CME-Article Submitted: 22.5.2014 Accepted: 9.7.2014 Conflict of interest Wedi: honoraria (Novartis, Dr. Pfleger), research grant (Novartis) Wieczorek: honoraria (Novartis) Raap: honoraria (Novartis), research grant (Novartis) Kapp: honorarira (ALK Abelló)
Bettina Wedi, Dorothea Wieczorek, Ulrike Raap, Alexander Kapp Department for Dermatology, Allergology, and Venereology, Hannover Medical School, Germany Section Editor Prof. Dr. Jan C. Simon, Leipzig
DOI: 10.1111/ddg.12441
Urticaria
Summary Urticaria is a very common skin disease which was already described in the ancient world. Questions still remain about its pathogenesis and management remain open. Compared to other common skin diseases, the published evidence is rather low. The clinical symptoms with pruritic transient wheals and/or angioedema are caused by mediators (particularly histamine) released by activated mast cells and basophils. The mechanism of target cell activation has not been clarified in detail for most urticaria subtypes. Different urticaria subtypes should be distinguished. Spontaneous forms are more common than inducible forms. Chronic urticaria and urticaria in certain age groups (children, pregnancy) can be difficult to manage. Therefore, international consensus resulting in the regular update of urticaria guidelines can be very helpful. Currently, these updated guidelines include a three-step treatment algorithm for chronic spontaneous urticaria. Only the first step of this algorithm, second generation H1-antihistamine in standard dose, utilized approved drugs. However after omalizumab was established as a third line choice in the guideline algorithm, it has approved in many countries for chronic spontaneous urticaria without response to H1-antihistamines. The exact mechanism of action of omalizumab in urticaria has not been fully elucidated. Unrevealing this mechanism might result in a deeper understanding of urticaria pathogenesis and the development of further therapeutic strategies.
Introduction Urticaria is a common skin disorder. It is defined by the occurrence of transient pruritic wheals (Figure 1a) and/or more deeply located swelling (angioedema) (Figure 1b). Although already known in ancient times, many aspects, especially with respect to the pathophysiology of various urticaria subtypes and thus their optimal management, still remain unclear. Chronic urticaria forms, such as chronic spontaneous urticaria and inducible urticaria variants, run a highly protracted course spanning years or even decades. Patients’ quality of life is substantially impaired, resulting in tremendous costs (missing work or school, “doctor hopping”, hospitalization, and others). Until recently, standard-dose H1 antihistamines represented the only approved treatment available. In March 2014, the humanized monoclonal IgE antibody omalizumab was added to the armamentarium of approved therapeutic agents for chronic spontaneous urticaria not responding to H1 antihistamines.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
1
CME Article
Figure 1 Clinical symptoms in urticaria. Wheals (a), angioedema (b).
Definition, pathophysiology, classification, and characteristics Urticaria is defined by the occurrence of transient pruritic wheals and/or angioedema. Pathophysiologically, the release of various mediators by activated subepidermal mast cells (also basophilic granulocytes) plays a paramount role.
In most urticaria variants, the mechanism of mast cell activation is unknown. Based on current knowledge, IgE-mediated mechanisms are virtually irrelevant in all other forms of urticaria except for acute urticaria. Chronic spontaneous urticaria and chronic inducible urticaria variants run a highly protracted course, potentially spanning many years and even decades.
Spontaneous urticaria forms are most common.
2
Urticaria is defined by the occurrence of transient pruritic wheals and/or angioedemas [1]. Pathophysiologically, the release of various mediators by activated subepidermal mast cells (also basophilic granulocytes) plays a paramount role. Released histamine causes local vasodilation and increased capillary permeability, resulting in intracutaneous (wheal) or subcutaneous (angioedema) edema. Moreover, activation of sensory nerves leads to pruritus and reflex erythema. Unlike wheals, which usually vanish after a few hours, angioedema frequently persist for 1–3 days and tend to be painful. In general, mast cell-mediated (histamine-induced) urticaria may be caused by various triggers: allergic (IgE-mediated), pseudoallergic (non-IgE-mediated), physical, infectious, autoreactive, paraneoplastic, psychologic, and by an increase in body core temperature. In most urticaria variants, the mechanism of mast cell activation is unknown. Based on current knowledge, IgE-mediated mechanisms are virtually irrelevant in all other forms of urticaria except for acute urticaria. The current classification distinguishes spontaneous from inducible urticaria forms (Table 1), the latter including physical and special variants. A combination of various subtypes is possible as, for example, shown by the frequent concurrence of urticaria factitia and chronic spontaneous urticaria. Chronic spontaneous urticaria and chronic inducible urticaria variants run a highly protracted course, potentially spanning many years and even decades (Table 1). The term “idiopathic” urticaria is no longer recommended [1, 2]. Valid data on the prevalence of individual urticaria forms does not exist. The overall prevalence of urticaria has been estimated between 1–1.5 % in the general population and 3 % in dermatologic patients. Spontaneous urticaria forms are most common. With a lifetime prevalence of 15–20 %, acute spontaneous urticaria represents the most common form, predominantly affecting children, adolescents, and young adults (potentially occurring at any age, though) as well as atopic individuals. Chronic spontaneous urticaria, on the other hand, primarily affects middle-aged women with an overall prevalence of 0.5 %. Regarding inducible urticaria forms, delayed pressure urticaria shows a male preponderance, whereas cholinergic urticaria and cold urticaria affect both genders equally. Pinpoint-sized wheals are a hallmark of cholinergic urticaria (Table 1). Triggers and other characteristics are listed in Table 1.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
CME Article
Table 1 Classification and characteristics of urticaria subtypes. Type
Subtype
Spontaneous Acute spontaneous urticaria urticaria (< 6 weeks)
Inducible urticaria: physical urticaria
Special forms
Trigger
Characteristics
Acute viral/bacterial infection (for examp-
Self-limiting, frequently only 1–2 weeks (by definition, < 6 weeks), more than half also show angioedema
le respiratory, gastrointestinal, urinary tract) Drugs (especially NSAIDS such as acetyl salicylic acid) IgE-mediated, allergic (food, bee/wasp venom)
Chronic spontaneous urticaria (> 6 weeks)
Chronic persistent infection (for example
Urticaria factitia
Shear forces
Most frequent physical urticaria, possible concurrence with chronic spontaneous urticaria, median duration 6.5 years
Cold urticaria
Cold (air, water, objects, beverages, ice)
Frequent physical urticaria, possible life-threatening; potential concurrence with cholinergic urticaria; median duration 5–10 years
Delayed pressure urticaria
Local pressure (delayed reaction after
Possible concurrence with chronic spontaneous urticaria; general symptoms such as fatigue, fever, arthralgias are possible; median duration 6–9 years
Heat-induced urticaria
Local heat
Very rare
Solar urticaria
U V light, visual light
Rare
Aquagenic urticaria
Contact with water (regardless of
Very rare
Cholinergic urticaria
Increase in body core temperature
Contact urticaria
Allergic: animal and plant allergens,
helicobacter, streptococci, yersinia, parasites) Autoreactivity (thyroid autoantibodies, positive autologous serum skin test, anti-FcεRIa) Pseudoallergens (especially NSAIDS such as acetyl salicylic acid, rarely additives)
3–6 h)
Highly chronic (spanning years to decades), in 40–50 % also angioedema
temperature) (through mental/physical exercise)
Especially at a younger age; transient, pinhead-sized wheals; possible concurrence with cold urticaria; median duration 7.5 years
Special form: oral allergy syndrome
ccupational chemicals, drugs o Non-allergic: plant substances (for example stinging nettle, spurges), foods (for example strawberries), animals (for example caterpillars, ants) or irritants (peruvian balm, benzoic acid, cinnamon aldehyde)
Abbr.: NSAIDS, nonsteroidal antiinflammatory drugs
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
3
CME Article
During the most recent international guidelines update proceedings (November 2012), there was consensus to no longer classify exercise-induced urticaria/ anaphylaxis as urticaria but rather as anaphylaxis. The existence of adrenergic urticaria is controversial [1].
Differential diagnosis
Further differential diagnoses have to be taken into consideration, especially in case of persistent individual lesions, absence of pruritus, or deep tissue swellings.
In case of only minor pruritus and failure to respond to H1 antihistamines, autoinflammatory syndromes with urticarial skin lesions, characterized by persistent or recurring fever, have to be excluded.
In case of deep angioedema at varying sites without concomitant superficial wheals, bradykinin-mediated angioedemas, potentially triggered by drugs (ACE inhibitors or sartans) or caused by C1 esterase inhibitor deficiency (hereditary or acquired), have to be taken into account. Diagnostic workup is based on a thorough and structured history, considering potential triggers. After taking a short history, most types of urticaria may easily be diagnosed at a glance.
4
Differential diagnoses of spontaneous urticaria include, for example, the initial urticarial stage of bullous pemphigoid, scabies and other reactions to arthropods, various forms of figurate erythemas, Sweet syndrome, and erythema elevatum diutinum; in pregnancy, also polymorphic eruption of pregnancy (PUPPP) and gestational pemphigoid [3]. Further differential diagnoses have to be taken into consideration, especially in case of persistent individual lesions, absence of pruritus, or deep tissue swellings. Individual urticarial lesions persisting for more than 24 hours (observation of progression after marking the borders) and showing a hemorrhagic component or residual hyperpigmentation warrant histopathologic evaluation to rule out urticarial vasculitis. In older patients, urticarial dermatitis has to be differentiated, characterized by intensely pruritic, partly urticarial, partly eczematous, plaques persisting for more than 24 hours [4]. Epidermal involvement, however, allows for differentiation from urticaria. In case of only minor pruritus and failure to respond to H1 antihistamines, autoinflammatory syndromes with urticarial skin lesions, characterized by persistent or recurring fever, have to be excluded. Hereditary autosomal dominant autoinflammatory syndromes with a mutation in NLRP3 (nucleotide-binding oligomerization domain-leucine rich repeats containing pyrin domain 3) include cryopyrin-associated periodic syndromes (CAPS) caused by a mutation of CIAS1 (cold-induced autoinflammatory syndrome 1) on chromosome 1q44 (coding for cryopyrin). These include familial cold-induced autoinflammatory syndrome (FCAS, also termed familial cold urticaria), NOMID (neonatal onset multisystem inflammatory disease), and Muckle-Wells syndrome (MWS) with urticaria, periodic fever, deafness, nephropathy, and amyloidosis. The acquired Schnitzler syndrome, characterized by arthralgias, periodic fever, and monoclonal IgM gammopathy, or adult Still's disease are considerably more common than hereditary autoinflammatory syndromes. For some IL-1-mediated autoinflammatory syndromes, anti-cytokine antibodies are therapeutically available. The IL-1 receptor antagonist anakinra and the IL-1ß antibody canakinumab, for example, have been approved for CAPS including NOMID, MWS, and FCAS. In case of angioedema without concomitant superficial wheals, bradykinin-mediated angioedema, potentially triggered by drugs (ACE inhibitors or sartans) or caused by C1 esterase inhibitor deficiency (hereditary or acquired), have to be taken into account [5]. Persistent swellings without wheals (particularly of the upper lip) should prompt consideration of chronic granulomatous inflammatory reactions such as granulomatous cheilitis, Melkersson-Rosenthal syndrome, and sarcoidosis.
Diagnostic workup of urticaria The diagnostic workup is based on a thorough and structured history, considering potential triggers [1, 5]. After taking a short history, most types of urticaria may easily be diagnosed at a glance. Even if the patient does not show any current skin lesions, the diagnosis may be exclusively based on typical history. In chronic
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
CME Article
Table 2 Diagnostic workup in spontaneous urticaria [3]. Subtype
Basic workup
Extended workup
Acute spontaneous urticaria
None
Depending on history: CBC with differential, CRP, ESR, specific ID workup, detection of IgE-mediated sensitization.
Chronic spontaneous urticaria
CBC with differential, CRP, ESR
Chronic persistent infection with…
Autoreactive
Pseudoallergy
Helicobacter pylori
Monoclonal stool antigen test or 13 C-urea breath test or histopathology
Streptococci
Anti-DNaseB titer, anti-streptolysin titer, (throat swab), possibly ENT/dental exam
Staphylococci
Anti-staphylolysin titer, possibly ENT/dental exam
Yersinia enterocolitica
Yersinia serology (IgA, IgG, immunoblot)
Thyroid gland
TSHbasal, thyroid autoantibodies
anti-FcεRI (anti-IgE), serum factor(s)
Autologous serum skin test, possibly functional workup (for example flow cytometry)
NSAID
History, avoidance
Food additives
Standardized pseudoallergen-free diet for 4 weeks
Abbr.: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; NSAIDS, nonsteroidal antiinflammatory drugs; ID, infectious disease; CBC, complete blood count
The diagnostic workup also includes a physical examination and checking for dermographism. Further workup is geared towards the urticaria subtype.
spontaneous urticaria, a patient diary documenting ingested foods, prescription drugs, and activities may be useful. The diagnostic workup also includes a physical examination and checking for dermographism. Further workup is geared towards the urticaria subtype and listed in Table 2. Tests for assessing autoreactivity, such as autologous serum skin test, autoantibodies against FcεRIα and thyroid autoantibodies, merely facilitate subclassification in chronic spontaneous urticaria but currently offer no therapeutic benefits. Further potential diagnostic measures not routinely required include ANA (especially in urticarial vasculitis to rule out lupus erythematosus), biopsy (in individual lesions persisting for more than 24 h, in order to differentiate from urticarial dermatitis, bullous pemphigoid, urticarial vasculitis, cutaneous mastocytosis), baseline serum tryptase levels (to exclude mastocytosis), testing for worm eggs in stool (in case of eosinophilia, elevated total IgE, suspected parasitosis), specific IgE antibodies (in case of suspected IgE-mediated triggers, predominantly in intermittent urticaria). With regard to inducible urticaria forms, standardized physical testing is recommended to diagnostically ascertain the subtype and determine the stimulus threshold. The question whether additional workup, as in chronic spontaneous urticaria, is warranted has been controversially debated. However, in some cases, treatable triggers (chronically persistent infection) may thus be identified, resulting
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
5
CME Article
in mitigation or resolution of urticaria [6]. So far, there has been no indication for autoreactivity (positive autologous serum skin test or detection of autoantibodies against IgE or the high-affinity IgE receptor) in inducible urticaria.
Useful diagnostic tools Numerous diagnostic tools have proven useful in the evaluation of severity and quality of life in affected patients, especially with chronic spontaneous urticaria.
Numerous diagnostic tools have proven useful in the evaluation of severity and quality of life in affected patients, especially with chronic spontaneous urticaria (Table 5) [7, 8]. They have been shown to be particularly helpful in assessing therapeutic response and have been incorporated in current guidelines [1, 2].
Therapy of urticaria
Therapeutic options include treatment and elimination of causes, inhibition of mediator release by mast cells, and inhibiting the effect of mediators at the target organ.
According to international guideline consensus, any treatment should be aimed at achieving complete freedom from symptoms [1, 9]. Therapeutic options include treatment and elimination of causes (for example eradication of helicobacter, avoidance of acetyl salicylic acid, discontinuation of ACE inhibitors or sartans in case of angioedema), inhibition of mediator release by mast cells (corticosteroids, phototherapy, cyclosporine A), and inhibiting the effect of mediators at the target organ (H1 antihistamines, leukotriene antagonists). While some agents exhibit effects on multiple levels, the exact mechanism of action of many drugs has not been fully elucidated. Although topical therapy is not very effective, many patients like using this form of treatment in addition to systemic therapy. In this context, anti-pruritic and cooling topical agents, for example polidocanol-containing (3–5 %) lotions and creams, have proven adequate. Due to potential sensitization, topical antihistamines are not recommended.
Acute urticaria (and also exacerbation of chronic urticaria)
In-patient treatment is indicated in case of dyspnea, circulatory dysregulation, severe generalized urticaria, and threatening angioedema.
Self-limiting acute spontaneous urticaria is usually treated symptomatically. In the absence of threatening angioedema and general symptoms (hypotension, globus sensation, dyspnea, nausea/vomiting), H1 antihistamines, possibly at an increased dose (up to 4-fold, off-label use), are commonly sufficient. If there is no response, additional (!) oral corticosteroids (up to 50 mg prednisolone equivalent per day) for a maximum 10 days may be helpful. Identifiable triggers, such as drugs (NSAIDS) or allergens, should be avoided and acute infections adequately treated. In-patient treatment is indicated in case of dyspnea, circulatory dysregulation, severe generalized urticaria, and threatening angioedema. In case of threatening symptoms (oral/pharyngeal angioedema), circulatory dysregulation, dyspnea, nausea, and generalized urticaria, intravenous H1 antihistamines (only early-generation agents are available for IV use: clemastine, dimethindene, promethazine) and corticosteroids (depending on the severity of symptoms 100–250 mg prednisolone equivalent, possibly even higher) should be given immediately. Further progression in terms of anaphylactic shock has to be countered by timely administration of epinephrine.
Chronic spontaneous urticaria In 2009, international urticaria guidelines proposed the first treatment algorithm for chronic spontaneous urticaria, which has been updated on the basis of
6
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
CME Article
Figure 2 Recommended treatment algorithm (international consensus November 2012) for chronic urticaria [8].
Table 3 Examples of treatment options approved for urticaria in Germany. Second and third generation H1-antihistamines approved for urticaria. Agent
Step 1 of the treatment algorithm includes standard-dose non-sedative or barely sedative H1 antihistamines for symptom control.
The next step of the treatment algorithm recommends an up to 4-fold dose increase (off-label use), taking potential side effects into account
Standard dose per day (adults)
Youngest approved age
Cetirizine
10 mg
2 years (drop preparation)
Bilastine
20 mg
12 years (tablets)
Desloratadine
5 mg
1 year (syrup)
Ebastine
10 mg
18 years (tablets)
Fexofenadine
180 mg
12 years (tablets)
Levocetirizine
5 mg
2 years (drop preparation, liquid)
Loratadine
10 mg
2 years (tablets)
Mizolastine
10 mg
12 years (tablets)
Rupatadine
10 mg
6 years (solution)
international consensus (Figure 2) [1]. Step 1 of the treatment algorithm includes standard-dose non-sedative or barely sedative H1 antihistamines for symptom control (in alphabetical order: azelastine, bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mizolastine, and rupatadine) (Table 3). Regular administration, possibly in multiple doses over the course of the day, is more effective than PRN usage. At a standard dose, however, complete freedom from symptoms can only be achieved in very few patients [10]. If there is no resolution of symptoms within two weeks using a standard dose, the next step of the treatment algorithm recommends an up to 4-fold dose increase (off-label use), taking potential side effects into account. Because of individually varying
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
7
CME Article
Table 4 Further examples of treatment options approved for urticaria in Germany.
In the treatment of severe recurrent urticaria, antihistamines may be prescribed at the expense of the statutory health insurance, according to article 34, section 1, German Social Code V. The third step additionally (in addition to H1 antihistamines) includes omalizumab (monoclonal anti-IgE antibody), cyclosporine A (immunosuppressant), or montelukast (leukotriene receptor antagonist). Since March of 2014, omalizumab, at a dose of 300 mg SQ q 4 weeks, has been approved as additional therapeutic agent in H1-antihistamine recalcitrant chronic urticaria in adults and children (12 years and above). Omalizumab thus represents the therapeutic agent with the highest evidence. A clinically relevant response may usually be seen within one to two weeks after the initial subcutaneous administration.
8
Agent
Standard Youngest dose per day age (adults) approved
Approved indication (according to SPC)
Omalizumab
300 mg q 4 weeks, subcutaneously
12 years
Additional therapy in the treatment of chronic spontaneous urticaria in adults and adolescents (12 years and above) s howing insufficient response to H1 antihistamine treatment
Prednisone, (depending prednisolone, on severity) methylprednisolone, triamcinolone
Infancy
Disorders of the skin and mucosa that, due to their severity and/or extent or systemic involvement, cannot be sufficiently treated with topical corticosteroids. This includes: allergic, pseudoallergic, and infection-triggered disorders (for example acute urticaria, anaphylactoid reactions, and others)
responses to certain H1 antihistamines, it may also be useful to try different H1 antihistamines (possibly at increased doses). In the treatment of severe recurrent urticaria, antihistamines may be prescribed at the expense of the statutory health insurance, according to article 34, section 1, German Social Code V. In case of continued lack of response, the third step of the current international treatment algorithm additionally (in addition to H1 antihistamines) includes omalizumab (monoclonal anti-IgE antibody), cyclosporine A (immunosuppressant), or montelukast (leukotriene receptor antagonist) (Figure 2). At the time of the guideline consensus (November 2012), none of the aforementioned three options had been approved for urticaria. This changed in March of 2014, when omalizumab, already approved for severer allergic asthma, was also approved at a dose of 300 mg SQ every 4 weeks, for H1-antihistamine recalcitrant chronic urticaria in adults and children (12 years and above) (Table 4). So far, the exact mechanism of its action in urticaria has not been clarified, but deactivation of mast cells/basophils has been suggested. Available data indicates that there is no need for dose reduction due to age (12–75 years), ethnicity, gender, body weight, body mass index, baseline IgE levels, anti-FcεRI autoantibodies, or simultaneous administration of H2 antihistamines or leukotriene receptor antagonists. In vivo and in vitro, omalizumab forms limited-size complexes with IgE. Deposition of complexes and complexes with a molecular weight of more than one million Dalton have neither been described in vitro nor in vivo. The approval is based on randomized placebo-controlled clinical trials on more than 1,000 patients, aged 12 to 75, with chronic spontaneous urticaria. Omalizumab thus represents the therapeutic agent with the highest evidence [11]. A clinically relevant response may usually be seen within one to two weeks after the initial subcutaneous administration of omalizumab, unlike asthma, where a clinical response can only be expected after 12–16 weeks. Compared to the placebo group (5–9 %), complete response (complete freedom from symptoms;
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
CME Article
Table 5 Useful tools in the management of chronic spontaneous urticaria Disease activity Abbreviation
Name
Description
Minimal – maximal score
UAS
UAS
Patient assessment of pruritus and number of wheals once daily
0–6
UAS7
Weekly UAS
Total of the daily UAS over the course of one week
0–42
AAS
AAS
Patient assessment of the severity of angioedema once daily (5 questions)
0–15
AAS7
Weekly AAS
Total of the daily AAS over the course of one week
0–105
UCT
Urticaria control test
Assessment of urticaria control over the past 4 weeks (4 questions)
0–16
Abbreviation
Name
Description
CU-Q2oL
Chronic Urticaria Questionnaire for Quality of Life
Assessment of impairment of quality of life over the past 14 days (23 questions)
0–92
AE-QoL
Angioedema Quality of Life
Assessment of impairment of quality of life over the past 4 weeks (17 questions)
0–100
Quality of life Minimal – maximal score
Abbr.: UAS, urticaria activity score; AAS, angioedema activity score;
Long-term therapy with systemic corticosteroids should be abandoned due to considerable side effects.
rticaria Activity Score 7 [UAS7] = 0) was achieved in 34–44 % of patients in the U omalizumab group. The studies did not reveal any new safety risks besides those already seen in severe allergic asthma. Until now, anaphylactic reactions have not been described in urticaria patients treated with omalizumab. With respect to off-label alternatives recommended in the treatment algorithm, there is good evidence for cyclosporine A (2,5–5 mg/kg body weight [BW] per day), with a therapeutic response usually occurring within 4–6 weeks. Potential side effects of cyclosporine A include arterial hypertension, impairment of kidney and liver function, immunosuppression as well as an increased risk for malignancy, requiring regular lab tests and check-ups. Although the evidence for montelukast, a leukotriene receptor antagonist with relatively few side effects, at a dose of 10 mg per day is less well documented in urticaria, some individuals may benefit. A response can be expected within four weeks. Systemic corticosteroids are also mentioned in the treatment algorithm, however, their use should be limited to a maximum of 10 days (initially recommended dose 0.5–1 mg/kg BW prednisolone equivalent) during times of acute exacerbation. Long-term therapy with systemic corticosteroids should be abandoned due to considerable side effects. They are not approved for the treatment of chronic urticaria (Table 4). Because of poor evidence, H2 antihistamines and dapsone are no longer part of the updated treatment algorithm. The latter may possibly play a role in case of an extensive inflammatory infiltrate with neutrophils and/or eosinophils (pressure-associated chronic spontaneous urticaria or delayed pressure urticaria). Smaller studies and case reports have also shown therapeutic success using a variety of other agents such as (hydroxy-) chloroquine, sulfasalazine, tacrolimus, methotrexate, mycophenolate mofetil, cyclophosphamide, and UVB phototherapy [9].
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
9
CME Article
Table 6 Therapeutic management of inducible urticaria (besides H1 antihistamines, there is no approved therapeutic agent available. Consider pragmatic course of action according to treatment algorithm (Figure 2). Urticaria subtype
Intervention
All forms of physical urticaria
Physical trigger avoidance; prophylactic, regular or as-needed use of new-generation H1 antihistamines (possible dose increase up to 4-fold)
Urticaria factitia
Further options: ketotifen, UVB phototherapy
Cold urticaria
Further options: montelukast, ketotifen, cyproheptadine, tetracycline, penicillin, o malizumab
Delayed pressure urticaria
Further options: montelukast, dapsone, oral corticosteroids below Cushing threshold, methotrexate, omalizumab
Heat urticaria
Further options: tolerance induction, (hydroxy-)chloroquine, omalizumab
Solar urticaria
Further options: photohardening, (hydroxy-) chloroquine, plasmapheresis, photopheresis, IVIG, omalizumab
Vibration urticaria/ angioedema
Avoidance
All special forms
Trigger avoidance; prophylactic, regular, or as-needed use new generation H1 antihistamines (possible dose increase up to 4-fold)
Cholinergic urticaria
Further options: “Exercise tolerance induction”, ketotifen, danazol, omalizumab
Contact urticaria
Avoidance
Aquagenic urticaria
Further options: barrier cream, phototherapy
Abbr.: IVIG, intravenous immunoglobulins
Most patients should be re-assessed at 3–6 month intervals, in order to ascertain whether dose reduction or, in case of potential spontaneous resolution, discontinuation of the medication is feasible.
Other agents such as antidepressants (doxepin), mast cell stabilizers (oxatomide, ketotifen), calcium channel blockers (nifedipine), sympathomimetics (terbutaline), anticoagulants (warfarin), and stanozolol have all failed to display any therapeutic success and/or are fraught with substantial adverse effects. Most patients should be re-assessed at 3–6 month intervals, in order to ascertain whether dose reduction or, in case of potential spontaneous resolution, discontinuation of the medication is feasible [1, 9].
Inducible urticaria The evidence base with respect to anaging inducible types of urticaria m is considerably poorer than for chronic spontaneous urticaria.
As a pragmatic approach, the treatment algorithm for chronic urticaria may be followed.
10
The evidence base with respect to managing inducible types of urticaria is considerably poorer than for chronic spontaneous urticaria. Therapeutic options for inducible urticaria forms are listed in Table 6. Trigger avoidance is frequently not feasible (Table 6). Symptomatic therapy consists of H1 antihistamines approved for the treatment of chronic urticaria. As a pragmatic approach, the treatment algorithm for chronic urticaria may be followed (Figure 2). Numerous case reports and case series on various types of inducible urticaria have shown that omalizumab represents an effective therapeutic option for patients not responding to H1 antihistamines and other agents listed in Table 6. In Germany, there is currently only one therapeutic agent explicitly approved for the treatment of inducible urticaria: cyproheptadine (first generation antihistamine with antiserotonergic effects) is approved (from the age of 7) for symptomatic treatment of primary acquired cold urticaria not sufficiently responding to non-sedative antihistamines or showing contraindications. It appears more than doubtful whether cyproheptadine, which is characterized by substantial adverse effects, is more effective in cold urticaria than modern H1 antihistamines (possibly at an increased dose).
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
CME Article
Urticaria in children
With regard to diagnostic workup and therapy, there is no fundamental difference between children and adults.
While chronic spontaneous urticaria in childhood is known to be less common than in adults [12], there is no exact epidemiologic data. Of the inducible urticaria forms, urticaria factitia, cholinergic urticaria, cold urticaria, and contact urticaria also occur in children. With regard to diagnostic workup and therapy, there is no fundamental difference between children and adults [1]. While streptococcal infections represent the most common trigger in children with chronic spontaneous urticaria, other triggers are generally comparable to the ones seen in adults [12]. Weighing risks and benefits on a case-by-case basis, the treatment algorithm (Figure 2) is also recommended for children. Omalizumab has been approved for the treatment of chronic spontaneous urticaria, insufficiently responding to H1 antihistamines, in adults and children (12 years and above) (6 years and above in severe allergic asthma).
Urticaria in pregnancy Taking individual risks and benefits into account, the same course of action presented in the guideline treatment algorithm is basically also recommended in pregnancy. The administration of loratadine and cetirizine in standard doses may be considered safe in pregnancy, the former having been prospectively followed up in more than 5,000 pregnancies, the most of any antihistamine (Center for Pharmacovigilance and Counseling for Embryonic Toxicology: www.embryotox.de). Thus, loratadine is the H1 antihistamines of choice in all phases of pregnancy. References 1
Correspondence to Prof. Dr. med. habil. Bettina Wedi Klinik für Dermatologie, Allergologie und Venerologie Medizinische Hochschule Hannover Carl-Neuberg-Straße 1 30625 Hannover Germany E-mail: wedi.bettina@mh- hannover.de
Zuberbier T, Aberer W, Asero R et al. The EAACI/GA2LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014; 69: 868–87. 2 Zuberbier T, Aberer W, Brockow K et al. Teil 1: Klassifikation und Diagnostik der Urtikaria – deutschsprachige Version der internationalen S3-Leitlinie. AWMF-Leitlinie 013–028. Allergo J 2011; 20: 249–58. 3 Wedi B. Urtikaria und Angioödem. In: Plewig G et al. (Hrsg): Braun-Falco's Dermatologie, Venerologie und Allergologie. Berlin, Heidelberg: Springer Verlag, 2012: 442–69. 4 Peroni A, Colato C, Schena D, Girolomoni G. Urticarial lesions: if not urticaria, what else? The differential diagnosis of urticaria: part I. Cutaneous diseases. J Am Acad Dermatol 2010; 62: 541–55. 5 Bork K, Maurer M, Bas M et al. Hereditäres Angioödem durch C1-Inhibitor-Mangel. AWMF-Leitlinie 061–029. Allergo J 2012; 21:109–18. 6 Schneider J, Wedi B. Retrospektive Untersuchung zu physikalischer Urtikaria und Sonderformen. Allergologie 2014, im Druck. 7 Staubach P, Groffik A. Nützliche Instrumente für die Dokumentation bei Urtikaria. Der Hautarzt 2013; 64: 650–5. 8 Weller K, Groffik A, Altrichter S et al. Instrumente zur Erfassung von Krankheitsaktivität, Krankheitskontrole und Lebensqualitätsbeeinträchtigung bei Patienten mit chronischer Urtikaria und Angioödemen. Allergologie 2014, im Druck. 9 Zuberbier T, Aberer W, Brockow K et al. Teil 2: Therapie der Urtikaria – deutschsprachige Version der internationalen S3-Leitlinie. AWMF-Leitlinie 013–028. Allergo J 2011; 20: 259–76. 10 Wedi B, Wieczorek D, Raap U, Kapp A. Urtikaria … und die Therapie versagt. Hautarzt 2013; 64: 656–63. 11 Maurer M, Rosen K, Hsieh HJ et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013; 368: 924–35. 12 Pite H, Wedi B, Borrego LM et al. Management of childhood urticaria: current knowledge and practical recommendations. Acta Derm Venereol 2013; 93: 500–8.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
11
CME Article
Fragen zur Zertifizierung durch die DDG 1.
Welche der folgenden Aussagen
zur Urtikaria ist falsch? a) Der Mechanismus der Mastzellaktivierung ist für die meisten Urtikariaformen im Detail unbekannt. b) Die akute Urtikaria besteht in der Regel mindestens sechs Wochen. c) Eine akute Urtikaria kann allergisch bedingt sein. d) Das NSAR Acetylsalicylsäure ist ein häufiger Triggerfaktor für eine Urtikaria. e) Die klinische Symptomatik der Urtikaria wird durch degranulierende Mastzellen vermittelt.
2. Welche der folgenden Aussagen ist richtig? a) Die meisten chronischen Urtikariaformen bestehen maximal sechs Monate. b) Unter dem Begriff induzierbare Urtikaria werden neuerdings akute und chronische Urtikaria zusammengefasst. c) Die chronische spontane Urtikaria betrifft vor allem Frauen im mittleren Lebensalter. d) Die cholinergische Urtikaria ist eine Sonderform und betrifft vor allem ältere Männer. e) Die anstrengungsinduzierte Urtikaria/Anaphylaxie ist die häufigste physikalische Urtikaria.
d) Zu den hereditären autosomal dominant vererbten autoinflammatorischen Syndromen mit Mutation von NLRP3 zählt das Schnitzler-Syndrom. e) Insbesondere bei nicht juckenden Quaddeln und rezidivierenden Fieberschüben muss das Vorliegen eines autoinflammatorischen Syndroms ausgeschlossen werden.
Welche der folgenden Aussagen
zur Differenzialdiagnose der Urtikaria ist falsch? a) Bei länger als 24 Stunden in loco persistierenden Urticae, hämorrhagischer Komponente oder Abheilung mit Hyperpigmentierung sollte eine Urtikaria-Vaskulitis histologisch ausgeschlossen werden. b) Das urtikarielle Frühstadium eines bullösen Pemphigoids kann mit einer Urtikaria verwechselt werden. c) Bei einer urtikariellen Dermatitis findet sich im Gegensatz zur Urtikaria eine epidermale Komponente.
12
7.
Ein junger Mann berichtet, dass
er stets bei Prüfungen und beim Sport stark juckenden Hautausschlag bekomme, der nach einer halben Stunde wieder verschwinde. Welche Aussage
4. Welche der folgenden Aussagen zur Differenzialdiagnose rezidivierender Angioödeme (ohne Urticae) ist zutreffend? a) Rezidivierende Angioödeme ohne Urticae können Histamin-vermittelt sein. b) Rezidivierende Angioödeme ohne Urticae können Bradykinin-vermittelt sein. c) ACE-Hemmer und Sartane können Bradykinin-vermittelte Angioödeme auslösen. d) Bei persistierender Oberlippenschwellung sollte eine Cheilitis granulomatosa histopathologisch ausgeschlossen werden. e) Alle Aussagen sind zutreffend.
5.
Welche der folgenden diagnos-
tischen Maßnahmen ist bei der Abklärung einer chronischen spontanen Urtikaria am wenigsten zielführend, um einen potenziellen Triggerfaktor
3.
c) AAS7 d) GEPARD-Bogen e) UCT
zu identifizieren? a) Helicobacter-pylori-Antigen-Stuhltest b) Antistreptolysin-Titer c) Yersinien-Serologie d) Nahrungsmittelpricktest e) Differenzialblutbild
6. Welches der folgenden Instrumente eignet sich nicht zur Beurteilung der Krankheitsaktivität der chronischen spontanen Urtikaria? a) UAS7 b) CU-Q2oL
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
ist falsch? a) Die wahrscheinlichste Verdachtsdiagnose ist cholinergische Urtikaria. b) Sie sollten einen standardisierten physikalischen Test zur Objektivierung durchführen, z. B. eine Ergometer-Belastung. c) Typischerweise treten strecknadelkopfgroße Urticae erst 3–6 Stunden verzögert nach der Ergometerbelastung auf. d) Zeitgleich könnte bei dem jungen Mann auch eine Kälteurtikaria vorliegen. Sie sollten nach entsprechender Beschwerdesymptomatik fragen. e) Die Therapie der 1. Wahl besteht aus nichtsedierenden H1-Antihistaminika (ggf. in erhöhter Dosierung).
8. Welche Aussage zum neuen Behandlungsalgorithmus im internationalen Leitlinien-Update ist falsch? a) Auf der 1. Stufe stehen H1-Antihistaminika der zweiten Generation in Standarddosierung. b) H1-Antihistaminika in vierfacher Dosierung sind für die Therapie der chronischen spontanen Urtikaria zugelassen. c) Auf der 3. Stufe des Algorithmus werden als Zusatztherapie entweder Omalizumab, Ciclosporin A oder Montelukast empfohlen. d) Auf jeder Stufe im Algorithmus ist die kurzfristige Gabe eines oralen Glukokortikoids bei einer akuten E xazerbation möglich. e) Alle 3–6 Monate sollte überprüft werden, ob eine Spontanremission eingetreten ist.
CME Article
9. Welcher Wirkstoff erhielt in 2014 die Zulassungserweiterung für die nicht auf H1-Antihistaminika ansprechende chronische spontane Urtikaria? a) Secukinumab b) Rupatadin c) Omalizumab d) Anakinra e) Canakinumab
10. Welche Aussage zu Omalizumab bei Urtikaria ist falsch? a) Der Wirkmechanismus von Omalizumab bei der Urtikaria ist bislang nicht geklärt.
b) Es wurden mehr als 1 000 Patienten mit chronischer spontaner Urtikaria in Zulassungsstudien eingeschlossen. c) Bisher sind keine Anaphylaxien bei Urtikaria beschrieben worden. d) In den klinischen Studien haben sich keine neuen Sicherheitsaspekte verglichen mit dem bekannten Nebenwirkungsprofil in der Therapie des persistierenden schweren allergischen Asthmas ergeben. e) Omalizumab ist zugelassen für Patienten mit chronischer spontaner Urtikaria, die nicht auf Ciclosporin A angesprochen haben.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 16. Juni 2014. Die richtige Lösung zum Thema „Therapie pathologischer Narben“ in Heft 12 (Dezember 2013) ist: (1b, 2c, 3d, 4e, 5d, 6d, 7c, 8b, 9c, 10e). Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg.akademie-dda. de ein.
13
Bettina Wedi, Dorothea Wieczorek, Ulrike Raap, Alexander Kapp Department for Dermatology, Allergology, and Venereology, Hannover Medical School, Germany Section Editor Prof. Dr. Jan C. Simon, Leipzig
DOI: 10.1111/ddg.12441
Urticaria
Summary Urticaria is a very common skin disease which was already described in the ancient world. Questions still remain about its pathogenesis and management remain open. Compared to other common skin diseases, the published evidence is rather low. The clinical symptoms with pruritic transient wheals and/or angioedema are caused by mediators (particularly histamine) released by activated mast cells and basophils. The mechanism of target cell activation has not been clarified in detail for most urticaria subtypes. Different urticaria subtypes should be distinguished. Spontaneous forms are more common than inducible forms. Chronic urticaria and urticaria in certain age groups (children, pregnancy) can be difficult to manage. Therefore, international consensus resulting in the regular update of urticaria guidelines can be very helpful. Currently, these updated guidelines include a three-step treatment algorithm for chronic spontaneous urticaria. Only the first step of this algorithm, second generation H1-antihistamine in standard dose, utilized approved drugs. However after omalizumab was established as a third line choice in the guideline algorithm, it has approved in many countries for chronic spontaneous urticaria without response to H1-antihistamines. The exact mechanism of action of omalizumab in urticaria has not been fully elucidated. Unrevealing this mechanism might result in a deeper understanding of urticaria pathogenesis and the development of further therapeutic strategies.
Introduction Urticaria is a common skin disorder. It is defined by the occurrence of transient pruritic wheals (Figure 1a) and/or more deeply located swelling (angioedema) (Figure 1b). Although already known in ancient times, many aspects, especially with respect to the pathophysiology of various urticaria subtypes and thus their optimal management, still remain unclear. Chronic urticaria forms, such as chronic spontaneous urticaria and inducible urticaria variants, run a highly protracted course spanning years or even decades. Patients’ quality of life is substantially impaired, resulting in tremendous costs (missing work or school, “doctor hopping”, hospitalization, and others). Until recently, standard-dose H1 antihistamines represented the only approved treatment available. In March 2014, the humanized monoclonal IgE antibody omalizumab was added to the armamentarium of approved therapeutic agents for chronic spontaneous urticaria not responding to H1 antihistamines.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
1
CME Article
Figure 1 Clinical symptoms in urticaria. Wheals (a), angioedema (b).
Definition, pathophysiology, classification, and characteristics Urticaria is defined by the occurrence of transient pruritic wheals and/or angioedema. Pathophysiologically, the release of various mediators by activated subepidermal mast cells (also basophilic granulocytes) plays a paramount role.
In most urticaria variants, the mechanism of mast cell activation is unknown. Based on current knowledge, IgE-mediated mechanisms are virtually irrelevant in all other forms of urticaria except for acute urticaria. Chronic spontaneous urticaria and chronic inducible urticaria variants run a highly protracted course, potentially spanning many years and even decades.
Spontaneous urticaria forms are most common.
2
Urticaria is defined by the occurrence of transient pruritic wheals and/or angioedemas [1]. Pathophysiologically, the release of various mediators by activated subepidermal mast cells (also basophilic granulocytes) plays a paramount role. Released histamine causes local vasodilation and increased capillary permeability, resulting in intracutaneous (wheal) or subcutaneous (angioedema) edema. Moreover, activation of sensory nerves leads to pruritus and reflex erythema. Unlike wheals, which usually vanish after a few hours, angioedema frequently persist for 1–3 days and tend to be painful. In general, mast cell-mediated (histamine-induced) urticaria may be caused by various triggers: allergic (IgE-mediated), pseudoallergic (non-IgE-mediated), physical, infectious, autoreactive, paraneoplastic, psychologic, and by an increase in body core temperature. In most urticaria variants, the mechanism of mast cell activation is unknown. Based on current knowledge, IgE-mediated mechanisms are virtually irrelevant in all other forms of urticaria except for acute urticaria. The current classification distinguishes spontaneous from inducible urticaria forms (Table 1), the latter including physical and special variants. A combination of various subtypes is possible as, for example, shown by the frequent concurrence of urticaria factitia and chronic spontaneous urticaria. Chronic spontaneous urticaria and chronic inducible urticaria variants run a highly protracted course, potentially spanning many years and even decades (Table 1). The term “idiopathic” urticaria is no longer recommended [1, 2]. Valid data on the prevalence of individual urticaria forms does not exist. The overall prevalence of urticaria has been estimated between 1–1.5 % in the general population and 3 % in dermatologic patients. Spontaneous urticaria forms are most common. With a lifetime prevalence of 15–20 %, acute spontaneous urticaria represents the most common form, predominantly affecting children, adolescents, and young adults (potentially occurring at any age, though) as well as atopic individuals. Chronic spontaneous urticaria, on the other hand, primarily affects middle-aged women with an overall prevalence of 0.5 %. Regarding inducible urticaria forms, delayed pressure urticaria shows a male preponderance, whereas cholinergic urticaria and cold urticaria affect both genders equally. Pinpoint-sized wheals are a hallmark of cholinergic urticaria (Table 1). Triggers and other characteristics are listed in Table 1.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
CME Article
Table 1 Classification and characteristics of urticaria subtypes. Type
Subtype
Spontaneous Acute spontaneous urticaria urticaria (< 6 weeks)
Inducible urticaria: physical urticaria
Special forms
Trigger
Characteristics
Acute viral/bacterial infection (for examp-
Self-limiting, frequently only 1–2 weeks (by definition, < 6 weeks), more than half also show angioedema
le respiratory, gastrointestinal, urinary tract) Drugs (especially NSAIDS such as acetyl salicylic acid) IgE-mediated, allergic (food, bee/wasp venom)
Chronic spontaneous urticaria (> 6 weeks)
Chronic persistent infection (for example
Urticaria factitia
Shear forces
Most frequent physical urticaria, possible concurrence with chronic spontaneous urticaria, median duration 6.5 years
Cold urticaria
Cold (air, water, objects, beverages, ice)
Frequent physical urticaria, possible life-threatening; potential concurrence with cholinergic urticaria; median duration 5–10 years
Delayed pressure urticaria
Local pressure (delayed reaction after
Possible concurrence with chronic spontaneous urticaria; general symptoms such as fatigue, fever, arthralgias are possible; median duration 6–9 years
Heat-induced urticaria
Local heat
Very rare
Solar urticaria
U V light, visual light
Rare
Aquagenic urticaria
Contact with water (regardless of
Very rare
Cholinergic urticaria
Increase in body core temperature
Contact urticaria
Allergic: animal and plant allergens,
helicobacter, streptococci, yersinia, parasites) Autoreactivity (thyroid autoantibodies, positive autologous serum skin test, anti-FcεRIa) Pseudoallergens (especially NSAIDS such as acetyl salicylic acid, rarely additives)
3–6 h)
Highly chronic (spanning years to decades), in 40–50 % also angioedema
temperature) (through mental/physical exercise)
Especially at a younger age; transient, pinhead-sized wheals; possible concurrence with cold urticaria; median duration 7.5 years
Special form: oral allergy syndrome
ccupational chemicals, drugs o Non-allergic: plant substances (for example stinging nettle, spurges), foods (for example strawberries), animals (for example caterpillars, ants) or irritants (peruvian balm, benzoic acid, cinnamon aldehyde)
Abbr.: NSAIDS, nonsteroidal antiinflammatory drugs
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
3
CME Article
During the most recent international guidelines update proceedings (November 2012), there was consensus to no longer classify exercise-induced urticaria/ anaphylaxis as urticaria but rather as anaphylaxis. The existence of adrenergic urticaria is controversial [1].
Differential diagnosis
Further differential diagnoses have to be taken into consideration, especially in case of persistent individual lesions, absence of pruritus, or deep tissue swellings.
In case of only minor pruritus and failure to respond to H1 antihistamines, autoinflammatory syndromes with urticarial skin lesions, characterized by persistent or recurring fever, have to be excluded.
In case of deep angioedema at varying sites without concomitant superficial wheals, bradykinin-mediated angioedemas, potentially triggered by drugs (ACE inhibitors or sartans) or caused by C1 esterase inhibitor deficiency (hereditary or acquired), have to be taken into account. Diagnostic workup is based on a thorough and structured history, considering potential triggers. After taking a short history, most types of urticaria may easily be diagnosed at a glance.
4
Differential diagnoses of spontaneous urticaria include, for example, the initial urticarial stage of bullous pemphigoid, scabies and other reactions to arthropods, various forms of figurate erythemas, Sweet syndrome, and erythema elevatum diutinum; in pregnancy, also polymorphic eruption of pregnancy (PUPPP) and gestational pemphigoid [3]. Further differential diagnoses have to be taken into consideration, especially in case of persistent individual lesions, absence of pruritus, or deep tissue swellings. Individual urticarial lesions persisting for more than 24 hours (observation of progression after marking the borders) and showing a hemorrhagic component or residual hyperpigmentation warrant histopathologic evaluation to rule out urticarial vasculitis. In older patients, urticarial dermatitis has to be differentiated, characterized by intensely pruritic, partly urticarial, partly eczematous, plaques persisting for more than 24 hours [4]. Epidermal involvement, however, allows for differentiation from urticaria. In case of only minor pruritus and failure to respond to H1 antihistamines, autoinflammatory syndromes with urticarial skin lesions, characterized by persistent or recurring fever, have to be excluded. Hereditary autosomal dominant autoinflammatory syndromes with a mutation in NLRP3 (nucleotide-binding oligomerization domain-leucine rich repeats containing pyrin domain 3) include cryopyrin-associated periodic syndromes (CAPS) caused by a mutation of CIAS1 (cold-induced autoinflammatory syndrome 1) on chromosome 1q44 (coding for cryopyrin). These include familial cold-induced autoinflammatory syndrome (FCAS, also termed familial cold urticaria), NOMID (neonatal onset multisystem inflammatory disease), and Muckle-Wells syndrome (MWS) with urticaria, periodic fever, deafness, nephropathy, and amyloidosis. The acquired Schnitzler syndrome, characterized by arthralgias, periodic fever, and monoclonal IgM gammopathy, or adult Still's disease are considerably more common than hereditary autoinflammatory syndromes. For some IL-1-mediated autoinflammatory syndromes, anti-cytokine antibodies are therapeutically available. The IL-1 receptor antagonist anakinra and the IL-1ß antibody canakinumab, for example, have been approved for CAPS including NOMID, MWS, and FCAS. In case of angioedema without concomitant superficial wheals, bradykinin-mediated angioedema, potentially triggered by drugs (ACE inhibitors or sartans) or caused by C1 esterase inhibitor deficiency (hereditary or acquired), have to be taken into account [5]. Persistent swellings without wheals (particularly of the upper lip) should prompt consideration of chronic granulomatous inflammatory reactions such as granulomatous cheilitis, Melkersson-Rosenthal syndrome, and sarcoidosis.
Diagnostic workup of urticaria The diagnostic workup is based on a thorough and structured history, considering potential triggers [1, 5]. After taking a short history, most types of urticaria may easily be diagnosed at a glance. Even if the patient does not show any current skin lesions, the diagnosis may be exclusively based on typical history. In chronic
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
CME Article
Table 2 Diagnostic workup in spontaneous urticaria [3]. Subtype
Basic workup
Extended workup
Acute spontaneous urticaria
None
Depending on history: CBC with differential, CRP, ESR, specific ID workup, detection of IgE-mediated sensitization.
Chronic spontaneous urticaria
CBC with differential, CRP, ESR
Chronic persistent infection with…
Autoreactive
Pseudoallergy
Helicobacter pylori
Monoclonal stool antigen test or 13 C-urea breath test or histopathology
Streptococci
Anti-DNaseB titer, anti-streptolysin titer, (throat swab), possibly ENT/dental exam
Staphylococci
Anti-staphylolysin titer, possibly ENT/dental exam
Yersinia enterocolitica
Yersinia serology (IgA, IgG, immunoblot)
Thyroid gland
TSHbasal, thyroid autoantibodies
anti-FcεRI (anti-IgE), serum factor(s)
Autologous serum skin test, possibly functional workup (for example flow cytometry)
NSAID
History, avoidance
Food additives
Standardized pseudoallergen-free diet for 4 weeks
Abbr.: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; NSAIDS, nonsteroidal antiinflammatory drugs; ID, infectious disease; CBC, complete blood count
The diagnostic workup also includes a physical examination and checking for dermographism. Further workup is geared towards the urticaria subtype.
spontaneous urticaria, a patient diary documenting ingested foods, prescription drugs, and activities may be useful. The diagnostic workup also includes a physical examination and checking for dermographism. Further workup is geared towards the urticaria subtype and listed in Table 2. Tests for assessing autoreactivity, such as autologous serum skin test, autoantibodies against FcεRIα and thyroid autoantibodies, merely facilitate subclassification in chronic spontaneous urticaria but currently offer no therapeutic benefits. Further potential diagnostic measures not routinely required include ANA (especially in urticarial vasculitis to rule out lupus erythematosus), biopsy (in individual lesions persisting for more than 24 h, in order to differentiate from urticarial dermatitis, bullous pemphigoid, urticarial vasculitis, cutaneous mastocytosis), baseline serum tryptase levels (to exclude mastocytosis), testing for worm eggs in stool (in case of eosinophilia, elevated total IgE, suspected parasitosis), specific IgE antibodies (in case of suspected IgE-mediated triggers, predominantly in intermittent urticaria). With regard to inducible urticaria forms, standardized physical testing is recommended to diagnostically ascertain the subtype and determine the stimulus threshold. The question whether additional workup, as in chronic spontaneous urticaria, is warranted has been controversially debated. However, in some cases, treatable triggers (chronically persistent infection) may thus be identified, resulting
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
5
CME Article
in mitigation or resolution of urticaria [6]. So far, there has been no indication for autoreactivity (positive autologous serum skin test or detection of autoantibodies against IgE or the high-affinity IgE receptor) in inducible urticaria.
Useful diagnostic tools Numerous diagnostic tools have proven useful in the evaluation of severity and quality of life in affected patients, especially with chronic spontaneous urticaria.
Numerous diagnostic tools have proven useful in the evaluation of severity and quality of life in affected patients, especially with chronic spontaneous urticaria (Table 5) [7, 8]. They have been shown to be particularly helpful in assessing therapeutic response and have been incorporated in current guidelines [1, 2].
Therapy of urticaria
Therapeutic options include treatment and elimination of causes, inhibition of mediator release by mast cells, and inhibiting the effect of mediators at the target organ.
According to international guideline consensus, any treatment should be aimed at achieving complete freedom from symptoms [1, 9]. Therapeutic options include treatment and elimination of causes (for example eradication of helicobacter, avoidance of acetyl salicylic acid, discontinuation of ACE inhibitors or sartans in case of angioedema), inhibition of mediator release by mast cells (corticosteroids, phototherapy, cyclosporine A), and inhibiting the effect of mediators at the target organ (H1 antihistamines, leukotriene antagonists). While some agents exhibit effects on multiple levels, the exact mechanism of action of many drugs has not been fully elucidated. Although topical therapy is not very effective, many patients like using this form of treatment in addition to systemic therapy. In this context, anti-pruritic and cooling topical agents, for example polidocanol-containing (3–5 %) lotions and creams, have proven adequate. Due to potential sensitization, topical antihistamines are not recommended.
Acute urticaria (and also exacerbation of chronic urticaria)
In-patient treatment is indicated in case of dyspnea, circulatory dysregulation, severe generalized urticaria, and threatening angioedema.
Self-limiting acute spontaneous urticaria is usually treated symptomatically. In the absence of threatening angioedema and general symptoms (hypotension, globus sensation, dyspnea, nausea/vomiting), H1 antihistamines, possibly at an increased dose (up to 4-fold, off-label use), are commonly sufficient. If there is no response, additional (!) oral corticosteroids (up to 50 mg prednisolone equivalent per day) for a maximum 10 days may be helpful. Identifiable triggers, such as drugs (NSAIDS) or allergens, should be avoided and acute infections adequately treated. In-patient treatment is indicated in case of dyspnea, circulatory dysregulation, severe generalized urticaria, and threatening angioedema. In case of threatening symptoms (oral/pharyngeal angioedema), circulatory dysregulation, dyspnea, nausea, and generalized urticaria, intravenous H1 antihistamines (only early-generation agents are available for IV use: clemastine, dimethindene, promethazine) and corticosteroids (depending on the severity of symptoms 100–250 mg prednisolone equivalent, possibly even higher) should be given immediately. Further progression in terms of anaphylactic shock has to be countered by timely administration of epinephrine.
Chronic spontaneous urticaria In 2009, international urticaria guidelines proposed the first treatment algorithm for chronic spontaneous urticaria, which has been updated on the basis of
6
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
CME Article
Figure 2 Recommended treatment algorithm (international consensus November 2012) for chronic urticaria [8].
Table 3 Examples of treatment options approved for urticaria in Germany. Second and third generation H1-antihistamines approved for urticaria. Agent
Step 1 of the treatment algorithm includes standard-dose non-sedative or barely sedative H1 antihistamines for symptom control.
The next step of the treatment algorithm recommends an up to 4-fold dose increase (off-label use), taking potential side effects into account
Standard dose per day (adults)
Youngest approved age
Cetirizine
10 mg
2 years (drop preparation)
Bilastine
20 mg
12 years (tablets)
Desloratadine
5 mg
1 year (syrup)
Ebastine
10 mg
18 years (tablets)
Fexofenadine
180 mg
12 years (tablets)
Levocetirizine
5 mg
2 years (drop preparation, liquid)
Loratadine
10 mg
2 years (tablets)
Mizolastine
10 mg
12 years (tablets)
Rupatadine
10 mg
6 years (solution)
international consensus (Figure 2) [1]. Step 1 of the treatment algorithm includes standard-dose non-sedative or barely sedative H1 antihistamines for symptom control (in alphabetical order: azelastine, bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mizolastine, and rupatadine) (Table 3). Regular administration, possibly in multiple doses over the course of the day, is more effective than PRN usage. At a standard dose, however, complete freedom from symptoms can only be achieved in very few patients [10]. If there is no resolution of symptoms within two weeks using a standard dose, the next step of the treatment algorithm recommends an up to 4-fold dose increase (off-label use), taking potential side effects into account. Because of individually varying
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
7
CME Article
Table 4 Further examples of treatment options approved for urticaria in Germany.
In the treatment of severe recurrent urticaria, antihistamines may be prescribed at the expense of the statutory health insurance, according to article 34, section 1, German Social Code V. The third step additionally (in addition to H1 antihistamines) includes omalizumab (monoclonal anti-IgE antibody), cyclosporine A (immunosuppressant), or montelukast (leukotriene receptor antagonist). Since March of 2014, omalizumab, at a dose of 300 mg SQ q 4 weeks, has been approved as additional therapeutic agent in H1-antihistamine recalcitrant chronic urticaria in adults and children (12 years and above). Omalizumab thus represents the therapeutic agent with the highest evidence. A clinically relevant response may usually be seen within one to two weeks after the initial subcutaneous administration.
8
Agent
Standard Youngest dose per day age (adults) approved
Approved indication (according to SPC)
Omalizumab
300 mg q 4 weeks, subcutaneously
12 years
Additional therapy in the treatment of chronic spontaneous urticaria in adults and adolescents (12 years and above) s howing insufficient response to H1 antihistamine treatment
Prednisone, (depending prednisolone, on severity) methylprednisolone, triamcinolone
Infancy
Disorders of the skin and mucosa that, due to their severity and/or extent or systemic involvement, cannot be sufficiently treated with topical corticosteroids. This includes: allergic, pseudoallergic, and infection-triggered disorders (for example acute urticaria, anaphylactoid reactions, and others)
responses to certain H1 antihistamines, it may also be useful to try different H1 antihistamines (possibly at increased doses). In the treatment of severe recurrent urticaria, antihistamines may be prescribed at the expense of the statutory health insurance, according to article 34, section 1, German Social Code V. In case of continued lack of response, the third step of the current international treatment algorithm additionally (in addition to H1 antihistamines) includes omalizumab (monoclonal anti-IgE antibody), cyclosporine A (immunosuppressant), or montelukast (leukotriene receptor antagonist) (Figure 2). At the time of the guideline consensus (November 2012), none of the aforementioned three options had been approved for urticaria. This changed in March of 2014, when omalizumab, already approved for severer allergic asthma, was also approved at a dose of 300 mg SQ every 4 weeks, for H1-antihistamine recalcitrant chronic urticaria in adults and children (12 years and above) (Table 4). So far, the exact mechanism of its action in urticaria has not been clarified, but deactivation of mast cells/basophils has been suggested. Available data indicates that there is no need for dose reduction due to age (12–75 years), ethnicity, gender, body weight, body mass index, baseline IgE levels, anti-FcεRI autoantibodies, or simultaneous administration of H2 antihistamines or leukotriene receptor antagonists. In vivo and in vitro, omalizumab forms limited-size complexes with IgE. Deposition of complexes and complexes with a molecular weight of more than one million Dalton have neither been described in vitro nor in vivo. The approval is based on randomized placebo-controlled clinical trials on more than 1,000 patients, aged 12 to 75, with chronic spontaneous urticaria. Omalizumab thus represents the therapeutic agent with the highest evidence [11]. A clinically relevant response may usually be seen within one to two weeks after the initial subcutaneous administration of omalizumab, unlike asthma, where a clinical response can only be expected after 12–16 weeks. Compared to the placebo group (5–9 %), complete response (complete freedom from symptoms;
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
CME Article
Table 5 Useful tools in the management of chronic spontaneous urticaria Disease activity Abbreviation
Name
Description
Minimal – maximal score
UAS
UAS
Patient assessment of pruritus and number of wheals once daily
0–6
UAS7
Weekly UAS
Total of the daily UAS over the course of one week
0–42
AAS
AAS
Patient assessment of the severity of angioedema once daily (5 questions)
0–15
AAS7
Weekly AAS
Total of the daily AAS over the course of one week
0–105
UCT
Urticaria control test
Assessment of urticaria control over the past 4 weeks (4 questions)
0–16
Abbreviation
Name
Description
CU-Q2oL
Chronic Urticaria Questionnaire for Quality of Life
Assessment of impairment of quality of life over the past 14 days (23 questions)
0–92
AE-QoL
Angioedema Quality of Life
Assessment of impairment of quality of life over the past 4 weeks (17 questions)
0–100
Quality of life Minimal – maximal score
Abbr.: UAS, urticaria activity score; AAS, angioedema activity score;
Long-term therapy with systemic corticosteroids should be abandoned due to considerable side effects.
rticaria Activity Score 7 [UAS7] = 0) was achieved in 34–44 % of patients in the U omalizumab group. The studies did not reveal any new safety risks besides those already seen in severe allergic asthma. Until now, anaphylactic reactions have not been described in urticaria patients treated with omalizumab. With respect to off-label alternatives recommended in the treatment algorithm, there is good evidence for cyclosporine A (2,5–5 mg/kg body weight [BW] per day), with a therapeutic response usually occurring within 4–6 weeks. Potential side effects of cyclosporine A include arterial hypertension, impairment of kidney and liver function, immunosuppression as well as an increased risk for malignancy, requiring regular lab tests and check-ups. Although the evidence for montelukast, a leukotriene receptor antagonist with relatively few side effects, at a dose of 10 mg per day is less well documented in urticaria, some individuals may benefit. A response can be expected within four weeks. Systemic corticosteroids are also mentioned in the treatment algorithm, however, their use should be limited to a maximum of 10 days (initially recommended dose 0.5–1 mg/kg BW prednisolone equivalent) during times of acute exacerbation. Long-term therapy with systemic corticosteroids should be abandoned due to considerable side effects. They are not approved for the treatment of chronic urticaria (Table 4). Because of poor evidence, H2 antihistamines and dapsone are no longer part of the updated treatment algorithm. The latter may possibly play a role in case of an extensive inflammatory infiltrate with neutrophils and/or eosinophils (pressure-associated chronic spontaneous urticaria or delayed pressure urticaria). Smaller studies and case reports have also shown therapeutic success using a variety of other agents such as (hydroxy-) chloroquine, sulfasalazine, tacrolimus, methotrexate, mycophenolate mofetil, cyclophosphamide, and UVB phototherapy [9].
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
9
CME Article
Table 6 Therapeutic management of inducible urticaria (besides H1 antihistamines, there is no approved therapeutic agent available. Consider pragmatic course of action according to treatment algorithm (Figure 2). Urticaria subtype
Intervention
All forms of physical urticaria
Physical trigger avoidance; prophylactic, regular or as-needed use of new-generation H1 antihistamines (possible dose increase up to 4-fold)
Urticaria factitia
Further options: ketotifen, UVB phototherapy
Cold urticaria
Further options: montelukast, ketotifen, cyproheptadine, tetracycline, penicillin, o malizumab
Delayed pressure urticaria
Further options: montelukast, dapsone, oral corticosteroids below Cushing threshold, methotrexate, omalizumab
Heat urticaria
Further options: tolerance induction, (hydroxy-)chloroquine, omalizumab
Solar urticaria
Further options: photohardening, (hydroxy-) chloroquine, plasmapheresis, photopheresis, IVIG, omalizumab
Vibration urticaria/ angioedema
Avoidance
All special forms
Trigger avoidance; prophylactic, regular, or as-needed use new generation H1 antihistamines (possible dose increase up to 4-fold)
Cholinergic urticaria
Further options: “Exercise tolerance induction”, ketotifen, danazol, omalizumab
Contact urticaria
Avoidance
Aquagenic urticaria
Further options: barrier cream, phototherapy
Abbr.: IVIG, intravenous immunoglobulins
Most patients should be re-assessed at 3–6 month intervals, in order to ascertain whether dose reduction or, in case of potential spontaneous resolution, discontinuation of the medication is feasible.
Other agents such as antidepressants (doxepin), mast cell stabilizers (oxatomide, ketotifen), calcium channel blockers (nifedipine), sympathomimetics (terbutaline), anticoagulants (warfarin), and stanozolol have all failed to display any therapeutic success and/or are fraught with substantial adverse effects. Most patients should be re-assessed at 3–6 month intervals, in order to ascertain whether dose reduction or, in case of potential spontaneous resolution, discontinuation of the medication is feasible [1, 9].
Inducible urticaria The evidence base with respect to anaging inducible types of urticaria m is considerably poorer than for chronic spontaneous urticaria.
As a pragmatic approach, the treatment algorithm for chronic urticaria may be followed.
10
The evidence base with respect to managing inducible types of urticaria is considerably poorer than for chronic spontaneous urticaria. Therapeutic options for inducible urticaria forms are listed in Table 6. Trigger avoidance is frequently not feasible (Table 6). Symptomatic therapy consists of H1 antihistamines approved for the treatment of chronic urticaria. As a pragmatic approach, the treatment algorithm for chronic urticaria may be followed (Figure 2). Numerous case reports and case series on various types of inducible urticaria have shown that omalizumab represents an effective therapeutic option for patients not responding to H1 antihistamines and other agents listed in Table 6. In Germany, there is currently only one therapeutic agent explicitly approved for the treatment of inducible urticaria: cyproheptadine (first generation antihistamine with antiserotonergic effects) is approved (from the age of 7) for symptomatic treatment of primary acquired cold urticaria not sufficiently responding to non-sedative antihistamines or showing contraindications. It appears more than doubtful whether cyproheptadine, which is characterized by substantial adverse effects, is more effective in cold urticaria than modern H1 antihistamines (possibly at an increased dose).
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
CME Article
Urticaria in children
With regard to diagnostic workup and therapy, there is no fundamental difference between children and adults.
While chronic spontaneous urticaria in childhood is known to be less common than in adults [12], there is no exact epidemiologic data. Of the inducible urticaria forms, urticaria factitia, cholinergic urticaria, cold urticaria, and contact urticaria also occur in children. With regard to diagnostic workup and therapy, there is no fundamental difference between children and adults [1]. While streptococcal infections represent the most common trigger in children with chronic spontaneous urticaria, other triggers are generally comparable to the ones seen in adults [12]. Weighing risks and benefits on a case-by-case basis, the treatment algorithm (Figure 2) is also recommended for children. Omalizumab has been approved for the treatment of chronic spontaneous urticaria, insufficiently responding to H1 antihistamines, in adults and children (12 years and above) (6 years and above in severe allergic asthma).
Urticaria in pregnancy Taking individual risks and benefits into account, the same course of action presented in the guideline treatment algorithm is basically also recommended in pregnancy. The administration of loratadine and cetirizine in standard doses may be considered safe in pregnancy, the former having been prospectively followed up in more than 5,000 pregnancies, the most of any antihistamine (Center for Pharmacovigilance and Counseling for Embryonic Toxicology: www.embryotox.de). Thus, loratadine is the H1 antihistamines of choice in all phases of pregnancy. References 1
Correspondence to Prof. Dr. med. habil. Bettina Wedi Klinik für Dermatologie, Allergologie und Venerologie Medizinische Hochschule Hannover Carl-Neuberg-Straße 1 30625 Hannover Germany E-mail: wedi.bettina@mh- hannover.de
Zuberbier T, Aberer W, Asero R et al. The EAACI/GA2LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014; 69: 868–87. 2 Zuberbier T, Aberer W, Brockow K et al. Teil 1: Klassifikation und Diagnostik der Urtikaria – deutschsprachige Version der internationalen S3-Leitlinie. AWMF-Leitlinie 013–028. Allergo J 2011; 20: 249–58. 3 Wedi B. Urtikaria und Angioödem. In: Plewig G et al. (Hrsg): Braun-Falco's Dermatologie, Venerologie und Allergologie. Berlin, Heidelberg: Springer Verlag, 2012: 442–69. 4 Peroni A, Colato C, Schena D, Girolomoni G. Urticarial lesions: if not urticaria, what else? The differential diagnosis of urticaria: part I. Cutaneous diseases. J Am Acad Dermatol 2010; 62: 541–55. 5 Bork K, Maurer M, Bas M et al. Hereditäres Angioödem durch C1-Inhibitor-Mangel. AWMF-Leitlinie 061–029. Allergo J 2012; 21:109–18. 6 Schneider J, Wedi B. Retrospektive Untersuchung zu physikalischer Urtikaria und Sonderformen. Allergologie 2014, im Druck. 7 Staubach P, Groffik A. Nützliche Instrumente für die Dokumentation bei Urtikaria. Der Hautarzt 2013; 64: 650–5. 8 Weller K, Groffik A, Altrichter S et al. Instrumente zur Erfassung von Krankheitsaktivität, Krankheitskontrole und Lebensqualitätsbeeinträchtigung bei Patienten mit chronischer Urtikaria und Angioödemen. Allergologie 2014, im Druck. 9 Zuberbier T, Aberer W, Brockow K et al. Teil 2: Therapie der Urtikaria – deutschsprachige Version der internationalen S3-Leitlinie. AWMF-Leitlinie 013–028. Allergo J 2011; 20: 259–76. 10 Wedi B, Wieczorek D, Raap U, Kapp A. Urtikaria … und die Therapie versagt. Hautarzt 2013; 64: 656–63. 11 Maurer M, Rosen K, Hsieh HJ et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013; 368: 924–35. 12 Pite H, Wedi B, Borrego LM et al. Management of childhood urticaria: current knowledge and practical recommendations. Acta Derm Venereol 2013; 93: 500–8.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
11
CME Article
Fragen zur Zertifizierung durch die DDG 1.
Welche der folgenden Aussagen
zur Urtikaria ist falsch? a) Der Mechanismus der Mastzellaktivierung ist für die meisten Urtikariaformen im Detail unbekannt. b) Die akute Urtikaria besteht in der Regel mindestens sechs Wochen. c) Eine akute Urtikaria kann allergisch bedingt sein. d) Das NSAR Acetylsalicylsäure ist ein häufiger Triggerfaktor für eine Urtikaria. e) Die klinische Symptomatik der Urtikaria wird durch degranulierende Mastzellen vermittelt.
2. Welche der folgenden Aussagen ist richtig? a) Die meisten chronischen Urtikariaformen bestehen maximal sechs Monate. b) Unter dem Begriff induzierbare Urtikaria werden neuerdings akute und chronische Urtikaria zusammengefasst. c) Die chronische spontane Urtikaria betrifft vor allem Frauen im mittleren Lebensalter. d) Die cholinergische Urtikaria ist eine Sonderform und betrifft vor allem ältere Männer. e) Die anstrengungsinduzierte Urtikaria/Anaphylaxie ist die häufigste physikalische Urtikaria.
d) Zu den hereditären autosomal dominant vererbten autoinflammatorischen Syndromen mit Mutation von NLRP3 zählt das Schnitzler-Syndrom. e) Insbesondere bei nicht juckenden Quaddeln und rezidivierenden Fieberschüben muss das Vorliegen eines autoinflammatorischen Syndroms ausgeschlossen werden.
Welche der folgenden Aussagen
zur Differenzialdiagnose der Urtikaria ist falsch? a) Bei länger als 24 Stunden in loco persistierenden Urticae, hämorrhagischer Komponente oder Abheilung mit Hyperpigmentierung sollte eine Urtikaria-Vaskulitis histologisch ausgeschlossen werden. b) Das urtikarielle Frühstadium eines bullösen Pemphigoids kann mit einer Urtikaria verwechselt werden. c) Bei einer urtikariellen Dermatitis findet sich im Gegensatz zur Urtikaria eine epidermale Komponente.
12
7.
Ein junger Mann berichtet, dass
er stets bei Prüfungen und beim Sport stark juckenden Hautausschlag bekomme, der nach einer halben Stunde wieder verschwinde. Welche Aussage
4. Welche der folgenden Aussagen zur Differenzialdiagnose rezidivierender Angioödeme (ohne Urticae) ist zutreffend? a) Rezidivierende Angioödeme ohne Urticae können Histamin-vermittelt sein. b) Rezidivierende Angioödeme ohne Urticae können Bradykinin-vermittelt sein. c) ACE-Hemmer und Sartane können Bradykinin-vermittelte Angioödeme auslösen. d) Bei persistierender Oberlippenschwellung sollte eine Cheilitis granulomatosa histopathologisch ausgeschlossen werden. e) Alle Aussagen sind zutreffend.
5.
Welche der folgenden diagnos-
tischen Maßnahmen ist bei der Abklärung einer chronischen spontanen Urtikaria am wenigsten zielführend, um einen potenziellen Triggerfaktor
3.
c) AAS7 d) GEPARD-Bogen e) UCT
zu identifizieren? a) Helicobacter-pylori-Antigen-Stuhltest b) Antistreptolysin-Titer c) Yersinien-Serologie d) Nahrungsmittelpricktest e) Differenzialblutbild
6. Welches der folgenden Instrumente eignet sich nicht zur Beurteilung der Krankheitsaktivität der chronischen spontanen Urtikaria? a) UAS7 b) CU-Q2oL
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
ist falsch? a) Die wahrscheinlichste Verdachtsdiagnose ist cholinergische Urtikaria. b) Sie sollten einen standardisierten physikalischen Test zur Objektivierung durchführen, z. B. eine Ergometer-Belastung. c) Typischerweise treten strecknadelkopfgroße Urticae erst 3–6 Stunden verzögert nach der Ergometerbelastung auf. d) Zeitgleich könnte bei dem jungen Mann auch eine Kälteurtikaria vorliegen. Sie sollten nach entsprechender Beschwerdesymptomatik fragen. e) Die Therapie der 1. Wahl besteht aus nichtsedierenden H1-Antihistaminika (ggf. in erhöhter Dosierung).
8. Welche Aussage zum neuen Behandlungsalgorithmus im internationalen Leitlinien-Update ist falsch? a) Auf der 1. Stufe stehen H1-Antihistaminika der zweiten Generation in Standarddosierung. b) H1-Antihistaminika in vierfacher Dosierung sind für die Therapie der chronischen spontanen Urtikaria zugelassen. c) Auf der 3. Stufe des Algorithmus werden als Zusatztherapie entweder Omalizumab, Ciclosporin A oder Montelukast empfohlen. d) Auf jeder Stufe im Algorithmus ist die kurzfristige Gabe eines oralen Glukokortikoids bei einer akuten E xazerbation möglich. e) Alle 3–6 Monate sollte überprüft werden, ob eine Spontanremission eingetreten ist.
CME Article
9. Welcher Wirkstoff erhielt in 2014 die Zulassungserweiterung für die nicht auf H1-Antihistaminika ansprechende chronische spontane Urtikaria? a) Secukinumab b) Rupatadin c) Omalizumab d) Anakinra e) Canakinumab
10. Welche Aussage zu Omalizumab bei Urtikaria ist falsch? a) Der Wirkmechanismus von Omalizumab bei der Urtikaria ist bislang nicht geklärt.
b) Es wurden mehr als 1 000 Patienten mit chronischer spontaner Urtikaria in Zulassungsstudien eingeschlossen. c) Bisher sind keine Anaphylaxien bei Urtikaria beschrieben worden. d) In den klinischen Studien haben sich keine neuen Sicherheitsaspekte verglichen mit dem bekannten Nebenwirkungsprofil in der Therapie des persistierenden schweren allergischen Asthmas ergeben. e) Omalizumab ist zugelassen für Patienten mit chronischer spontaner Urtikaria, die nicht auf Ciclosporin A angesprochen haben.
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014
Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 16. Juni 2014. Die richtige Lösung zum Thema „Therapie pathologischer Narben“ in Heft 12 (Dezember 2013) ist: (1b, 2c, 3d, 4e, 5d, 6d, 7c, 8b, 9c, 10e). Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg.akademie-dda. de ein.
13
