Urticaria is a common condition with lifetime
incidence of approximately 15%.
Affected females > males.
Peak age of onset in adults - between 20 and 40 years.
‘Acute’ if it lasts < 6 weeks and ‘Chronic’ if it lasts > 6
Chronic urticaria - 1% of acute cases.
50% of them, no specific cause could be identifiedchronic idiopathic urticaria.
CU causes severe impairment of quality of life
The degree of personal, social and occupational
disability matches that of patients with triple
coronary heart disease awaiting bypass surgery.
(O`Donnell B et al, the impact of chronic urticaria on quality of life. Br J
Dermatol. 1997; 136: 553-6)
Adequate treatment should enable patient to lead
an essentially normal life.
Reassurance : Patients are often frustrated and fearful.
rarely permanent, and that almost 50 percent of patients undergo
remission within one year.
Rarely puts the patient at any acute risk.
symptoms can be successfully managed in the majority of
Avoidance of exacerbating factors : physical factors, Anti
inflammatory medications and alcohol.
Dietary manipulations : Pseudoallergens include
artificial preservatives and dyes in processed foods
naturally-occurring aromatic compounds in certain foods (many
fruits and vegetables, seafood, others).
The recognised benchmark routine treatment of
chronic urticaria: the European guidelines
(Zuberbieret al, EAACI/GA2LEN/EDF guideline: management of urticaria.
Allergy 2006; 61: 321-331)
The recommended first line standard treatment is non
–sedating H1 antihistamines and if necessary
increasing dosage up to fourfold (off -label dosage).
The guidelines “strongly recommend not to use old
However “first generation” H1 antihistamines do have a
role particularly in patients with sleep disturbance due
How can “difficult”patients get the most out of
H1 antihistamine treatment ?
Regular dosage avoids “pseudotachyphylaxis”
Using Off -label dosages of 2nd generation antihistamines
efficacy : supported by mounting experimental evidence
safety : generally assumed safe even in 3-4x licensed dosages on the
basis of derivative evidence.
Also off -label dosages of 1st generation antihistamines have
been used for years without safety problems.
Another approach is to administer first generation
antihistamines as a single dose in the evening, in
combination with a second generation antihistamine given
in the morning
Do H2 antihistamines have a role in H1
antihistamine -resistant urticaria?
Rationale – skin and blood vessels express both H1 and H2 receptors;
cimetidine(but not ranitidine) and all first generation H1
antihistamines + mizolastine and loratidine are metabolised via
RDBCT have shown a significant benefit of combining H1 and H2
(Bleehenet al. Cimetidine and chlorpheniramne in the treatment of chronic
idiopathic urticaria: a multicentre randomised double blind study. BJD
1987; 117: 81-88)
However this statistical difference may not be clinically significant.
(Sharpe and Shuster. In dermographic urticaria H2 receptor antagonists
have a small but therapeutically irrelevant effect compared with H1
antagonists alone. BJD 2006; 129: 575-9)
In practice H2 antihistamines are useful in patients with chronic
urticaria suffering gastro-oesophageal reflux, and those with dyspepsia
complicating systemic corticosteroid treatment.
Second line therapies
Narrow band UVB.
Doxepin is a tricyclic antidepressant- useful in the treatment of
antihistamine resistant urticaria.
Dose range is 25-75mg daily.
High affinity for H1 receptor (8x greater than diphenhydramine).
Significant H2 blocking activity
1.Never withdraw abruptly, carries significant drug interactions.
2.Do not administer concurrently with other anti-depressants
3.Do not administer to patients with significant heart and liver disease
4.Possesses significant anti-muscarinic activity
Role for systemic corticosteroids
No controlled trials of systemic steroids in chronic urticaria.
In European guidelines, systemic steroids are not recommended
for maintenance, but can be used as short tapering courses to
deal with relapses.
(Zuberbieret al, EAACI/GA2LEN/EDF guideline: management of
urticaria. Allergy 2006; 61: 321-331)
In USA 10mg / day or 20mg alternate days systemic
corticosteroid treatment is regularly used on a long term basis
and minimal adverse consequences are claimed.
J Investig Allergol Clin Immunol. 2010;20(5):386-90.
Usefulness of a short course of oral prednisone in antihistamine-resistant
chronic urticaria: a retrospective analysis.
Asero R, Tedeschi A. Source Ambulatorio di Allergologia, Clinica San Carlo, Paderno Dugnano,
To assess the proportion of patients with antihistamine-resistant CU that respond to a course of
We studied 750 adult patients with CU and prescribed a course of oral corticosteroids (starting with
prednisone 25 mg/day for 3 days) to those who reported little or partial response to antihistamine
treatment. The corticosteroid treatment was considered effective if it resulted in long-term control of
the disease with antihistamines only. Patients showing a temporary response were offered a second
course of prednisone, at the end of which temporary responders and nonresponders were offered
ciclosporin therapy for 3 months.
A total of 660 patients (male/female, 194/556) (88%) responded to antihistamine treatment. In 40/86
patients (47%), prednisone induced remission of the disease and subsequent control with
antihistamines at licensed doses only. Thirty-five patients responded well but relapsed when
prednisone doses were tapered or shortly after withdrawal. In all responders, the effect was
appreciable as early as the day after the first 25 mg dose. In 8/23 temporary responders, a second
course of prednisone induced remission of the disease; the other 15 patients responded well but only
A single short course of prednisone induced remission in nearly 50% of patients with CU, and a
second course induced remission in a further 9%. Less than 15% of patients did not respond at all to
Evidence suggests that leukotrienes antagonists are
effective, especially in aspirin sensitive urticaria and
Montelukast- 10mg at night.
No significant drug interactions.
Adverse effects- flu like symptoms, dry mouth, gi
disturbances may occur but unpredictable.
Can be indicated as steroid sparing drug and delayed
Starting dose – 75mg/day. Can be increased upto 150
Starting dose- 1 gm BD. Increasing by 500 mg daily at
intervals of 2 weeks to a maximum regular dose of 4
J Eur Acad Dermatol Venereol 2008 Apr;22(4):481-6. Epub 2007 Dec 13.
Prospective randomized non-blinded clinical trial on the use of dapsone plus
antihistamine vs. antihistamine in patients with chronic idiopathic urticaria.
Engin B, Ozdemir M. Source- Dermatology Department, Meram Medical Faculty, Selcuk University,
Konya, Turkey. email@example.com
The purpose of this study was to evaluate the efficacy and safety of dapsone in CIU.
The response to dapsone was evaluated in 65 CIU patients with a randomized, two armed study: 3month dapsone + desloratadin and 3-month desloratadin. All were followed for up to 3 months and 3
months after; all took desloratadine 10 mg daily throughout the study. The primary measure of
efficacy was a daily urticaria activity score (UAS) of weal numbers and itch (maximum score, 42 per
Mean reduction in UAS from baseline at 3 months was 7 [95% confidence interval (95% CI), 6.927.08] for active group and 5.77 (95% CI, 5.47-6.08) for control subjects (P < 0.001). The reduction in
visual analogue score (VAS) at 3 months for active group (mean, 2.58; 95% CI, 2.33-2.83) and control
subjects (mean, 2.55; 95% CI, 2.38-2.73) was also significant (P < 0.001). The reduction of UAS and
VAS at 3 months compared between active group and control subjects showed no significant
difference. Mean reduction in UAS from the end of the study at 3 months after was 1.16 and -4.8 for
active and control subjects, respectively. These results were compared with each other, and it was
statistically significant (P <or= 0.05).
No placebo was used. The study was not blinded. Lack of blinding may have led to bias. The follow-up
period was short.
This study shows that dapsone leads to a persistent decrease in VAS and UAS and is associated with
complete remission in some patients.
Acta Derm Venereol 2008; 88: 247–251, December 5, 2007.
Treatment of Chronic Urticaria with Narrowband Ultraviolet B
Phototherapy: a Randomized Controlled Trial
Burhan Engin, Mustafa Özdemir, Ali Balevi and İnci Mevlitoğlu Department of
Dermatology, Meram Medical Faculty, Selcuk University, Konya, Turkey
AIM - open, controlled study to determine whether NB-UVB is effective in
treating urticaria in combination with antihistaminics.
Method- A total of 81 patients with chronic urticaria were recruited, 48 of
whom were randomized into the NB-UVB plus antihistamine group. The
control group (n = 33) received only antihistamine. Patients were assessed
using the urticaria activity score and a visual analogue score (VAS). The 2
groups were evaluated at the same time-points: at treatment sessions 10 and 20
and at follow-up 3 months post-treatment.
Results -The reduction in urticaria activity score and VAS was statistically
significant (p < 0.05 for both groups). When comparing the groups, the mean
urticaria activity score was significantly lower in the NB-UVB group at session
10 (22.6 vs. 27.3) and session 20 (17.4 vs. 20.7). Statistically significant
differences were also noted in VAS between the 2 groups (p < 0.01) at 3 months
Conclusion - We conclude that NB-UVB may be an effective complementary
treatment for patients with chronic urticaria
Treatments that don`t work
Trying yet another antihistamine : No evidence in “playing
roulette” with antihistamines (“you havnt tried this
antihistamine have you ?”)
Anti –Helicobacter pylori treatment : Many people with or
without chronic urticaria have H pylori infection. There is no
evidence that this infection has anything to do with the
pathogenesis of urticaria and this notion will, if we wait long
enough, be dropped.
Thyroxine replacement : It has been claimed that euthyroid
chronic urticaria patients with thyroid autoantibodies respond
to thyroxine supplements. Again, this claim is unsubstantiated.
Special diets : These are strongly advocated by some European
groups, but dietary causation can only be substantiated by
placebo controlled oral challenge.
What to do if all these measures fail :
THIRD LINE TREATMENT (IMMUNOTHERAPIES)
Cyclosporin for severe refractory chronic urticaria
3 RCTs have attested to the safety and efficacy of cyclosporin in
selected patients with chronic ordinary urticaria.
(Grattan et al, BJD 2000; 143: 365-72; Vena et al, JAAD 2006; 5: 705-09;
Inalozet al, J Dermatol. 2008; 35: 276-82)
daily or almost daily extensive urticaria/ angioedema with severe
QOL impairment, resistant to antihistamines.
Patients previously on long –term systemic steroids
Works in autoimmune or non –autoimmune cases.
Dose range : 3-6mg/kg/day, usually given for 2-3 months
Outcome : about 80% experience remission ( total or almost
total cessation of urticaria)
Relapse rate : about 1/3 -remain in remission; 1/3 –minor
relapse; 1/3 more severe relapse
Cautions : hypertension, renal impairment.
Ann Allergy Asthma Immunol, 2011 Dec;107(6):523-8. doi: 10.1016/j.anai.2011.08.013.
Factors that predict the success of cyclosporine treatment for chronic
Hollander SM, Joo SS, Wedner HJ. Source-Washington University School of Medicine, St. Louis,
Missouri, USA. firstname.lastname@example.org
To describe our low-dose cyclosporine-treated CU population and factors predicting a
A retrospective chart review was conducted of adult CU patients treated with
cyclosporine. Elements of the history, physical examination, diagnostic testing, efficacy,
and side effects were extracted for statistical analysis.
Sixty-eight adults with CU who completed a course of cyclosporine were identified. 53
(78%) patients attained complete remission defined as ≤ 1 day of hives per month.
Recurrence occurred in only 7 patients; all achieved remission with resumption of
cyclosporine. A history of hives (P = .01), shorter duration of urticaria (mean: 55.2 weeks
vs 259.63 weeks; P = .03), and positive CU Index (P = .05) predicted a favorable response
to cyclosporine. Notably, autologous serum skin testing, prior response to steroids, atopic
status, or presence of antithyroid antibodies was not predictive. Male sex and a positive
ANA trended toward significance (P = .1). Side effects were generally mild and seen in
35% of patients; all were reversible by dose reduction.
Cyclosporine is an effective treatment for CU, and a history of hives, shorter duration of
There are no RCT`s of MTX in chronic urticaria.
There are several anecdotal reports describing
successful outcomes in selected cases.
(Weiner, Ann IntMed.1989;110: 848; Gachet al. BJD 2001; 145: 340-43; Perez et
al. Abs WCD 2007)
Dosage : 10-15mg per week for 3-6 months.
Despite paucity of published data MTX is used often
for severe treatment resistant urticaria, mainly in
patients unresponsive / intolerant to cyclosporin.
Right choice in Indian setting where cost is an
important factor in deciding the therapy.
Br J Dermatol 2010 Jan;162(1):191-4. doi: 10.1111/j.1365-2133.2009.09538.x. Epub 2009 Nov 6.
Methotrexate: a useful steroid-sparing agent in recalcitrant
Perez A, Woods A, Grattan CE.
St John's Institute of Dermatology, St Thomas' Hospital, London SE1 7EH, UK.
Objectives : To assess the effectiveness of methotrexate in steroid-dependent chronic urticaria, its
impact on steroid reduction and any differences in response between patients with and without
Methods : A retrospective case-note review of 16 patients with steroid-dependent chronic urticaria
treated with methotrexate was carried out. Ten patients had chronic ordinary/spontaneous urticaria
(CU), including three with associated delayed-pressure urticaria; four patients had
normocomplementaemic urticarial vasculitis (UV); and two patients had idiopathic angio-oedema
without weals. Median disease duration before methotrexate was 48.5 months (range 12-164). All were
unresponsive to antihistamines and second-line agents, except prednisolone. Eleven were assessed for
autoimmune urticaria with the basophil histamine release assay (n = 5), autologous serum skin test (n
= 5) or both (n = 1). Response to methotrexate was scored : no benefit; some benefit (fewer weals and
symptomatic improvement but no steroid reduction); considerable benefit (improvement with
steroid reduction); or clear (no symptoms, off steroids but on antihistamines).
Results : Twelve of 16 patients (eight CU, three UV, one idiopathic angio-oedema) responded. Three
showed some benefit, seven considerable benefit and two cleared. Four of eight responders and three
out of three nonresponders showed evidence of functional autoantibodies. The dose to achieve a
steroid-sparing effect was 10-15 mg weekly (cumulative dose range 15-600 mg, median 135 mg).
Methotrexate was well tolerated.
Conclusions : Methotrexate may be a useful treatment for steroid-dependent chronic urticaria.
Functional autoantibodies do not correlate with response. The beneficial effects of methotrexate may
be anti-inflammatory and immunosuppressive. It may therefore benefit chronic urticaria
independently of the pathogenic mechanism, whether autoimmune or not.
Intravenous immunoglobulin and plasmapheresis
Intravenous immunoglobulin (0.4 g/kg for 5 days) -
effective in relieving symptoms in patients with chronic
AIU and achieving ASST negativity as well as long-term (>3
Complete, permanent remission reported in patients who
attained ASST negativity within six months of therapy.
Although the exact mechanism of action is unknown,
presence of anti-idiotypic antibodies capable of
suppressing IgE autoantibodies, in the intravenous
immunoglobulin (IVIG) preparation has been suggested.
Plasmapheresis - found to be beneficial in a small series of
patients with AIU by eliminating the functional
autoantibodies from system.
Ann Allergy Asthma Immunol 2010 Mar;104(3):253-8. doi: 10.1016/j.anai.2009.12.007.
Effect of high-dose intravenous immunoglobulin treatment in therapy
resistant chronic spontaneous urticaria.
Mitzel-Kaoukhov H, Staubach P, Müller-Brenne T. Source - Department of
Dermatology, University Medical Center Mainz, Mainz, Germany.
To assess the efficacy and safety of high-dose IVIG as a treatment option in
patients with therapy-resistant CSU.
Six patients with severe CSU unresponsive to other treatment options
according to the newest guidelines for several weeks were treated with highdose IVIG (2 g/kg every 4-6 weeks). The response to treatment was observed on
the basis of clinical signs and reduction of co-medications using a special
treatment score. Patients were studied during the treatment period and were
followed up for an average of 16 months. Adverse events were assessed.
Patients showed an improvement in symptoms and a reduction in comedication use just after the first cycle. Symptoms such as itching, wheals, and
edema were reduced after the first or second cycle of IVIG treatment. Four of 6
patients had complete remission after 2 to 4 cycles. One patient needed a
longer continuation of treatment to reach a stable state of improvement, and
another patient had a slight relapse after the seventh cycle. Adverse effects,
such as headache and increased blood pressure, were observed only at the
beginning of treatment.
High-dose IVIG represents an important therapeutic option in patients with
Lancet 1992 May 2;339(8801):1078-80.
Plasmapheresis for severe, unremitting, chronic urticaria.
Grattan CE, Francis DM, Slater NG, Barlow RJ, Greaves MW.
Source- St John's Institute of Dermatology, UMDS, London, UK.
Histamine-releasing autoantibodies have been identified in
chronic idiopathic urticaria. 8 patients with severe disease and
histamine-releasing activity in their sera underwent
plasmapheresis. Symptoms were abolished for 2 months in 1
patient and for 3 weeks in another, 2 showed almost complete
resolution of symptoms, 2 had temporary relief, and the other 2
showed little change. Further investigation in 4 of the patients
showed significantly reduced skin-test responses to fresh postexchange autologous sera after plasmapheresis compared with
stored pre-exchange sera, but the response to intradermal
histamine remained unchanged. Blood cellular histamine
increased as in-vitro serum histamine-releasing activity fell after
plasmapheresis. These results favour a pathogenetic role for
histamine-releasing autoantibodies in patients with chronic
Is there anything new “round the corner”?
Omalizumab is a recombinant humanised mAb that selectively
binds to, and lowers serum IgE and as a consequence lowers the
population density of IgE receptors expressed on mast cells and
Patients with autoimmune urticaria due to autoantibodies
directed against FcεR1 or IgE itself should benefit from
treatment with Omalizumab since there would be a sufficient
FcεR1 reduction to nullify antibody mediated cross linking.
In a open study in 12 patients with CAU 11 out of 12 patients
showed a good or excellent response
(Kaplan et al. JACI 2008; 122: 569-73)
In an RDBPCT in 20 patients with unselected treatment
resistant CU, all patients allocated to Omalizumab(given
every 2-4 weeks for 16 weeks) showed substantial
improvement in symptom score and QOL
(Goberet al JACI 2008; 121: S147)
Three patients with unselected treatment resistant CU all
responded well to omalizumab
(Spectoret al. Ann Allergy 2007; 99: 190-03)
The results are impressive but mechanism of action is unclear.
If nothing works : reconsider the diagnosis
Consider the following alternative diagnoses :
Urticarial vasculitis(do skin biopsy)
Schnitzler`s syndrome (paraprotein screen)
Adult –onset Still`s disease (fever, joint pain)
Autoinflammatory syndrome (early onset periodic
Urticarial dermatitis (“wheals” desquamate)
Chronic urticaria is a disabling condition and patients
deserve adequate treatment, beyond “playing roulette”
with the latest antihistamines.
Don’t waste time on unproven and ineffective treatments
and “allergy tests”.
Don’t be afraid of trying off –label dosages of low sedation
antihistamines -before going on to second and third line
Follow a stepwise approach.
When all else has failed –revisit the diagnosis.