermatological and allergological practice. The variety of underlaying factors and diverse mechanisms responsible for the development of urticaria causes controversy in regard to classification. In addition, the fact that one patient might be affected by different types of urticaria at the same time makes creating a practically useful classification of urticaria difficult. According to the newest European guidelines chronic urticaria is divided into induced and spontaneous depending on the presence or absence of noticeable triggers for the appearance of wheals (table 2).
In spontaneous urticaria, wheals or angioedema develop without a noticeable triggering factor. In the group of spontaneous urticaria with known cause, autoimmune urticaria and infectious urticaria are most common.
In individuals with autoimmune urticaria serum IgG autoantibodies directed against: immunoglobulin E (IgE), high-affinity immunoglobulin E receptor (FcεRI) a-chain, or thyroid antigens. These autoantibodies cause mast cell degranulation with release of inflammation mediators and wheal development.
Induced chronic urticaria includes a number of types such as: inducible urticaria (dermatographism), cold-induced urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibratory urticaria, cholinergic urticaria, contact urticaria, and aquagenic urticaria (table 3).
Diagnosis of urticaria
Acute urticaria does not require diagnostic testing in most cases. In most cases the cause of skin lesions may be determined on the basis of a detailed anamnesis. An exception is a suspicion of acute urticaria caused by food allergy in the first immunological mechanism (IgE-dependent) or a suspicion of other factors that might have caused it, e.g. nonsteroidal anti-inflammatory drugs (NSAIDs). In patients with acute urticaria triggered by a bite of an insect from the hymenoptera order it is recommended to perform allergological tests (the level of sIgE) to decide on further procedures.
The diagnostic procedure in chronic urticaria is based on an attempt to detect factors causing or leading to disease exacerbation, assessment of the activity level, determination of the disease influence on patients’ daily activities, assessment of treatment efficacy, and exclusion of disease entities, in which symptoms (wheals and oedema) depend on other mediators than the ones produced by mast cells, including interleukin 1 or bradykinin. It includes the following:
– taking detailed medical history with regard to frequency and circumstances of symptom developments, morphology of skin lesions and accompanying subjective symptoms (pruritus, burning sensation), possible provocative factors, skin reaction to physical stimuli, drugs taken, eating habits, infectious foci, concomitant diseases (including allergic, mental and infectious diseases), history of urticaria or angioedema in the family, atopy, past surgeries including anaesthesia, orthopaedic surgeries including implants, and reactions to past treatments;
– basic laboratory tests – obligatory tests: CBC, ESR, or CRP;
– widened laboratory diagnostics – facultative tests in justified cases depending on the medical history may include: thyroid hormone tests, antithyroid and antinuclear antibodies, diagnosis of infections depending on the patient’s exposure and geographical region (e.g. Helicobacter pylori), viral hepatitis tests, parasitological tests, cryoglobulin level, complement components, as well as C1-INH level and activity;
– basic imaging tests (chest X-ray, abdominal ultrasound);
– consultations with individually selected specialists (dentist, laryngologist, gynaecologist, urologist in order to search for foci of infections);
– allergy tests (skin prick test and specific IgE concentration) – advisable only in patients with suspected IgE-dependant allergy to airborne and food allergens and hymenoptera venom allergy order;
– physical tests (TempTest, FricTest, dermographometer, tests involving wooden blocks, straps and cylinders with weights, warm water, light exposure, exercise stress test);
– test involving autologous serum (ASST; positive for autoimmune urticaria);
– provocative and elimination diets (an attempt to identify food types inducing the symptoms);
– discontinuation of drugs that are believed to provoke appearance of urticaria (acetylsalicylic acid, other NSAIDs, ACE inhibitors);
– drug provocation tests;
– determination of the level of blood serum triptase;
– skin biopsy for histopathological evaluation, especially when wheals persist for over 24 hours or disappear leaving visible marks (table 4).
Differential diagnosis of urticaria
In the majority of cases the diagnosis of urticaria can be easily established, thanks to its characteristic clinical presentation. Urticaria should be differentiated from other diseases that might manifest with wheals, angioedema, or both of these symptoms such as:
– anaphylactic shock;
– mastocytosis;
– autoimmune inflammatory syndromes;
– urticarial vasculitis;
– isolated bradykinin-mediated angioedema, e.g. hereditary angioedema (HAE).
Solar urticaria requires differentiation with porphyria, and polymorphous light eruptions.
Diagnosing urticaria requires differential diagnosis especially in cases when appearance of wheals is accompanied by systemic – headaches, fever, joint pain, swollen lymph nodes, or symptoms originating from abdominal cavity organs.
General rules for the treatment of urticaria
Therapeutic procedures for urticaria include:
– avoidance of factors triggering clinical symptoms;
– treatment of concomitant diseases;
– pharmacotherapy (treatment of symptoms).
Detection and elimination of factors causing urticaria (food, drugs, physical factors) as well as treatment of concomitant diseases that may cause chronic urticaria are of key importance in therapies. This allows achieving complete, pharmacotherapy free remission in most cases.
Current guidelines for pharmacotherapy in urticaria are presented in table 5.
Second-generation antihistamines
Symptomatic treatment of urticaria should start with the second-generation antihistamine drugs (bilastine, cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, rupatadine), which can be used in long-term therapies thanks to their good safety profile (no significant sedative effects or influence on the cardiovascular system). Because of different efficacy and tolerance as well as patient’s preferences for given drugs in this group, when there are no satisfactory clinical effects after the administration of one drug, it may be attempted to change it for another second-generation antihistamine drug. In patients who fail to react to a standard drug dose, the dose may be increased even 4-fold compared to the dose indicated in the summary of product characteristics (SPC). Despite the fact that none of the above antihistamines has such a dosage in the SPC, there is significant scientific evidence that increasing the dose of these antihistamines is safe and allows achieving better control over chronic urticaria in a greater number of patients. In Europe, the first-generation antihistamines are not recommended for long-term use in urticaria.
Omalizumab
In patients, in whom no improvement is achieved after 2–4 weeks and in cases of intense urticaria. It is recommended to add omalizumab, a biological drug from the group of anti-IgE monoclonal antibodies. In most cases, the use of omalizumab brings spectacular improvement both in chronic spontaneous urticaria and the majority of types of induced urticaria. The most commonly recommended dose is 300 mg administered in one injection – every 4 weeks. The use of this drug is limited by the high cost of treatment in some countries.
Since January 2020 treatment of chronic urticaria with omalizumab may be reimbursed within the framework of drug program called Treatment of Spontaneous Chronic Urticaria (ICD-10: L50.1) (table 6). It ensured the access to biological therapy for patients affected by a severe form of the disease. Treatment within the program should be led by physicians specializing in dermatology and allergology that have experience in administration of biological therapies.
Cyclosporin (CsA)
When there is no satisfactory reaction to high doses of the second-generation antihistamines and omalizumab is either ineffective or unavailable, after 6 months of treatment (or earlier of urticaria is exacerbated) it is recommended to add cyclosporin, an immunosuppressive drug that inhibits release of mediators from the mast cells. Despite the possibility of adverse effects, cyclosporin is considered safer as compared to systemic glucocorticoids.
Glucocorticosteroids
Long-term use of glucocorticosteroids in urticaria is contraindicated because of possible adverse events. Short-term therapy with glucocorticosteroids may be considered in patients with a severe disease course.
Topical use of preparations containing glucocorticosteroids in urticaria is not recommended.
Conclusions
Clinical diagnosis of urticaria is not problematic in the majority of cases as its clinical presentation is characteristic. In many cases it is difficult to determine the factors that cause symptoms to appear.
Chronic urticaria constitutes a challenging clinical problem due to long-term and troublesome nature of symptoms, unsatisfactory treatment results observed in numerous patients and significant decrease in their quality of life associated with it.
To diagnose the cause of chronic urticaria it is of key importance to take detailed medical history that allows for directing further course of tests as well as limit intense and pricey diagnostics.
The Polish programme of chronic spontaneous urticaria treatment using omalizumab, which is currently implemented, adapts instructions how to use this medicine contained in the recommendations and will certainly improve its availability.
It should be emphasized that all diagnostic and therapeutic decisions are made by the physician individually for each patient. These recommendations are solely a general summary of the most current knowledge about urticaria. This article is not a recommendation for a particular product or manufacturer.
Conflict of interest
The authors declare no conflict of interest.
References/Piśmiennictwo
Criado P.R., Criado R.F., Maruta C.W., Dos Reis V.M.S.: Chronic urticaria in adults: state-of-the-art in the new millennium. An Bras Dermatol 2015, 90, 74-89.
Ferrer M., Bartra J., Gimenez-Arnau A., Jauregui I., Labrador-Horrillo M., Ortiz de Frutos J., et al.: Management of urticaria: not too complicated, not too simple. Clin Exp Allergy 2015, 45, 731-743.
Fine L.M., Bernstein J.A.: Urticaria guidelines: consensus and controversies in the European and American Guidelines. Cur Allergy Asthma Rep 2015, 16, 30.
Kaplan A.: Diagnosis, pathogenesis and treatment of chronic spontaneous urticaria. Allergy Asthma Proc 2018, 39, 184-190.
Kocaturk E., Maurer M., Metz M., Grattan C.: Looking forward to new targeted treatments for chronic spontaneous urticaria. Clin Transl Allergy 2017, 7, 11.
Pokrzywki – rozpoznawanie i leczenie. Stanowisko Panelu Ekspertów Polskiego Towarzystwa Alergologicznego. J. Kruszewski, R. Nowicki, R. Śpiewak (eds.): Medycyna Praktyczna, Kraków 2011.
Maurer M., Magerl M., Metz M., Siebenhaar F., Weller K., Krause K.: Practical algorithm for diagnosing patients with recurrent wheals or angioedema. Allergy 2013, 68, 816-819.
Naaman S., Sussman G.: Chronic idiopathic urticaria: treatment with omalizumab. Skin Therapy Lett 2014, 19, 1-4.
Najafipour M., Zareizadeh M., Najafipour F.: Relationship between chronic urticarial and autoimmune thyroid disease. J Adv Pharm Technol Res 2018, 9, 158-161.
ABC pokrzywki. Pokrzywka w pytaniach i odpowiedziach. R. Nowicki (ed.). Termedia, Poznań, 2017.
Staevska M., Popov T.A., Kralimarkova T., Lazarova C., Kraeva S., Popova D., et al.: The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria. J Allergy Clin Immunol 2010, 125, 676-682.
Zuberbier T., Aberer W., Asero R., Abdul Latiff A.H., Baker D., Ballmer-Weber B., et al.: The EAACI/GA2 LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria. Allergy 2018, 73, 1393-1414.
