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Chronic Idiopathic Urticaria

Chronic Spontaneous Urticaria

Chronic idiopathic urticaria is defined as the occurrence of erythematous, pruritic plaques for at least six weeks on a daily or almost daily basis without obvious cause. It may often last for months or sometimes years, and can have a significant impact on the quality of life. The diagnosis is made after excluding all potential causes, and treatment includes symptomatic measures and antihistamines.


Presentation

The clinical presentation of all forms of urticaria includes the presence of well-circumscribed, erythematous, pruritic plaques. In patients with chronic urticaria, these plaques (wheals) may vary in size, and they appear in abrupt fashion almost every day for a prolonged period of time, usually months, or even years in some cases. In chronic urticaria, the presence of one wheal usually lasts between 4 and 36 hours, and is distinguished from acute urticaria, in which wheals appear and last for 30-120 minutes. Wheals may appear either in localized sites, such as the thigh or the forearms, or they may be disseminated. Because pruritus is one of the most prominent components of this syndrome, patients may report substantial irritation by these lesions, as they have been established to have a significant impact on the quality of life [10] [11].

In addition to wheals, edema of the face, lips, or tongue may be observed, accompanied by breathing difficulties, stridor, and wheezing.

Thrombosis
  • Increases in rates were observed for transient ischemic attack (0.7 vs 0.1), myocardial infarction (2.1 vs 0.8), pulmonary hypertension (0.5 vs 0), pulmonary embolism/venous thrombosis (3.2 vs 1.5), and unstable angina (2.2 vs 1.4), while the rates observed[xolairhcp.com]
Leg Pain
  • pain (4%), fatigue (3%), dizziness (3%), fracture (2%), arm pain (2%), pruritus (2%), dermatitis (2%), and earache (2%).[xolairhcp.com]
Urticaria
  • In 59% of these patients, complete control of urticaria was achieved, which included 70% of patients with autoimmune urticaria and 43% with chronic idiopathic urticaria.[ncbi.nlm.nih.gov]
  • Miscellaneous causes - exposure to sunlight (Solar Urticaria), cold temperatures (Cold Urticaria), strenuous exercise (Cholinergic Urticaria), and other forms that may cause chronic development of wheals may also be considered as potential causes.[symptoma.com]
Chronic Urticaria
  • Unfortunately, a large number of patients are diagnosed with CIU, since in many cases of chronic urticaria the cause is not identified.[symptoma.com]
  • Hypocomplementemia may provide clues to pathophysiologic mechanisms operative in some patients with chronic urticaria.[ncbi.nlm.nih.gov]

Workup

Before establishing the diagnosis of chronic idiopathic urticaria, an extensive diagnostic workup should be performed to rule out all possible causes of chronic urticaria. Prior to obtaining blood tests, a detailed patient history should be obtained, and information regarding prior history with allergies, prior drug use [12], presence of other illnesses that may be the cause of urticaria, and travel history together with potential risk factors for transmission of certain diseases.

A range of diseases should be excluded, including [13]:

  • Endocrine dysfunction - A substantial number of patients have positive anti-TBG and anti-microsomal antibodies, indicating a thyroid dysfunction, such as Hashimoto's thyroiditis, but also other thyroid diseases, and these patients have symptoms such as heat or cold intolerance, cardiac disturbances, and abnormal reflex patterns. Because of these facts, thyroid hormone levels, including TSH, free T3 and T4, and autoantibodies should be evaluated.
  • Infectious causes - Urticaria has been described in a number of infectious diseases, including hepatitis A, B, and C [14], Human immunodeficiency virus (HIV) infection, various parasitic infections, including Giardia Lamblia, Toxocara canis, and many others, which is why a detailed panel targeted at excluding infectious pathogens should be performed. Travel and social history may significantly aid in choosing the pathogens to be tested for.
  • Autoimmune diseases - Systemic autoimmune disorders, including Systemic Lupus Erythematosus (SLE), Sjogren's syndrome, urticarial vasculitis, cryoglobulinemia, dermatomyositis, connective tissue disorders, and other illnesses are important causes of chronic urticaria. Patients with these diseases will usually experience additional symptoms, including joint pain, involvement of other organs, including the liver and kidneys, and for these reasons, full evaluation should be performed, including testing for rheumatoid factor (RF), sedimentation rate (ESR), C-reactive protein (CRP), and various antibodies, including antinuclear (ANA), anti-Sjogren syndrome (anti SS-A and anti-SS-B), anti-Jo-1, and anti-RNP antibodies. In addition to laboratory test, skin biopsy may be indicated in patients that develop bruising, joint pain, and fever, because of presumptive diagnosis of urticarial vasculitis, which should be excluded as well.
  • Malignancies - Tumors of the lungs, gastrointestinal tract, and tumors of lymphoid origin may present with chronic urticaria, but they are commonly followed with constitutional symptoms, such as malaise, fever, weight loss, fatigue, and other symptoms depending on the primary localization of the tumor. Detailed work-up, including tumor markers and imaging studies should be performed.
  • Genetic causes - Hereditary angioedema (HAE) is an autosomal dominant disorder that may be life-threatening, and involves abnormalities of the complement system and bradykinin formation. Although urticaria rarely occurs in this syndrome, it is observed in a number of patients, and this syndrome may be life-threatening if not treated properly.
  • Miscellaneous causes - exposure to sunlight (Solar Urticaria), cold temperatures (Cold Urticaria), strenuous exercise (Cholinergic Urticaria), and other forms that may cause chronic development of wheals may also be considered as potential causes.

Once all potential causes of chronic urticaria have been excluded, the diagnosis of chronic idiopathic urticaria can be made, and proper treatment strategies can be implemented.

Treatment

When the cause is not identified, chronic urticaria is managed by symptomatic and antihistaminic therapy.

Antihistamines are the primary choice in long-term treatment, as they have little or no side-effects and are generally tolerable [15]. Histamine-receptor (H1) antagonists are taken orally, and include cetirizine 10mg q24h, levocetirizine 5mg q24h, fexofenadine 180mg q24h and desloratadine 5mg q24h. Newer generation drugs have less sedating properties, and are favorable over older antihistamines, such as diphenhydramine, but they are equally effective. Patients should take antihistamines in a long-term administration, to prevent potential recurrences.

Other drugs that may be used include corticosteroids, which are used for severe symptoms, and include prednisone, in doses of 30-40mg q24h. For patients that develop angioedema, epinephrine should be administrated immediately, in a subcutaneous dose of 0.3mL of 1:1000 solution. Epinephrine administration may be life-saving, particularly in patients with respiratory obstruction as a result of edema.

Symptomatic therapy primarily includes alleviation of rash. Some recommendations include avoiding tight clothes, cool baths, limited exposure to sunlight, and change of medication that may aggravate rash, such as angiotensin-converting enzyme (ACE) inhibitors used in hypertension.

Prognosis

Although patients with CIU have little or no complaints that can compromise their overall health, the disease might cause a significant disability, and often requires long-term management with medication. It is estimated that about 40% of patients with chronic urticaria, regardless of the cause, will develop lesions for up to 10 years, while 20% of patients with develop lesions for > 20 years. Despite these facts, the prognosis is generally good, but patients who develop angioedema may require immediate treatment, as angioedema may lead to respiratory compromise.

Etiology

CIU is termed "idiopathic" because the disease has no identifiable cause. Certain studies have indicated that a substantial number of patients with chronic urticaria have an underlying autoimmune disease, but CIU remains a disease with an undisclosed cause.

Epidemiology

It is estimated that about 15-23% of the population had an episode of urticaria during their life, and about 25% of these cases progress to chronic urticaria. Of those 25%, it is estimated that 80% of cases remain without an identifiable cause, and are classified as CIU [2]. Chronic urticaria primarily develops in adults, and it is observed almost four times more frequently in women than in men. Certain studies estimated point prevalence rates of 0.5-1% [3] [4], but the actual rates are still unknown.

Sex distribution
Age distribution

Pathophysiology

The pathogenesis of all forms of urticaria, including CIU, starts with activation of mast cells and basophils by a drug, allergen, or some diseases, which leads to release of vasoactive substances, such as bradykinin, kallikrein, prostaglandins, and histamine, the most important mediator in this disorder. These substances are released into the superficial part of the dermis, and cause both capillary and venous dilation, which leads to intradermal edema and erythema. Mast cells also release cytokines that serve as chemoattractants, i.e. they cause leukocytes to migrate into the site, which also contribute to edema and local inflammation. All of these events lead to development of wheals and the typical appearance of dermal plaques. Because of release of vasoactive mediators and prostaglandins, these plaques are pruritic.

It is known that acute urticaria is characterized by type I hypersensitivity reactions, and activation of IgE antibodies [5]. In patients with chronic urticaria, a different type of antibody is increasingly being recognized as one of the key elements in the pathogenesis. Anti-Fc epsilon (Fcε) autoantibodies belonging to the class of IgG have been identified in a substantial number of patients [6], and they cause degranulation of mast cells and release of histamine and other vasoactive substances [7].

In addition to Anti-Fcε antibodies, approximately 30% of patients with chronic urticaria have positive antithyroglobulin (TBG) antibodies or antimicrosomal antibodies, implying that the thyroid gland plays an important role in the pathogenesis of this syndrome. Stress has also been extensively researched in patients with CIU, and several correlations have been hypothesized, bridging stress, post-traumatic stress disorder (PTSD), and emotional distress [8] [9].

Prevention

Prevention of this disorder is not possible, but strategies to reduce the burden of this disease is to thoroughly investigate all possible causes of chronic urticaria, and try to find the underlying disorder. Proper therapy will reduce the burden of this disease among individuals, and prevent possibly life-threatening events, such as angioedema. Unfortunately, a large number of patients are diagnosed with CIU, since in many cases of chronic urticaria the cause is not identified.

Summary

Chronic idiopathic urticaria (CIU) is defined as daily or almost daily occurrence of pruritic, erythematous, well-circumscribed plaques on the skin, known as wheals, for at least 6 weeks without a determined cause. Numerous disorders, including primary skin diseases, systemic and autoimmune illnesses, infections, and malignancies are all identified as causes of chronic urticaria, but iatrogenic causes, including drugs and certain allergens may also be triggers. However, in a substantial number of individuals, chronic urticaria remains idiopathic, and may last for months, or even years, which can be a serious disability for patients [1]. The pathogenesis of urticaria in general starts with the release of vasoactive substances from mast cells and basophils in the dermis, including histamine and bradykinin, which leads to edema of the dermis and vasodilation. In the setting of chronic urticaria, anti-Fc epsilon (Fcε) autoantibodies belonging to the class of IgG have been identified, and presumably play a key role in mast cell degranulation, while other agents or factors may be involved. The clinical presentation involves the presence of previously mentioned wheals, which can develop at any part of the skin, and can be either localized or disseminated. In some patients, edema of the dermis and the surrounding subcutaneous tissue may develop, resulting in angioedema, which usually occurs on the face. Because it can involve tongue and larynx, it is potentially life-threatening and necessitates prompt treatment. The diagnostic workup of patients with these changes is extensive, and involves exclusion of numerous diseases before establishing the diagnosis of CIU. The mainstay of treatment of patients with chronic urticaria are antihistamines, since they are tolerable and have been used on a long-term basis, even though recurrence can be noted shortly after cessation of therapy. Cetirizine, fexofenadine, desloratadine, and other histamine-receptor antagonists may be used, while corticosteroids are indicated only for severe patients. For patients with angioedema and airway compromise, immediate administration of epinephrine is vital in preventing further complications.

Patient Information

Chronic idiopathic urticaria (CIU) implies the development of one of the most common skin rashes - hives - for a prolonged period of time without an identifiable cause. The disease is defined as the presence of red, itching, skin rash that is identical to the one occurring in food allergies - for more than 6 weeks on a daily basis, without an apparent cause. As the name implies, the cause is not known, and presumably involves activation of specific antibodies that elicit an autoimmune reaction. These skin changes develop because numerous substances, including histamine, are released into the dermis, and cause dilation of blood vessels and local inflammation. As a result, appearance of large, red, and itching hives occur. Numerous diseases may cause urticaria, and before establishing the diagnosis of CIU, all potential causes have to be excluded. Patients with CIU report daily eruptions of hives that last for a few hours, and then subside. In some case, the face may appear puffy, because the same processes occur in the subcutaneous tissues of the tongue, lips, and eyelids, and in rare cases, the airways may be partially obstructed. When this occurs, symptoms such as voice changes and breathing difficulties may be observed. To diagnose CIU, many diseases need to be excluded, including autoimmune (Systemic Lupus Erythematosus, Sjogren's Syndrome, Dermatomyositis, etc.), endocrine (thyroid disease), infectious (viral and parasitic infections), and malignant, while drug exposure, as well as history of recent travel may provide valuable data in establishing the cause of rash. Treatment involves administration of antihistamine drugs, while alleviation of rash through cold baths, avoidance of tight clothes, and other strategies is recommended. This disorder carries a good prognosis, but may be debilitating in many patients, as it often recurs. In severe forms, angioedema (very rapid swelling of the skin) may necessitate rapid treatment to prevent further complications.

References

Article

  1. O'Donnell BF, Lawlor F, Simpson J, et al The impact of chronic urticaria on quality of life. Brit J Dermatol 1997; 136:553-556.
  2. Wolff K, Johnson RA. Fitzpatrick's Color Atlas & Synopsis of Clinical Dermatology. 7th Edition. McGraw-Hill Education. 2013;
  3. Zazzali JL, Broder MS, Chang E, et al. Cost, utilization, and patterns of medication use associated with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2012;108(2):98-102.
  4. Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy. 2011;66(3):317-330.
  5. Bossi F, Frossi B, Radillo O, et al. Mast cells are critically involved in serum-mediated vascular leakage in chronic urticaria beyond high-affinity IgE receptor stimulation. Allergy. 2011;66(12):1538-1545.
  6. Sabroe RA, Seed PT, Francis DM, et al Chronic idiopathic urticaria: comparison of clinical features of patients with and without anti-FcεR1 or anti-IgE autoantibodies. J Am Acad Dermatol 1999;40:443-450.
  7. Fiebiger E, Maurer D, Holub H, et al Serum IgG autoantibodies directed against the α chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients. J Clin Invest 1995;96:2606-2612.
  8. Mitchell JH, Curran CA. Some psychosomatic aspects of allergic diseases. Psychosom Med. 1947;9(3):184-91.
  9. Uguz F, Engin B, Yilmaz E. Axis I and Axis II diagnoses in patients with chronic idiopathic urticaria. J Psychosom Res. 2008;64(2):225-9.
  10. Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy. 2009;39(6):777-87.
  11. Maurer M, Ortonne JP, Zuberbier T. Chronic urticaria: a patient survey on quality-of-life, treatment usage and doctor-patient relation. Allergy. 2009;64(4):581-8.
  12. Mathelier-Fusade P. Drug-induced urticarias. Clin Rev Allergy Immunol. 2006;30(1):19-23.
  13. Porter RS, Kaplan JL. Merck Manual. 19th Edition. Whitehouse Station, N.J.:Merck Sharp & Dohme Corp. 2011;
  14. Kanazawa K, Yaoita H, Tsuda F, Okamoto H. Hepatitis C virus infection in patients with urticaria. J Am Acad Dermatol. 1996 Aug; 35(2 Pt 1):195-8.
  15. Belsito DV. Second-generation antihistamines for the treatment of chronic idiopathic urticaria. J Drugs Dermatol. 2010;9(5):503-12.

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Last updated: 2019-07-11 20:20