A Review on Urticaria

 

Rohit R. Patil*, Mayur A. Chaudhari, Dr. Tushar A. Deshmukh

SES Arunamai College of Pharmacy, Mamurabad, Jalgaon-425001 [M.S.] India

 

ABSTRACT:

Urticaria is related to the rising wheals, angioedema. It is the edema of the superficial dermis, angioedema is the the subcutaneous layer and the gastrointestinal tract as pro First-line pharmacotherapy for acute and chronic urticaria is nonsedating second-generation antihistamines (histamine H1 blockers), which can be titrated to larger than standard doses found dermis. Types of urticarial include acute, chronic, physical, adrenergic, contact urticarial. Sign and symptoms are mild angioedema, lesions, diaphoresis.The diagnosis is based primarily on the clinical presentation. The need for investigations to elucidate a possible underlying cause should be guided by the presentation and response to antihistamines. Treatment includes 1st-generation H1 antihistamines, 2nd-generation H1 antihistamines (e.g. Loratadine), drug treatment therapy First generation or classic H1 receptor anti- histamine, Second-Line therapy-Anti-depressants, corticosteroids, calcium channel antagonists,Third-line therapy, other drug and future drugs also.

 

 

 

INTRODUCTION:

Urticaria is characterized by the fast arising of wheals, which may be accompanied by angioedema.Edema of the superficial dermis is named urticaria, whereas edema of the profound dermis, the subcutaneous layer and the gastrointestinal tract, is named angioedema⁽¹⁾.A wheal is an elementary dermatological lesion comprising three typical features: (I) central edema of varying size, surrounded by a reflex erythema; (II) associated pruritus; (III) ephemeral nature, with the skin usually returning to its normal aspect within one to 24 hours.

 

 

 

Angioedema is defined by: (I) sudden and pronounced edema of the profound dermis and the subcutaneous layer; (II) pain as amore frequent symptom than pruritus; (III) frequent involvement of the mucous membranes; and (IV) resolution of the condition within approximately 72 hours, which is slower than in wheals. ⁽²⁾

Urticaria (hives) is a vascular reaction of the skin characterized by wheals surrounded by a red halo or flare (area of erythema) Cardinal symptom is PRURITUS (itch) Urticaria is caused by swelling of the upper dermis § Up to 20% of the population experience urticaria at some point in their lives.^(5-6)

 

Urticaria was described by Hippocrates as a distinct entity. As the understanding of molecular mechanisms involved in the pathogenesis of this affection improves, there is increasing evidence of its heterogeneity.1 Some studies demonstrated that about 0.1% of the population has urticaria, and that the cumulative prevalence rates vary between 15% and 20%.2,3 Among those affected by urticaria, 50% will still be presenting the condition one year after the first visit to the doctor, and 20% will go on experiencing episodes of the disease for over 20 years.^(1-4)

 

The urticarial wheal is characterized by dermal edema, vasodilatation, and perivascular nonnecrotizing infiltrate comprising primarily of mononuclear cells, predominantly CD4+ lymphocytes, with variable numbers of monocytes, neutrophils, eosinophils, and basophils ⁽⁹⁾.The dermal neutrophilia is strikingly evidentat sixty minutes of evolution of wheal with neutrophils representing the main component of the cellular infiltrate ⁽¹⁰⁾. Mast cell numbers remain unaltered and are comparable to those in uninvolved skin and healthy controls ⁽¹¹⁾. The cytokine profile is characterized by an increase in interleukin-4 (IL-4), interleukin-5 (IL-5), and interferon-gamma RNA (IFN-gamma), suggestive of a mixed Th1/Th2response .Chemokinesareupregulatedand increased expression of adhesion molecules is evident. The uninvolved skin is characterized by upregulation of soluble mediators and adhesion molecules, almost identical to lesional skin, and significantly higher T-cell numbers, while accumulation of neutrophilsis an exclusivity of whealing skin ^[11](Tables1and2).

 

PATHOPHYSIOLOGY:

All mast cells express high affinity igE receptors (FceRi,s) means igE dependent reaction. The constant region domain of IgE is the major site of interaction with igE receptor, when igE forms a complex with FceRi,s on the mast cell to which an allergen binds, degranulation occurs. Mast cell degranulation can also occur by other mechanisms, - including cross-linking of adjacent FceRi, binding of receptor – bound-IgE, anti-IgE by allergen anti-FceRi antibodies.

Non-immunologic stimuli, such as opioids, c5a anphylotoxin and stem cell factor as well as neuro- peptides such as substance p can cause degranulation via direct stimulation. These non-imunologic stimuli initiate calcium and energy-dependent steps that cause storage granules to fuse with the cell membrane and externalise  their contents which include preformed and newly synthesised mediators of inflation.A decrease in basophil (basopenia) is a common feature of chronic uricaria& may be useful for screening for the autoimmune form of the disease. ⁽¹²⁾ TABLE 1

 

Thyroid function tests and test for thyroid antibodies are necessary only when the clinical findings suggest the presence of thyroid disease. Challenge test to confirm the diagnosis of a physical urtecaria is done as cholinergic urticaria can be diagnosed with exercise or hot bath testing. The lesion of cold urticaria can be induced with the iCECubE test. Aquagenicurticaria can be confirmed with application of water compresses. Testing of pressure urticaria can be performed by applying a 80kg to the patient thigh and, if still cause of the urticaria is not found some recommend screening for H.pylori infection. Patient suspected of having urticariavasculitis should undergo a skin biopsy to confirm the diagnosis. Patients with angioedema but without urticaria should have C4 levels measured to screen for C1 – inhibitor deficiency, as C1 inhibitor levels can be measured if the C4 level is low. So taking a detailed history and specialised test is usually adequate to establish a diagnosis of chronic urticaria. Allergy skin tests (SPT and Patch Tests) with various group of allergen (pollens & foods)  are done if associated with allergic rhinitis, or history of sensitivity to foods. Drugs, contact chemicals and latex allergen.  TABLE 2.

 

Table1:infiltrating cells: pattern in urticarial level wheal, uninvolved skin, Healthy control subjects⁽²²⁾

Cell type	Urticarial wheal	Uninvolved skin	Healthy control subjects
Mast cells	Normal count	Normalcount	Normalcount.
lymphocytes	RaisedT-lymphocytecount	MorenumerousT-lymphocytesthanin lesionalskin.	Low T-lymphocytecount.
neutrophils	Majorcellularinfiltrateat60minutesof evolutionofurticarialwheal	Significantlylessinfiltrationthanin lesionalskin.	Insignificant
eosinophils	Significantlyhighernumber	Insignificant	Insignificant
Basophils	Significantnumber,especiallyat30minutes ofevolution,ofurticarialwheal	Lessbutrelevantnumber.	Insignificant

 

Table2:Cytokine,chemokine, and adhesion molecule expression:urticarial wheals, uninvolved skin, and healthy control subjects⁽²²⁾

	Urticarial wheal	Uninvolved skin	Healthy control subjects
Cytokines
Interferon gamma	High expression	Significantly low expression	Notexpressed
Interleukin-4	High expression	Significantly low expression	Notexpressed
Interleukin-5	High expression	Significantly low expression	Notexpressed
Interleukin-8	Moderate expression	Moderate expression	Not expressed
Chemokines
CXCR3/CCR3	Expression similar to control skin.	High expression	Expression similar in lesional and healthy control skin
Adhesion molecules
Cellular adhesion  molecule.	High expression	intense expression	Significant expression

 

TYPES OF URTICARIA:

Acute urticaria

·      Wheals less than 6 weeks

·      Wheals resolve in < 24 hours.

·      20 to 30% progress to chronic or recurrent urticaria.

·      Aetiology % Idiopathic – 50% u R T I – 40%

·      Drugs – 9% Foods – 1%

·      Chronic Urticaria

·      Wheals, on regular daily > 6 weeks

·      Wheals last for 4 to 36 hours.

·      >50% are due to autoimmune  aetiology.

·      35% associated with physical urticarial

·      5% due to  urticariavasculitis

* Physical urticarial

*Adrenergic urticarial

·      Dermographism

·      Exercise induced anaplylaxis

·      Aquagenicurticaria

·      Cholinergic urticaria

·      localized heat urticaria

·      Cold urticaria

·      Solar urticarial

·      Delayed Pressure urticaria

·      Vibratory urticarial

*Contact Urticaria

*(induced by biologic or chemical skin contact)

* urticariaVasculitis (defined by vasculitis on skin biopsy)

* Angioedema without wheals (a) Hereditory angioedema (b) Idiopathic or drug indused like ACE inhibitor etc.

* UrticariaVasculitis It occurs in 1% to 10%  patients with chronic urticaria. It is component of a chronic systemic illness, such as systemic lupus erythematosus, hypocompementermic urticarial vasculitis syndrome, sjogren, syndrome or mixed cryoglobulinaemia. The lesion tend to last longer than 24 hours and are associated with bruning and pain in addition to itching, heals with purpura or patechiae. Skin biopsy of the lesion typically shows evidence of leukocyte clasticvasculitis.⁽¹³⁾

 

SIGNS AND SYMPTOMS:

1.    mild (skin) urticaria, generalized erythema or angioedema

2.    moderate (findings suggesting respiratory, cardiovascular dyspnea, stridor, wheezing, nausea, vomiting, syncope, or gastrointestinal involvement) diaphoresis, thoracic or larynx discomfort or abdominal pain

3.    severe (hypoxia, hypotension or neurological damage)  cyanosis, 02 saturation by pulse oximetry below 92%, hypotension (systolic BP < 90 mmHg), confusion, collapse and loss of conscience or fecal and urinaryincontinence.⁽¹⁾

4.    Lesions typically appear over the course of minutes, enlarge, and then disappear within hours Individual wheals rarely last >12hrs Surrounding erythema will blanch with pressure Urticaria may be acute or chronic Acute = new onset urticaria< 6 weeks

5.    Chronic = recurrent urticaria (most days) > 6 weeks Most urticaria is acute and resolves.

 

 

Figure 1.  Example Of Urticaria.

 

DIAGNOSIS:

•Differential diagnoses of urticarial

1.    PrurigoStrophulus

2.    Polymorphic Erythema

3.    Bullous Pemphigoid

4.    Mastocytosis

5.    Vasculites And Polyarthritis

6.    Lupus Erythematosus

7.    Morbilliform Drug Eruptions

 

As the clinical features of autoimmune chronicurticaria are indistinguishable from those of chronic idiopathic urticaria. Unfortunately no reliable direct antibody test is available but the ASST is helpful in distinguishing cases of chronic autoimmune urticarial from chronic idiopathic urtecaria. The sensitivity of ASST is 65% to 81% and the specificity is 71% to 78%.A decrease in basophil (basopenia) is a common feature of chronic uricaria& may be useful for screening for the autoimmune form of the disease.

 

Thyroid function tests and test for thyroid antibodies are necessary only when the clinical findings suggest the presence of thyroid disease. Challenge test to confirm the diagnosis of a physical urtecaria is done as cholinergic urticaria can be diagnosed with exercise or hot bath testing. The lesion of cold urticaria can be induced with the ICE CUB E test. Aquagenicurticaria can be confirmedwith application of water compresses. Testing of pressure urticaria can be performed by applying a 80kg to the patient thigh and, if still cause of the Urticaria is not found some recommend screening for H.pyloriinfection. Patient suspected of having urticariavasculitis should undergo a skin biopsy to confirm the diagnosis. Patients with angioedema but without urticaria should have C4 levels measured to screen for C1 – inhibitor deficiency, as C1 inhibitor levels can be measured if the C4 level is low. So taking a detailed history and specialised test is usually adequate to establish a diagnosis of chronic urticaria. Allergy skin tests (SPT and Patch Tests) with various group of allergen (pollens & foods) are done if associated with allergic rhinitis, or history of sensitivity to foods. Drugs, contact chemicals and latex allergen.⁽¹⁴⁾

 

INVESTIGATION:

The diagnosis is based primarily on the clinical presentation. The need for investigations to elucidate a possible underlying cause should be guided by the presentation and response to antihistamines (Table 3) .Allergy testing. Patients are often referred to hospital in the belief that foods are responsible for their chronic urticaria. A practical approach could be to exclude an atopic diathesis by skin prick testing (SPT) to a panel of aeroallergens and suspect foods. The sight of negative SPTs in certain patients helps to reassure the patient that allergy is not the cause of their symptoms and may contribute to improved adherence with long-term antihistamines. When urticaria symptoms are linked to exertion or exercise, there can be a role for limited specific IgE testing to related food allergens, e.g. omega-5-gliadin or lipid transfer proteins ^[15]. In certain Mediterranean areas, Anisakis simplex hypersensitivity associated with the consumption of raw fish should be considered ^[16]. Full blood count (FBC)—The eosinophil count may beelevated in parasitic infections and in some druginduced reactions.^[17]

 

TREATMENT:

Table no.3 Dose Of Licensed Drugs^[17]

 

•Oral H1 antihistamines are the first-line treatment for acute and chronic urticaria.

•1st-generation H1 antihistamines are less well-tolerated due to sedation, so are often taken at bedtime e.g. 10-50 mg hydroxyzine 1-2 hours before bedtime Can start with smaller doses (10 mg) to allow the patient to manage the sedative effects.

•2nd-generation H1 antihistamines (e.g. Loratadine) are better tolerated with fewer sedative and anticholinergic effects and may be used in patients intolerant of or inadequately controlled by 1st-generation agents.⁽¹⁹⁾

•Certain populations, including children, the elderly, and patients with renal or hepatic impairment may require dosage calculation or adjustments when using H1 antihistamines.⁽²⁰⁾

 

1st Generation Diphenhydramine (OTC)

Hydroxyzine (Rx, generic)

Chlorpheniramine (OTC)

2nd Generation Cetirizine (OTC)

Loratadine (OTC)

Fexofenadine (OTC)

 

DRUG:

•First generation or classic H1 receptor anti- histamine

like hydroxyzine, pephenhydramine, cyprohepatidine and chlorphenaramine are rarely used because of their sedative and anticholinergic effects.

 

H2 Receptor antagonist.

As 15% of histamine receptor in the skin are H2 type, H2 receptor antagonists like cimetidine, ranitidine and famatodine has been shown to be additive effect.⁽²¹⁾

 

•Second-Line therapy

Anti-depressants, corticosteroids, calcium channel antagonists, levorthyroxine sodium supplements, levkotriene receptor antagonists & other drugs are used in secondline therapy.

 

Corticosteroids.

Short courses of systemic corticosteroids can be prescribed for severe urticarial symptoms, but long term therapy is not recommended because of numerous adverse effect.

 

Nifedipine.

The proposed mechanism of action is modification of calcium influx into cutaneous mast cells.It is effective in decreasing pruritus and whealing in patients with chronic urticaria associated with co-morbid hyperationsion or on ACE inhibitor.⁽²²⁾

 

•Third-line therapy.

It involves the use of immunomodulatory agents in patients with chronic urticaria which include cyclosporine, tacrolimus, methotrexate, cyclophospamide my –cophenolatemofetil and intravenous immunoglobulin.

 

Other drugs:

Dapsose and colechine, suafasalazine may be beneficial in the managing urticaria having neutrophilic infiltration (urticariavasaulitis).

Hydroxychlorquine has shown promising results in the treatment of chronic indiopthicurticaria and inhypocomplementemic urticarial vasculitis.

 

The Future. Speeder and tanetal recently reported on three patients with chronic urticaria, who responded toomalizumab, a humanized monoclonal antibody, that binds free IgE.

 

Pharmacological Action OfAcrivastine

 

 

From reference ^(22).Table no. 4

Generation	Drug	Tmax*(hours)	Time to action (hours)**
First	Chlorpheniramine	2.8 ± 0.8	3
Second	Acrivastine	1.4 ±0.4	1

 

Mast cells release the histamine and it binds with histaminergic receptors (H1, H2, H3 or H4) to elicit a series of events mediates the characteristic response through second messenger systems. All histaminergic receptors are G-protein coupled type.

 

H2 receptor produces cAMP-dependent protein kinase to elicit the response in GIT. The H2 receptor bound reversibly by H2 antagonist and reduces the cAMP formation. Further, it is responsible for the activation of proton pump and subsequently reduces the gastric acid secretion in GIT.

 

CONCLUSIONS:

H1 antihistamines are able to control the symptoms of chronic urticaria in most cases. The recommended treatment in patients with CU should be individualized for each patient. H1 antihistamines significantly reduce plasma levels of IL-1β, IL-2, IL-4 IL- 6, IFN-γ, TNF-α, IL-17 and IL-31, but not IL-10 levels. Patients treated with Desloratadine recorded a greater decrease in IL-1β than those treated with Levocetirizine. There are no differences between the two compounds in terms of their effects on other cytokines investigated.⁽²³⁾

 

 

 

 

 

 

 

 

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Received on 17.03.2018       Modified on 20.04.2018

Accepted on 29.04.2018       ©A&V Publications All right reserved