This is a post from our archive.Current information on the subject can be found on our Urticaria topic page.The stinging nettle is one of the few plants that gives its name to a disease: nettle rash, nettle fever or nettle rash, as urticaria is colloquially called.The medical term is based on the botanical name of the nettle - Urtica.The reason for the link lies in the characteristic symptom of hives: wheals on the skin, such as occur after touching stinging nettles.The term nettle addiction also refers to the sometimes extreme itching that can make scratching an addiction.One form of urticaria: wheal formation on the skin.Photo: Lippe.Shutterstock/MH-LeeThe term urticaria summarizes a number of diseases that are characterized by the occurrence of wheals or swelling of the skin and mucous membranes (angioedema) or both.Fever, fatigue, sleep disorders, anxiety and depression can also occur.But not every disease with wheals or angioedema is hives, according to the international guideline published in the journal Allergy in early 2018 (DOI: 10.1111/all.13397).Another form of urticaria: angioedema on the lip.Photo: Shutterstock/Velimir IsaevichDoctors describe a raised change in the skin surrounded by redness as a wheal.It is usually accompanied by itching, sometimes with burning.In principle, angioedema that occurs suddenly is also a swelling that affects the deeper layers of the skin and/or the mucous membrane (Table 1 at the end of the article).Angioedema occurs primarily on the face (lips, eyelids), hands, feet, arms, legs, or genitals.Angioedema can last up to three days, be painful, and less often itchy.Depending on the location, it can be life-threatening.The classification of the various forms of urticaria is based on the duration of the disease and the causes.By definition, acute urticaria is present if the disease lasts a maximum of six weeks and resolves spontaneously during this time.If the symptoms persist or recur again and again, it is chronic urticaria.There are two forms: spontaneous and the rarer inducible urticaria (Table 2 at the end of the article).In the case of chronic spontaneous urticaria (csU), the symptoms appear suddenly, usually for no apparent reason.The presentation varies: more than half of the patients develop wheals and angioedema, up to a third have only wheals and about one in ten exclusively angioedema (1).The hives can be a few millimeters to a few centimeters in size on average and appear on different skin areas within minutes to hours.Chronic inducible urticaria is triggered by certain stimuli.These can be physical stimuli such as cold, heat, pressure, light, scratching or contact with water.The most common inducible form is cholinergic urticaria.It occurs primarily after physical activity, and in some sufferers also during emotional stress or the consumption of hot, spicy foods.Cold urticaria ranks second among the inducible forms.It appears within a few minutes after the skin has been exposed to the cold and then warmed up again.The cold stimuli can come from cold air, liquid or solid objects.The hives, or angioedema, usually last about an hour.In severe cases, general reactions up to and including anaphylaxis can occur.Perhaps most impressive is the rare form of urticarial dermographism (urticaria factitia).If you run an object over the skin, the result is an image as if someone had written on it, because line-shaped wheals form.Urticaria can occur at any age.However, women between the ages of 20 and 40 are particularly frequently affected (3).With a lifetime prevalence of around 20 percent, acute spontaneous urticaria is one of the most common diseases.In about one tenth of patients, the symptoms persist for more than six weeks, so they develop a chronic disease.Duration and severity are very different;on average, chronic urticaria lasts three to seven years before it goes away on its own.Between 0.5 and 1.0 percent of the population suffer from a chronic spontaneous form, with about a quarter of them also having an inducible form (2).The sudden onset of the symptoms and the very variable frequency and frequency put a heavy strain on the daily life of the patients.Similar to psoriasis, csU is one of the skin diseases that impairs the quality of life the most (4, 5).In a Japanese study, more than 50 percent of urticaria patients reported that the disease disturbed their night's sleep.About 64 percent felt restricted in their activity and performance at work (6).Urticaria in all its forms is a skin mast cell mediated disease.The release of histamine plays a central role in this.Among other things, this causes vasodilatation and the subsequent escape of plasma fluid into the tissue – the cause of the swelling.By stimulating the sensory nerve endings, histamine also triggers itching.In addition, the mast cells release leukotrienes and prostaglandins as well as somewhat delayed inflammatory cytokines (3).These mediators are also significantly involved in the course of the disease.The pathogenesis of urticaria is very complex and has not yet been elucidated in detail.Scientists observed increased expression of adhesion molecules, neuropeptides and growth factors in the skin during the acute phase.They also found a perivascular infiltrate of neutrophils and/or eosinophils, basophils, macrophages, and T cells (7).After the acute wheals have subsided, a refractory phase occurs in which the affected skin area remains symptom-free.When the mast cells have regenerated, they can release histamine and other mediators again when activated.Physical stimuli such as cold can also trigger hives.Photo: Fotolia/ExQuisineWhat causes the activation and degranulation of the dermal mast cells in individual cases varies depending on the form of the disease.The modulating factors that change the stimulation threshold in patients with chronic urticaria also vary from person to person.Scientists suspect two autoimmune mechanisms to be the most common causes of mast cell degranulation: On the one hand, IgE autoantibodies against endogenous antigens bind to the mast cells and lead to degranulation.Furthermore, IgG autoantibodies against endogenous IgE or the IgE receptor can degranulate the mast cells (7).It is striking that chronic spontaneous urticaria often occurs as an accompaniment to autoimmune diseases such as rheumatoid arthritis or lupus erythematosus.A link with autoimmune diseases is also shown by the observation that around 27 percent of those affected had thyroid antibodies (3).Scientists suspect that in the case of inducible urticaria, the corresponding triggers such as cold, heat or vibration act on pre-autoallergens and thus lead to a de novo synthesis of autoallergens (8).In addition to autoimmune reactions, infections or pseudoallergic reactions to food or drugs can trigger chronic spontaneous urticaria.The clinical appearance of urticaria is usually clear, so that the diagnosis is usually easy to make.If hives occur acutely, it can initially be assumed that they will subside within six weeks.Therefore, in most cases, doctors do without a time-consuming search for the cause and limit themselves to symptomatic treatment.In two cases, however, it makes sense to search for the cause directly: if drug-induced urticaria (Box) or a food allergy is suspected.In particular, non-steroidal anti-inflammatory drugs (NSAIDs) and ACE inhibitors relatively often trigger or worsen urticaria.However, this side effect has also been described for antibiotics, especially beta-lactams and sulfonamides, and opioids (3).Discontinuing the relevant medication or replacing it with a drug from a different class of substance often causes the symptoms to disappear or subside.An intolerance reaction to acetylsalicylic acid (ASA) and other non-steroidal anti-inflammatory drugs (NSAIDs) is referred to as Samter's triad or Widal's disease.The disease, which is called aspirin-exacerbated respiratory disease in Anglo-American parlance, is a pseudoallergic reaction to NSAIDs with a characteristic symptom complex:• nasal symptoms (obstruction, rhinorrhea, nasal polyps),• non-allergic asthma with severe asthma attacks and• Skin symptoms in the form of urticaria and angioedema.There is also a form in which practically only skin symptoms occur (NSAID exacerbated cutaneous disease).The disease can occur after taking drugs that inhibit cyclocoxigenase-1 (COX-1).According to the current state of knowledge, the cause is a misdirection of the arachidonic acid metabolism, which leads to an accumulation of lipoxygenase products.The leukotrienes (LTC4, LTD4, LTE4) in particular have a strong inflammatory and bronchoconstrictor effect.NSAID intolerance runs more frequently in some families.Presumably, there is a polymorphism of the promoter gene in people who are sensitive to this, which leads to increased expression of the leukotriene genes.A prevalence of 0.5 to 5.7 percent is given for the normal population.At around 15 percent, it is significantly higher in asthmatics (16, 17).If a type I food allergy is suspected, an allergy test is indicated.If the assumption is confirmed, those affected should avoid the trigger if possible.However, an IgE-mediated food allergy is very rarely the cause.If the urticaria persists for more than six weeks, a detailed investigation is required.The first thing to do here is to rule out other diseases that are also associated with the formation of wheals and/or angioedema.Examples include urticaria vasculitis, chronic vascular inflammation, or congenital or acquired angioedema.It is recommended that those affected keep a complaints diary and document how often and under what circumstances the hives appear and how long they remain.Location, shape and size are also of interest.Can they be associated with temperature, stress, food, medication, the menstrual cycle or infections?Are there accompanying symptoms?Does angioedema occur at the same time?The pharmacy team can recommend that those affected start with such a diary before they consult a doctor.Because if the patient already brings this information to the doctor's appointment, this speeds up the diagnostic process.In patients with recurrent angioedema without wheals, bradykinin-mediated diseases such as hereditary angioedema, ACE inhibitor-induced angioedema, or acquired C1 inhibitor deficiency should be considered as the cause (Box) (7).Angioedema can occur in various diseases.A basic distinction must be made between mast cell-mediated and bradykinin-mediated angioedema.The former are much more common and are mainly mediated by histamine.They occur in urticaria, as well as in allergic and pseudoallergic reactions.Angioedema in the area of ​​the upper respiratory tract can cause shortness of breath and, due to the unpredictability of the further course, pose a potentially life-threatening risk.Bradykinin-mediated angioedema can be genetic or acquired during life, for example by ACE inhibitors and angiotensin II receptor blockers (sartans).Angioedema as a side effect of ACE inhibitors occurs in 0.2 to 0.7 percent of patients, depending on the preparation.Gliptins or neprilysin inhibitors such as sacubitril in combination with ACE inhibitors or sartans can increase their risk of angioedema (18).The triggers of inducible forms of chronic urticaria are usually easy to diagnose, since the symptoms are easily provoked.In the case of a spontaneous illness, however, it is often not possible to clearly assign the symptoms to a cause.CSU is associated with inflammatory and/or infectious diseases with striking frequency.However, it is unclear how to interpret this finding.Do the diseases play a role in the development of urticaria or do they only aggravate the symptoms?Even if possible pathophysiological mechanisms have not been elucidated, in many cases there seems to be a connection (7).It is therefore worthwhile to treat infections and other inflammatory diseases in a targeted manner.There is hope that this will also cure or alleviate urticaria.Good experiences have been made, for example, with Helicobacter infections of the gastrointestinal tract and bacterial infections of the nose, throat or mouth.The aim of the therapy is to achieve complete freedom from symptoms.This succeeds in a large majority of patients (8).Only chronic, inducible urticaria often has a severe and protracted course and responds poorly to therapy (3).According to the German version of the guidelines on chronic urticaria (DOI: 10.1111/ddg.13531), chronic urticaria should be treated until spontaneous remission occurs.If the cause of the hives is known, the patient can possibly avoid the triggering factors and achieve freedom from symptoms in this way.A suspicion of a pseudoallergic food intolerance should be specifically investigated.Diet trials under the guidance of a nutritionist should last at least two to three weeks.Otherwise, it is not possible to assess whether avoiding certain foods is actually successful.In some forms of urticaria, namely cold or solar urticaria and cholinergic urticaria, tolerance induction can be attempted under medical supervision.Similar to desensitization for an allergy, the aim is for those affected to learn to tolerate the triggering stimulus by getting the body used to it with increasing amounts.However, the success is very limited and often lasts only a few days, so that frequent and regular repetition of the stimulus is required.Better effects can be achieved with pharmacotherapy for all forms of urticaria, even if this is only symptomatic.It aims to inhibit mast cell activation or block mediators released by mast cells.Drug therapy follows a step-by-step scheme that applies to all chronic forms and also to children if there is a special benefit-risk assessment (Figure).Drugs of first choice are antihistamines, which is obvious in view of the pathomechanism of the disease.Finally, most urticaria symptoms are due to the action of histamine on the H1 receptors of endothelial cells and sensory nerves.Because of better tolerability, the guideline recommends second-generation H1 antihistamines, such as cetirizine and levocetirizine, desloratadine and loratadine, ebastine, fexofenadine and rupatadine.Antihistamines are also the drug of choice for children under the age of 12 (sometimes off-label), although chronic urticaria is rare in them (10).Local treatment with antihistamines is not effective.H1 antihistamines should be used continuously and not only when symptoms reappear.Important to know: In the case of urticaria, the usual daily dose is often not sufficient to achieve symptom control.If no adequate improvement is achieved after two to four weeks - or earlier in the case of severe symptoms - the guideline recommends increasing the dose of the antihistamine to a maximum of four times the daily dose specified in the product information.A meta-analysis showed that up to 63% of patients respond positively to a higher dose, while the standard dose is only sufficiently effective in 39% of patients (11).As an alternative to increasing the dose, the active ingredient can be changed, since urticaria patients respond differently to individual antihistamines.In the case of acute flare-ups, high-dose oral glucocorticoids can supplement the therapy for a short time (maximum ten days).For prednisone, a dosage of 20 to 50 mg per day is recommended for adults.Non-sedating antihistamines are the first choice for chronic urticaria.Photo: Fotolia/CarballoSince the severity of urticaria fluctuates over time and spontaneous remissions can occur, a withdrawal attempt should be performed about every three to six months to determine whether treatment is still necessary.If, despite increasing the dose, antihistamines do not bring satisfactory results after two to four weeks (even earlier in the case of severe symptoms), therapy with omalizumab can also be started.The recombinant humanized monoclonal IgE antibody is approved for the treatment of chronic spontaneous urticaria in adults and adolescents aged 12 and over.One subcutaneous injection is recommended every four weeks (two pre-filled syringes of 150 mg each).In many patients, the effect begins within the first week.However, since an improvement in symptoms can only occur later, the success of the treatment should be assessed after four weeks at the earliest.A small number of patients even need several treatments before they respond adequately (9).According to the guideline, depending on the individual response, the off-label administration interval can be lengthened or shortened, or the dose changed.In symptom-free patients, it is advisable to try to stop the treatment regularly, i.e. about every six months, in order not to overlook a possible spontaneous healing.If the symptoms recur, the therapy can be resumed without loss of effectiveness (12).Omalizumab is also effective and safe in chronically inducible urticaria, but is not approved for this (13, 14).If the symptoms are not adequately controlled after six months (even earlier if the symptoms are severe), the fourth possible treatment step is to combine ciclosporin A with an H1 antihistamine instead of omalizumab.Ciclosporin A directly inhibits the release of mast cell mediators.Use is reserved for severe cases and requires careful management of side effects.It is used off-label for chronic urticaria.Another last treatment option in the past was the leukotriene receptor antagonist montelukast.However, more recent assessments question its usefulness (3).The pharmacy team should recommend that patients with chronic spontaneous urticaria refrain from drinking alcohol and taking NSAIDs, as these can exacerbate the course of the disease.Cutting out histamine-rich and/or spicy foods is also worth trying.Prevention: It is better to avoid hot spices.Photo: Fotolia/Anna ChelnokovaOtherwise, however, diets are not recommended, as they do not promise success and further reduce the quality of life (3).As with many other skin conditions, stress can make symptoms worse.It is therefore worthwhile for many patients to learn stress-relieving techniques or sports.A look into the future: Rituximab and TNF-alfa inhibitors are currently also used outside of approval (15).Of the possible future therapy options for the chronic spontaneous form, the active ingredient ligelizumab has made the most progress in clinical testing.Like omalizumab, ligelizumab is an IgE antibody, but has a much stronger effect.In addition, numerous biologicals with different targets are being tested, for example to block certain interleukins or mast cell receptors (15)./Table 1: Features of the characteristic skin reaction patterns in urticaria (7)Table 2: Classification of the subtypes of chronic urticaria (7)Zuberbier, T., et al., The EAACI/GA2LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria.The 2017 Revision and Update.Allergy 73 (2018) 1393-1414.DOI:10.1111/all.13397Maurer, M., et al., CME article: Chronic urticaria - what does the new guideline bring?J German Soc Dermatol (2018) 585-595.DOI: 10.1111/ddg.13531Allergy information service, www.allergieinformationsdienst.de/diagnosesbilder/weitere-diagnosesbilder/urtikaria.htmlFurther literature from the authordrAnnette Immel-Sehr studied pharmacy in Bonn and Frankfurt am Main.After her license to practice medicine in 1988, she did her doctorate with a thesis on a pharmacological topic at the Pharmacological Institute for Natural Scientists at the University of Frankfurt.From 1992 to 1999, Immel-Sehr worked as a consultant for training and further education at the ABDA - Federal Union of German Pharmacists' Associations.Since then she has been working as a freelance consultant for science PR and as a specialist journalist.