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Pathophysiology of Chronic Urticaria

Categories of Ocular Inflammation, Etiology and Mast Cell Involvement

Urticaria is triggered by activation and degranulation of mast cells. This results in the release of various vasoactive substances that act on the small venules. Among the mediators secreted is histamine.

“Although other substances are also released, histamine swamps the system,” said Allen Kaplan, MD, Professor of Medicine at the Medical University of South Carolina in Charleston. “In physically-induced urticaria, the hive seen is due to the histamine released, and it resolves in a short period of time, typically 1-2 hours. In contrast, chronic urticaria (CU) has hives with different shapes and sizes, can occur on a daily basis, is erythematous, elevated, pruritic and lasts between four hours and two days.”

There are also differences on biopsy. A person with dermatographism primarily presents with dilated vessels, collagen bundles separated by edema and little else. With CU there is a cellular infiltrate with CD4+ lymphocytes, which are a mixture of TH1 and TH2 subtypes. There are also neutrophils, eosinophils, monocytes and basophils. The integrity of the vessel is preserved and there is usually no immunoglobulin or complement deposition.

When urticaria is related to allergy, there is IgE-dependent mast cell degranulation, the allergen crosslinks with the IgE molecules activating the cells, and releasing inflammatory products. With CU, while there is a stimulus causing mast cell degranulation, there is no identifiable allergen in over 95% of patients.

“When I was in medical school, many suggested that CU was a psychogenic disease,” said Dr. Kaplan. “The next theory to gain attention was that ingesting occult substances such as food additives caused the symptoms. However, an autoimmune association with thyroiditis and antireceptor antibodies as a pathogenic mechanism, have stood the test of time for about a decade.”

One of the first clues that CU might be autoimmune was an association with antithyroid antibodies. A study by Finn and Kaplan found that 27% of their
patients had antithyroglobulin and/or antimicrosomal antibodies (Kaplan, et al. Can J Aller Clin Immunol. 1999;4: 286).

Another study by the group took nearly 300 patients and divided them into groups who had antithyroglobulin, antimicrosomal or both antibodies. This was roughly 25% of the entire group. When they looked at those with the anti-IgE receptor antibody, there was a 27.7% incidence of anti-thyroid antibodies compared to only 10.9% in those who did not (Kikuchi, et al. J Allergy Clin Immunol. 2003;112:218). (Table 1)

“When you screen a general population with no urticaria, the incidence of antithyroid antibodies is around 8%,” said Dr. Kaplan. “When you have antithryroid antibodies, you are more likely to have an individual with chronic autoimmune urticaria (CAU). But don’t forget that remains only 40% of the total and the remaining 60% are still called chronic iodiopathic urticaria.”

Other studies have shown that, in most individuals, release of histamine from basophils and mast cells is augmented by complement. Even though the pathogenic antibody crosslinks IgE receptors to activate the cells, there is a boost when complement is present.

Researchers compared responsiveness of basophils from three donors. Two had histamine release of 20% to 100% when incubated with chronic urticaria sera. Donor number three was of interest to the group, as the sample did not respond to anti-IgE and was a so-called “non-releaser”. In this case, the basophils do not “fire” through the IgE receptor, were unresponsive to chronic urticaria sera, but were responsive to other stimuli.

“If you use a different stimuli to cause basophil release, like the cytokine MCP1, there was a response,” said Dr. Kaplan. “This person’s basophils will respond to a cytokine through a G protein, but not through the IgE receptor. This is an indirect demonstration that sera from chronic urticaria patients activated basophils through the IgE receptor. The same is true for cutaneous mast cells.”

Other studies employ the alpha chain of the IgE receptor, a single chain passing through the plasma membrane with the N-terminus on the outside and C-terminus inside. The pathogenic antibody reacts with the extra-cellular domain making it essentially an anti-alpha antibody.

Kaplan and his group looked at four subjects whose sera caused varying amounts of histamine release. Basophils were incubated with an IgE myeloma protein to saturate all of the receptors. They noticed that suddenly the pathogenic antibody became nonfunctional. IgG anti-alpha does not seem to bind when all of the IgE receptors are occupied by IgE.

Therefore, Dr. Kaplan feels it is theoretically possible that saturating the receptors with IgE could stop urticaria even with the pathogenic antibody present. “One of the parameters that modulates urticaria is the number and saturation percentage of the IgE receptors,” he stated.

They next purified IgG from the serum and determined that it caused histamine release. They postulated that IgG would crosslink unoccupied IgG
receptors and it did. However, histamine release when serum was added to the basophils was different from that found when purified IgG was used.

“There is something in the serum that augmented the reaction,” said Dr. Kaplan. “We took IgG, serially diluted it and checked the different dilutions for histamine release. As the IgG concentration became higher, histamine release was increased. Adding normal serum increased histamine release at every
IgG concentration.”

There was, however, great variability. If the IgG was what Dr. Kaplan called “a great histamine releaser”, then the augmentation by serum was borderline. Thus, he noted, the relative contribution of the IgG and complement depends on the potency of the particular pathogenic antibody.

The next phase of the work demonstrated that the augmentation by complement was due to C5a expression. They first measured C5a stimulation of the basophils and noted a plateau of 50 nanograms per ml. They introduced antibody to the C5 receptor prior to serum stimulation and tried different
dilutions until they significantly depressed histamine release. In almost every instance, histamine release was inhibited if the donor basophils were preincubated with an optimal amount of anti-C5a receptor antibody. The average percent inhibition of histamine release was about 30%.

To confirm that the reaction was C5 dependent as well as requiring C5a, the group added a pathogenic IgG to serum that was depleted of C5. They found that they lost augmentation in the depleted serum. When C5 was replaced, augmentation returned.

“The bottom line is that the pathogenic antibody seen in 35%-40% of patients is an anti-IgE receptor and an additional 5% to 10% have an anti-IgE antibody,” said Dr. Kaplan.

One of the problems remaining is the lack of a simple test to identify these patients because some sera have antibodies that bind to the alpha chain, but are not functional. A possible method of addressing this issue is to purify IgG subclasses and identify which ones are important. They have so far been able to eliminate IgG2 and found that IgG1 and IgG3 are involved in the majority of patients with urticaria. They have not yet been able to come to any conclusions on the importance of IgG4.

Using subclass-specific antibody, the group attempted to make an Enzyme-Linked Immunosorbent Assay test (ELISA) to look at each subgroup against the alpha subunit. The correlation of histamine release with binding for IgG1 exceeded .9 and for IgG3 was .7. The other two were in the .4 range. However, they all cross-reacted, meaning that the results are an approximation at best.

“While we have moved along in our understanding of the processes, to devise an assay and to improve treatment, we still have a long way to go,” said Dr. Kaplan.

Evidence-Based Therapies in Chronic Idiopathic Urticaria

Treatment of chronic idiopathic urticaria (CIU) falls into four categories, according to Eugene Monroe, MD, Department of Dermatology at Ad-vanced Healthcare in Milwaukee, WI. The first blocks the effects of previously released histamine on receptor sites in cutaneous blood vessels. The second blocksrelease of histamine and other mediators from the mast cell. A third treatment option blocks mediators other than histamine that might be involved in the process. Finally, it may be possible to modulate the inflammatory, cellular and immunologic components of urticaria.

“There are three choices available to block the effects of already-released histamine,” said Dr. Monroe. “They include the H-1 antihistamines, tricyclic antidepressants (TCA) and a combination of H1 and H2 antihistamines.”

The first generation of H1 medications have been in use for years and are generally thought to be moderately effective in controlling urticaria. These include hydroxyzine (considered the gold standard comparator), diphenhydramine, and chlorpheniramine.

“There are very few placebo-controlled studies using the first-generation medications, yet they have been ingrained in our minds as the first line of treatment,” noted Dr. Monroe.

Although efficacious, use of these medications is limited by side effects. Of special concern to patients are central nervous system (CNS) effects such as
sedation and anticholinergic effectsincluding dry mouth.

More recently, a second generation of H1 antihistamines has been released. Among those currently available in the United States are loratadine, cetirizine, fexofenadine and desloratadine.

“Clinical studies of CIU show these medications to be statistically superior to placebo and clinically comparable to the strongest first generation antihistamines,” said Dr. Monroe.

A study by Dr. Monroe and others compared loratadine, hydroxyzine, and placebo. After one week, the pruritus scores improved around 50% in the two active groups and at the end of four weeks there was improvement of more than 60% (Monroe E, et al. Arzneimittel Forschung. 1992; 42:1119). Other studies have shown similar results comparing cetirizine and fexofenadine’s precursor (terfenadine) with hydroxyzine. (Figure 1)

CIU can have an impact on quality of life (QOL) issues. These are generally focused on interference with daily activities, physical appearance, sleeping, and work productivity.

A study by Nelson and others comparing fexofenadine with placebo found highly significant QOL improvements, especially in sleep and daily activities (Nelson H, et al. Ann Allergy Asthma Immunol. 2000;84:517). The studies with desloratadine show similar findings (Monroe E, et al. J Am Acad Dermatol. 2003;48:535).

“The other point to emphasize about second generation agents is that studies comparing these agents with each other are few in number,” said Dr. Monroe. “Those that are available show no statistically significant differences in efficacy.”

The second-generation drugs are a more heterogeneous group when looking at side effects. Loratadine, desloratadine, and fexofenadine are all non-sedating at recommended doses and are labeled as such. Cetirizine shows double the incidence of sedation versus placebo in studies submitted to the Food and Drug Administration (FDA).

“Despite anecdotal reports, no published controlled studies show higher doses are more effective than the approved doses in urticaria,” stressed Dr. Monroe. “Indeed the dose-ranging studies for both fexofenadine and loratadine saw no added benefits at higher doses than those approved for labeling. At least based on the controlled studies, recommended doses are the best.”

What are the options if H1 antihistamines do not control urticaria? Dr. Monroe suggests adding other agents to the routine. Since the approval studies all saw maximum effect by the second week, if he does not see a response to one agent by the third week, he suggests going to another.

“At baseline I would add another second-generation H1,” he said. “While studies show these medications are equal in efficacy, we all know from personal experience that there are some patients who do not respond to agent A yet do to agent B.”

Another option is adding a low-dose first generation H1 antihistamine at night. While this does not totally eliminate sedation, it may reduce it. The next step in Dr. Monroe’s practice would be to add either a TCA or H2-antihistamine.

There is clear evidence that cutaneous blood vessels possess H2 receptors involved in the mediation of vasodilation and vascular permeability. Theoretically, if all of the H1 and H2 receptors are blocked, there should be a better outcome.

“There are clinical studies utilizing a combination of H1 and H2 antihistamines using either cimetidine or ranitidine in patients with CIU,” said Dr. Monroe. “Approximately two-thirds of the studies show statistically superior results for the combination. My personal bias is that there is a subset of patients who respond to the combination and it is a safe therapy to try.”

The literature behind the use of TCAs, such as doxepine, show they are clearly superior to diphenhydramine. However, these are also sedating medications with anticholinergic properties.

“Make sure you tell your patients that you are giving the TCAs because of their antihistaminic, not antidepressant properties,” he said. “It is embarrassing when the patient calls and says they have talked to the pharmacist and why didn’t I tell them they were depressed?”

Recently, there have been three well-controlled studies looking at leukotriene receptor agonists (LRA) in treating CIU. Pakor and others showed that a combination of LRA and antihistamine was superior to the antihistamine alone. A study by Erbagci found the same thing with montelukast. However, Reimers, et al., showed no added benefit. (Pacor, et al. Clin Exp Allergy. 2001;31:1607. Reimers, et al, Clin Exp Allergy. 2002; 32:1763. Erbagci. JACI. 2002;116:484). Again, Dr. Monroe thinks this is useful in a small subset of patients.

“I strongly believe that there are some indications for using systemic corticosteroids,” he said. “But they have absolutely no place in extended therapy because I don’t want to introduce greater problems from the therapy than the underlying condition. They can be used short-term to break the cycle in refractory patients.”

“Treatment starts with a detailed history, physical and limited diagnostic tests that are followed with patient education and pharmacotherapy,” said Dr. Monroe.

Immunomodulatory Therapies in Chronic Urticaria

Despite correct and aggressive treatment with antihistamines and other medications, large subsets of patients remain with debilitating outbreaks of hives and itching. For this group, immunomodulatory therapies (IMT) may be a viable alternative.

“There are two major reasons why we consider IMT in these patients,” said Malcolm Greaves, MD, Senior Consultant Specialist in Dermatology at Singapore General Hospital and emeritus Professor of Dermatology at the University of London, St. Thomas Hospital. “The first is that there is a group of these patients with immunological problems underlying their disease. The other is that it may help lessen the severe quality of life impairment seen in CAU.”

Dr. Greaves and others used the Nottingham Health Profile, a QOL instrument applicable to any chronic disease, to study a group with urticaria and another with triple coronary artery disease (CAD) awaiting angioplasty.

The results showed that impairments in social and emotional activity, sleep disturbances, sexual activity disruptions and other indicators were basically equal in both groups (O’Donnell, et al. Br J Dermatol.1997;136:553).

A major problem in treating urticaria with IMT is patient identification. As was noted earlier immunoassays, immunoblotting, and western blotting all lack sufficient specificity. Most of the research has only looked at non-specific immunomodulation making it impossible to tease out those antireceptor antibodies causing the problems. Finally, IMTs only suppress the disease and do not cure it.

“Patient selection is very important since you can’t scatter aroundimmunomodulatory treatments like confetti without getting into trouble,” noted Prof. Greaves. “Most of mypatients have autoimmune urticaria demonstrated by autologous skin test and possibly by in vitro tests. They’ll also have severely impaired QOL.”

Prof. Greaves suggests adding cyclosporine to the existing antihistamine regimen if IMT is deemed appropriate. His normal dose is 3.5 to 4 mg/kg per day. If the cyclosporine is ineffective or not well tolerated, then he would substitute methotrexate.

“Cyclosporine is an immunosuppressant, but I don’t think it works that way in CAU,” he noted. “Studies show that it has a suppressive effect on
basophil and mast cell activation. I think that has a lot to do with the very rapid response seen in urticaria. Cyclosporine also works in non-autoimmune CU, although less well.”

Grattan and others looked at patients with severe, unremitting urticaria who had a positive autologous skin test. After three months of cyclosporine therapy, 80% had totally or almost totally cleared their symptoms. There was a rapid improvement in whealing and itching that corresponded to a parallel fall in autoantibody levels and skin testreactivity (Grattan, et al. Br J Dermatol. 2000;143:368).

“When the medication was withdrawn at three months, one-third remained clear, probably having spontaneous remission,” said Prof. Greaves. “One-third relapsed mildly but still could be controlled with antihistamines. The final third relapsed back to square one.”

As of yet, there are no controlled trials studying use of methotrexate. The medication works by down-regulating activated T-cells and by inhibiting DNA synthesis through inhibition of folate reductase. Prof. Greaves suggests a dose of 7.5 to 20 mg once weekly.

“There are a small number of patients with bad idiosyncratic reactions to methotrexate,” he stressed. “I use a test dose of 5 mg and do white blood cell counts and liver function tests a few days later. If everything is okay, then I put them on the suggested dose.”

In both cases, there are side effects that could be of concern. Physicians should acquaint themselves with these before using either cyclosporine or methotrexate.

Another treatment for consideration in refractory cases is intravenous immunoglobulin (IVIG). A study by O’Donnell and Greaves looked at ten
patients with recalcitrant and autoimmune urticaria. Nine improved, five completely and two of these were still clear for at least three years (O’Donnel, et al. Brit J Dermatol.1998;138:101).

Again, this is not a cure and the disease tends to come back. He has used repeated courses in the same patient and some have returned and demanded IVIG when their urticaria relapsed.

“Of the therapies we’ve discussed, only cyclosporine has been subjected to a controlled clinical trial and is evidence-based,” he said. “While the others are not evidence-based, personal experience and anecdotal evidence supports their use in highly selected patients with chronic urticaria.”

 

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