Dr. Gord Sussman discussed chronic urticaria. Dr. Jacques Hebert also discussed classification of urticaria. The 4th international consensus meeting on urticaria was in Berlin in 2012.Chronic urticaria is still defined as at least 2 episodes per week lasting longer than 6 weeks. Acute urticaria is self limited.
Chronic Spontaneous Urticaria (CSU)
If it is not an inducible urticaria, suggestion is to call it chronic spontaneous urticaria (rather than idiopathic). Remember the new term Chronic Spontaneous Urticaria (CSU) rather than “Idiopathic urticaria”, which is still used by many.
The new classification for urticaria includes:
- spontaneous urticaria (acute/chronic)
- inducible urticaria (physical, others)
Chronic urticaria affects 1.3% of the population. It is spontaneous in 20% vs inducible in 80% of patients. Approximately 50% of chronic urticaria lasts more than 6 months, 20% will have symptoms more than 10 years.
In chronic urticaria, 100% lasts more 6 weeks, 50% more 6 months, 20% more than 10 years. There is no test to confirm or predict course.
Chronic idiopathic urticaria is now becoming known as "chronic spontaneous urticaria" and is felt to be an autoimmune disease. Autoimmunity is felt to be the predominant mechanism behind chronic spontaneous urticaria (CSU).
If urticaria are described as burning, you should be thinking it's not traditional chronic spontaneous urticaria.
Inducible urticaria includes symptomatic dermographism, and a variety of other physical triggers such as pressure, cholinergic, cold-induced, solar, aquagenic and others.
Anti-FceR1 autoantibodies in chronic autoimmune urticaria: IgG against FceRI (receptor for IgE) (click to enlarge the image).
Testing devices for inducible urticaria
Diagnostic tools for inducible urticaria include tongue depressor stroke (dermatographism), ice cube test (cold urticaria), solar challenge, and many others, depending on the cause.
More sophisticated (and more expensive) testing tools are available in Europe, such standardized pressure and temperature testing tools. There are now standardized devices from Germany to test for many physical urticarias, including heat/cold, and different wavelengths. A special device now exists for €20 to "officially" diagnose dermographism. It is a square piece of white plastic with sharp areas.
Quote: “Chronic Urticaria is Not an Allergy. Repeat after me.” Urticaria is not an allergic condition - there is less than 1% relevant allergic sensitization in chronic spontaneous urticaria, 0% in physical urticarias.
Few investigations are recommended for CSU. CSU patients do not require a million dollar work up - CBC, ESR, and antithyroid antibodies are usually enough. Not much else is helpful.
IVIG is occasionally used to treat severe refractory CSU - possible side effects include hemolytic anemia and aseptic meningitis.
Urticaria activity score (UAS7)
Urticaria activity score may be as important as spirometry for asthma. However, many allergists do not use it clinically yet. The urticaria activity score (UAS7) assesses wheal and pruritus over 7 days.
The chronic urticaria quality of life questionnaire from Italy includes 23 questions.
There also exists an Angioedema Activity Score (AAS), which was recently developed by European researchers.
For both, there are standardized and validated quality of life questionnaires - CU-Q2oL and AE-QoL. Quality of life in chronic urticaria patients is the worst of any dermatologic condition and is comparable to heart disease.
Treatment
The first line CSU treatment is a non-sedating H1 antihistamine (nsAH). The second line is nsAH at up to 4 times the licensed dose. The third line treatments gets “interesting” now - add omalizumab, cyclosporin A or LTRA.
Chronic Urticaria Treatment (click to enlarge the image).
Omalizumab
Kaplan et al, JACI 2013, investigated omalizumab for chronic spontaneous urticaria (CSU). Omalizumab was used in CSU patients on H1/H2 AH with or without LTRA, 60% had a prior use of OCS. Using a dose of 300 mg of Xolair showed effect within 2 weeks of starting. However, there was a gradual relapse over time after stopping infusions. The dose of 300 mg of Xolair q 4 wk resulted in significant improvements in UAS7 scores, similar to previous shorter course studies.
The addition of omalizumab for refractory CSU has been shown to be very effective add-on to second generation antihistamines. At 2013 CSACI, 100% of the panel agreed that omalizumab should be offered to CSU patients who fail high dose antihistamines. However, the use of omalizumab for CSU is not yet FDA-approved.
There is a rapid response (within 1 week of first dose) to omalizumab in CSU. The fixed dose is not based on IgE levels. It decreases symptom scores. Saini study in JACI was the first to use Xolair for urticaria treatment and showed improvement with a single dose: especially at 300 mg. A single dose of 300 mg of omalizumab was very effective for 28 days. However, most patients gradually returned to baseline symptoms by day 60 after the single dose therapy.
The MYSTIQUE trial of Xolair for CSU showed that a 300 mg single dose reduced UAS significantly for one month. However, again, by day 60 all patients were back to baseline.
A 3 dose omalizumab study confirmed continued benefit while on therapy. However, again patients relapsed after completing therapy. Maurer et al. NEJM study showed that 300 mg of Xolair q 4 wks resulted in sustained benefit while on treatment. However, many relapsed once therapy was stopped.
A small group of 34 patients in Dr. Sussman's clinic with refractory CSU was treated with Xolair, 80% had a remission (44% after the first injection), 4/34 became refractory. Overall, 44% of patients remit after 1st injection.
Unfortunately, as of 2013, Xolair for urticaria is an out of pocket treatment. No insurance pays for it.
The mechanism of omalizumab response is unclear, but there is a consistently rapid response in many to the 150 mg dose (increase to 300 mg if not helpful). As all patients are paying out of pocket, it is reasonable to start with 150 mg, and go up to 300 mg if they don't respond.
H2-blockers
H2-antihistamines are not terribly helpful. They are not considered 1st, 2nd or 3rd line therapy now because of low level of evidence. The use of H2 receptor antihistamines is suggested as an optional add-on, given the safety and anecdotal benefit. There is a clear distinction between suggestions and recommendations. Recommendations have solid EBM behind them, suggestions don't.
Cyclosporin A is clearly effective, but has some degree of toxicity, hence the the third line therapy designation.
How to use steroids in chronic urticaria
For CSU exacerbations, prescribe systemic steroids for a maximum of 10 days (EAACI/GALEN/AAAAI/WAO 2012 guidelines). Corticosteroids should be reserved as an intervention, not a chronic treatment. Prescribe short courses, not long term chronic use.
First generation antihistamines
Dr. Estelle Simons discussed antihistamines for urticaria in the 21st century.
H1 antihistamines are inverse agonists - not receptor blockers. H1 antihistamines were first developed in 1940s and these older drugs remain very widespread in use despite significant side effects. First generation antihistamines are still in widespread use worldwide for urticaria mainly through primary care recommendation. Dr. Simons is frustrated by the continued reliance on old first generation antihistamines, especially in primary care.
First generation antihistamines' side effects are summarized as: "reduced ability to 'multi-task'. First generation anti-H1 blockers occupy more than 50% of CNS H1-receptors, correlate with impaired cognition and memory with or without sedation (impairment without sedation). First generation antihistamines have clearly been shown to cause cognitive impairment, impair memory formation, alertness, learning. Use of 1st-generation antihistamines is associated with injuries and traffic fatalities, OD, homicide, suicide. First-gen product use is regulated in many countries for pilots, etc. but not consistently worldwide. In Edinburgh & Glasgow they routinely do blood tests after fatal accidents looking for drug impairment and find 1st generation AH.
Harms of 1st generation antihistamines in elderly also include risk of sedation, cognitive impairment, confusion, falls, increased IOP, urinary retention and constipation.
No data supports use of diphenhydramine (Benadryl) in children - the 2nd generation agents have actually been studied to show safety.
All 2nd generation agents have undergone strict randomized controlled trials for safety and efficacy unlike grandfathered 1st generation agents. Effects of levocetirizine on suppression of wheal and flare response persists long after plasma levels of drug become undetectable. Levocetirizine safety profile in one study of long term treatment for CSU was completely equivalent to placebo.
2nd generation antihistamines are the agents of choice for acute, chronic and inducible urticaria.
Updosing with 2nd-generation anti-H1 blocker at 2-4 times the regular dose provides greater benefits, with no apparent increase in adverse effects. Very high doses have been studied in CSU: bilastine, rupatadine, levocetirizine & desloratadine without “apparent” side effects. 2nd generation agents have not been associated with fatalities even after a 40-fold overdoses.
In one study, 25% of patients were able to achieve symptom-free state on 20 mg of levocetirizine (normal dose is 5 mg).
Differential diagnosis of urticaria
It is important to inquire if urticaria patients have systemic symptoms of fever, joint/bone pain, malaise - it could mean autoinflammatory disorder rather than urticaria. If hives/lesions last more than 24 hrs, this could indicate urticarial vasculitis rather than CSU.
Schnitzler's syndrome
Schnitzler's syndrome has been described in 100 patients and consists of chronic hives, spiking fever, arthralgia, bone pain, adenopathy, and inflammatory markers.such as leukocytosis.
There are only approximately 100 cases of Schnitzler's reported in literature, it likely under-recognized.
Most patients with Schnitzler's syndrome will also have a monoclonal gammopathy, typically IgM kappa and some will go on to develop Waldenstrom's macroglobulinemia.
Schnitzler's syndrome has other generalized symptoms but diagnosis comes from elevated IgM or IgG kappa on electrophoresis.
There are elevated IL-1 levels in Schnitzler's, and patients respond quickly and substantially to IL-1 receptor antagonists.
Acquired cold urticaria vs familial cold autoinflammatory syndrome (FCAS)
Familial cold urticaria now is renamed familial cold autoinflammatory syndrome (FCAS) after the genetics have been identified - CIASI/NLRP3.
FCAS is an autosomal dominant condition, with onset in childhood and is lifelong. This is in contrast to acquired cold urticaria which is of adult onset, and often has remissions.
FCAS is generally life-long, and has a delayed onset after exposure. The symptoms may last days, there is a negative ice cube challenge, and elevated inflammatory markers.
Autoinflammatory disease is interestingly not associated with autoantibodies.
Treatment for FCAS is Canakinumab, a new monoclonal antibody therapy, also known as Elaris. Canakinumab (anti-IL-1 beta) can result in rapid improvement in such chronic autoinflammatory diseases.
Twitter summary made possible by @IgECPD @allergydoc4kidz @DrAnneEllis
Three allergists did a great job posting updates from the 2013 meeting of the Canadian Society of Allergy and Clinical Immunology (#CSACI): @IgECPD @allergydoc4kidz @DrAnneEllis. Compared to year 2011, this represents 300% growth in Twitter use by the Canadian allergists (from one to three participants, stable since 2012.
For comparison, here are the tweets from the previous #CSACI meetings: http://allergynotes.blogspot.com/search/label/CSACI
Sign up for 2014 #AAAAI Twitter list and meeting of tweeting allergists in real life (tweetup)
The AAAAI has the advantage of a larger membership base compared to #CSACI and not surprisingly ten times more allergists (30) posted Twitter updates from the 2012 #AAAAI meeting. The AAAAI is now on Twitter at @AAAAI_org
This is a list of the allergists who are planning to use Twitter to post updates from the 2014 #AAAAI meeting. The list is open for edit, please feel free to add your own info.
The list shows the availability of the allergists by date and if they are planning to attend a tweetup (meeting of people who use Twitter or are following the tweets). See you at 2014 #AAAAI meeting in sunny San Diego!
Comments from Twitter:
Dr John Weiner @AllergyNet: Have you had hives for over 6 weeks? This summary is great
David Fischer, MD @IgECPD: Thanks Ves for summarizing our tweets