URTICARIA:A chalenging URTICARIA:A chalenging disorder to physiciansdisorder to physicians

ProfProf. M.YOUSRY ABDEL-MAWLA.. M.YOUSRY ABDEL-MAWLA.

DEFINITIONDEFINITION

Recurrent attacks of itchy ,short lived ,reddish,evansent swellings (WHEALS) that affect skin and / or mucosa

Classification of urticariaClassification of urticaria

• Urticaria : acute or chronic.• Acute urticaria is defined as urticaria that

has been present for less than 6 weeks. • Chronic urticaria is defined as urticaria that

has been continuously or intermittently present for at least 6 weeks.

• The 6-week period is a guide and not an absolute demarcation.

• When no underlying cause is found, chronic urticaria is referred to as chronic idiopathic urticaria (CIU).

AngieoedemaAngieoedema

• Angioedema : involves swelling of the deepdermal and subcutaneous/submucosal tissues..

Pathophysiology of urticariaPathophysiology of urticaria::

• Skin lesions and pruritus : caused by an allergic or nonallergic mechanism.

• Histamine is an important biochemical mediator in urticaria causing the classic wheal-and-flare response observed with urticaria.

• Mast cells are the major histamine-releasing cells of the skin. The mast cell possesses high-affinity receptors for immunoglobulin E (IgE).

• In allergic reactions, adjacent IgE molecules, which are bound to the surface of mast cells by the high-affinity IgE receptors, are cross-linked by allergens, leading to the release of histamine and other mediators.

• Nonallergic mechanisms : (aspirin, neuropeptides NSAIDs, opiates, succinylcholine, , polymixin, ciprofloxacin, rifampin, vancomycin, some beta-lactams).They induce direct degranulation of mast cell

HistopathologyHistopathology

• A lymphocytic infiltrate is commonly found in the lesions of both acute and chronic types of urticaria.

• Autoimmune-mediated chronic urticaria lesions have a mixed cellular infiltrate ( lymphocytes, polymorphonuclear leukocytes (PMNs), and other inflammatory cells).

• Some patients have vasculitis on skin biopsy. • A spectrum in histopathology seems to exist,

ranging from lymphocytic to vasculitic, correlating with disease severity, from mild to severe.

MortalityMortality in urticaria in urticaria

• Mortality is rare, unless the condition is accompanied by severe anaphylaxis or severe respiratory tract angioedema.

AnaphylaxisAnaphylaxis

• Anaphylaxis: a systemic syndrome of immediate hypersensitivity caused by an IgE-mediated release of mediators from mast cells and basophils, presents clinically with bronchospasm, angioedema, hives, and cardiovascular collapse.

• Anti-IgE autoantibodies : as a possible cause of idiopathic anaphylaxis,. Such autoantibodies act on mast cells to crosslink the FcERI or IgE bound to this Fc receptor.

History taking in urticariaHistory taking in urticaria

• Typical features• Typical lesions are described as edematous pink or red wheals

of variable size and shape, with surrounding erythema. The lesions :generally pruritic.

• A painful or burning sensation may be described (such lesions are often associated with angioedema).

• Pruritus of nonlesional skin occurs.• Dermographism:Itching, erythema, and a raised wheal occur in

areas that are scratched or stroked . • Individual lesions fade within 24 hours• With delayed pressure urticaria, lesions last as long as 48

hours. • The lesions of urticarial vasculitis, : palpable and purpuric,

lasting for several days or more and leading to residual hyperpigmented changes.

Questions asked to determine possible Questions asked to determine possible allergic vs non allergic causesallergic vs non allergic causes

• Are the hives associated with any foods? Have any new foods been added to the diet?

• Is the patient taking any regular medications or have any new medicines been started? aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, over-the-counter medications, herbs, and supplements.

• Does the patient have any recent or chronic infections?

• Are the hives caused by any physical stimuli (eg, heat, cold, pressure, vibration)?

• Does the patient have any chronic medical conditions?

Questions askedQuestions asked …………… ……………

• Is the urticaria associated with any substances that are inhaled or in contact with the skin (which may occur in an occupational setting)?

• Is the urticaria associated with insect bites or stings?

Physical examination in Physical examination in urticaria:urticaria:

• Features of anaphylaxis (eg, hypotension, respiratory distress, stridor, gastrointestinal distress)

• Angioedema(deep tissue or submucosal edema).• resembles idiopathic anaphylaxis, but other anaphylactic

symptoms are absent • Angioedema tends to progress slowly, often painful, and

without pruritus.• Look for typical skin lesions: edematous pink or red wheals of

variable size and shape, with surrounding erythema..• Lesions that are purpuric, nonblanchable, palpable with

residual pigmented changes are characteristic of urticarial vasculitis.

• Examine for dermographism.

Features of angioedemaFeatures of angioedema

• Angioedema : to progress slowly, often painfully, and without pruritus. A positive family history of similar symptoms offers an obvious clue to the role of this disease in a patient's symptoms.

• Episodes : provoked by dental procedures or other causes of local trauma. Making the diagnosis is important because life-threatening symptoms of upper airway obstruction may not respond to epinephrine.

• The manifestations : prevented by daily doses of androgens such as danazol or stanozolol, which increase the ability of hepatic cells to make C1 esterase inhibitor.

• Diagnosis : decreased levels of C4, CH50, and C1 esterase inhibitor concentration or function.

• An acquired form : associated with lymphoproliferative and autoimmune diseases.

Chronic idiopathic urticaria (CIU)Chronic idiopathic urticaria (CIU)

• Urticaria : no specific cause is identified by history, physical examination, or laboratory findings.

• Clinical features• Daily, or almost daily, occurrence of urticarial

wheals for at least 6 weeks. Angioedema occurs concurrently with CIU in about 50% of cases and delayed pressure urticaria in about 40%.

• The individual urticarial wheals last longer—at least 8 to 12 hours.

• Unlike UV wheals, wheals of CIU do not cause residual pigmentation.

• Systemic symptoms are minimal.

Lab Studies in a case of urticariaLab Studies in a case of urticaria:: • Skin tests or radioallergosorbent assay test (specific IgE)• Common screening laboratory tests that are ordered are as follows: • CBC with differential • Total eosinophil count • Sedimentation rate • Urine analysis • Liver function tests• Evaluation of the complement system, including total hemolytic complement (CH50),

C3, and C4 with prominent angioedema and rticarial lesions lasting more than 24 hours.

• Thyroid studies, including thyroid autoantibody levels (antimicrosomal, antithyroglobulin):

• Chemistry panel • Stool analysis for ova and parasites • H pylori workup • Hepatitis B and C workup • Sinus radiography (if symptomatic) • Antinuclear antibody (ANA) • Rheumatoid factor • Cryoglobulin levels .• Autologous serum skin testing: for CIU

Medical Care of cases of Medical Care of cases of urticaria:urticaria:

• Acute urticaria (<6 wk) : try to pinpoint a trigger • In a small number of cases, a pattern may emerge, pinpointing

the offending agent. • Avoidance• If a trigger can be identified • Aspirin, NSAIDs, opiates, and alcohol :are avoided• Intravenous gammaglobulin, plasmapheresis, and

cyclosporin :n severe urticaria of the autoimmune type.• Colchicine and dapsone : in urticarial vasculitis, because of

their ability to modulate PMN function. • Antileukotriene agents : provide a synergistic response when

used in conjunction with antihistamines.

Adrenergic agentsAdrenergic agents

• Epinephrine: Any patient who has had a potentially life-threatening allergic reaction should have injectable epinephrine available for use at all times (Any use of epinephrine necessitates an immediate evaluation in the nearest emergency department

• Dose: 0.2-0.5 mg IM/SC single dose; can be repeated in 15- to 20-min intervals IM administration has been associated with a faster time of onset than S.C.

• Paediatric Dose :0.01 mg/kg, up to 0.5 mg, IM/SC single dose; can be repeated in 15- to 20-min intervals prnIM administration has been associated with a faster time of onset than SC .

• Contraindications: Documented hypersensitivity; coronary insufficiency; cardiac arrhythmias; glaucoma se with caution during labor (may delay second stage of labor

THERAPY OF ANGIOEDEMATHERAPY OF ANGIOEDEMA

• Androgens -- Synthetic attenuated androgens (eg, danazol, stanozolol) taken prophylactically increase the serum concentration of C1INH, presumably by enhancing the function of the C1INH gene. When danazol is used prophylactically in adolescents or preadolescents, the concentration of C1INH and C4 are increased in the plasma.

• Danazol 200 mg/d PO initially; if abdominal discomfort recurs, increase to 400 mg/d PO for 1-2 mo; once symptoms are controlled, reduce dose to 200 mg/d PO; continue attempt to titrate downward to minimum effective dose .

THERAPY OF ANGIOEDEMA 2THERAPY OF ANGIOEDEMA 2

• Antifibrinolytic agents -- Used successfully as preventive therapy. Their effect may depend on physiologic or pathologic enhancement of plasminogen activation in blood, which may promote activation of C1INH

• Aminocaproic acid (4-5 g) IV over 1 h initially, followed by 1 g/h IV for 8 h; dilute IV solution to obtain concentration of 1 g/50 mLLength of treatment may be adjusted depending on response of patient

• C1-esterase inhibitor, human (investigational Prophylaxis: 500-1000 U IV for 2h prior to surgeryAcute treatment: 500-1000 U IVDose can be increased significantly depending on history and seriousness of previous attacks

• Complement replacement agents: Fresh frozen plasma (FFP) 2 U IV initially; may be gradually increased until improvement of symptoms observed

TABLE-- PHARMACOLOGIC ACTIONS OF H1 ANTIHISTAMINES

Action Receptor Comment

Anti-inflammatory H1 H2 Competitive antagonist at H1 (and H2

) receptors

Sedative (mainly first generation) H1 Antagonises "arousal" action of histamine in CNS; depends on

lipophilicity of the antihistamine

Anticholinergic Muscarinic Involves blockade of central and peripheral muscarinic receptors; second-generation antihistamines

have little or no effect on muscarinic receptors

Antiallergic Unknown Probably requires dose level in excess of the licensed dosage

Not H1 or H2

Negative feedback inhibition of histamine synthesis and release

H3 Not yet demonstrated in skin

TABLE-- ANTIHISTAMINES CURRENTLY LICENSED

First Generation Adult Single Dose (mg) Special Features

Hydroxyzine 25-50 Strongly sedative anxiolytic, useful to allay itching as nighttime

treatment in urticaria, eczema

Chlorpheniramine 4-8 Sedative, rapid action, useful in acute urticarias and angioedema

Brompheniramine 4-8 As for chlorpheniramine

Azatadine 1-2 Sedative, no special features

Clemastine 1-2

Diphenhydramine 25-50

Mequitazine 5

Phenindamine 25-50

Promethazine 25-50 Powerful sedative action, rapid action, useful in acute urticaria,

angioedema

Trimeprazine 10-20 As for promethazine

180 Cyproheptadine 4-8 Sedative antihistamine with additional antiserotonin activity

Second Generation

Acrivastine 8 Low sedation

Cetirizine 10 Low sedation, claimed to possess additional antiallergic action

Loratadine 10 Low sedation

Mizolastine 10 Low sedation

Third Generation

Fexofenadine Nonsedative

Miscellaneous

Ketotifen 1-2 Sedative, claimed to have mast cell-stabilizing activity

Doxepin 10-50 Tricyclic antidepressant with potent H1 and H2 antihistamine activity,

powerfully sedative and anxiolytic

Adult single dose for allergic rhinitis is 120 mg.

Non & Non & Minimally SedatingMinimally Sedating Anti histamines in Urticaria Anti histamines in Urticaria

• Cetirizine (Zyrtec):10mg :Minimally sedating

• Fexofenadine(Telefast):180mg

• Loratadine(Claritin):10mg

• Desloratadine(Clarinex):5mg

H2antagonistsH2antagonists ( (antihistamines)antihistamines)

• Cimetidine (Tagamet) -- If no response to H1 antagonist alone occurs, coadministration with this H2 antagonist can be useful to treat urticaria.

•Adult Dose: 300 mg PO qid or 400 mg PO bid Pediatric Dose: Infants: 10-20 mg/kg/d PO q6hChildren: 20-40 mg/kg/d PO in divided doses separated at least 6 h

• Interactions: Can increase blood levels of theophylline, warfarin, tricyclic antidepressants, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine

CorticosteroidsCorticosteroids in urticaria in urticaria

• Prednisolone: Reduces capillary permeability.

• Adult Dose: 40-60 mg/d PO divided 1-2 doses per d

• Paediatric Dose: .5-2 mg/kg/d PO divided 2-4 doses per d

• Interactions: Decreases effects of toxoids (for immunizations). Phenytoin, carbamazepine, barbiturates, and rifampin decrease effects of corticosteroids

TABLE -- Comparison of Annular Lesions including urticaria

Diagnosis Clinical presentation Treatment options

Tinea corporis

Scaly, annular, erythematous plaques or papules on glabrous skin

Topical and systemic antifungals

Pityriasis rosea

Small, fawn-colored, oval patches with fine scale along the borders, following skin cleavage lines

Topical and systemic corticosteroids; UVA, UVB

Granuloma annulare

Indurated, nonscaly, skin-colored annular plaques and papules, usually on the extremities

Topical and intralesional corticosteroids

Sarcoidosis Indurated, erythematous plaques Topical, intralesional and systemic corticosteroids; antimalarials; thalidomide

Hansen's disease

Erythematous annular plaques, with or without scale

Dapsone; rifampin (Rifadin)

Urticaria Evanescent annular, nonscaly, erythematous plaques

Oral antihistamines

Subacute cutaneous lupus erythematosus

Annular or papulosquamous plaques, with or without scale, on sun-exposed areas

Topical, intralesional and systemic corticosteroids; antimalarials

Erythema annulare centrifugum

Annular patches with trailing scale inside erythematous borders

Topical and systemic corticosteroids; oral antihistamines; treatment of the underlying cause

UVA = ultraviolet A light; UVB = ultraviolet B light.

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