Introduction

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 weeks. 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 (QOL). 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.

1. 2. 3.

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 patients.

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

sedating antihistamines
However first generation H1 antihistamines do have a

role particularly in patients with sleep disturbance due to urticaria.

How can difficultpatients 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 Cyp450.

RDBCT have shown a significant benefit of combining H1 and H2

antihistamines. (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

Doxepin Leukotriene antagonists

Corticosteroids
Dapsone Sulfasalzine Narrow band UVB.

Doxepin
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 Cautions :
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, Milan, Italy.Abstract OBJECTIVE: To assess the proportion of patients with antihistamine-resistant CU that respond to a course of corticosteroids. METHODS: 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. RESULTS: 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 temporarily. CONCLUSIONS: 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 this treatment.

Leukotriene antagonists
Evidence suggests that leukotrienes antagonists are

effective, especially in aspirin sensitive urticaria and autoimmune urticaria.

Montelukast- 10mg at night. No significant drug interactions. Adverse effects- flu like symptoms, dry mouth, gi

disturbances may occur but unpredictable.

Dapsone Can be indicated as steroid sparing drug and delayed pressure urticaria. Starting dose 75mg/day. Can be increased upto 150 mg/day. Sulfasalazine Starting dose- 1 gm BD. Increasing by 500 mg daily at intervals of 2 weeks to a maximum regular dose of 4 gm daily.

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. burhanengin2000@yahoo.com Abstract OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of dapsone in CIU. METHODS: 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 week). RESULTS: 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). LIMITATIONS: No placebo was used. The study was not blinded. Lack of blinding may have led to bias. The follow-up period was short. CONCLUSION: 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: 247251, December 5, 2007. Treatment of Chronic Urticaria with Narrowband Ultraviolet B Phototherapy: a Randomized Controlled Trial Burhan Engin, Mustafa zdemir, Ali Balevi and nci Mevlitolu 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 post-treatment. 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. Rituximab

What to do if all these measures fail : THIRD LINE TREATMENT (IMMUNOTHERAPIES)

Cyclosporin
Methotrexate Intravenous immunoglobulin Plasmapheresis Mycophenolate mofetil

Tacrolimus

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)

Indications : 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

urticaria.

Hollander SM, Joo SS, Wedner HJ. Source-Washington University School of Medicine, St. Louis, Missouri, USA. seth.m.hollander@gmail.com

Abstract OBJECTIVE: To describe our low-dose cyclosporine-treated CU population and factors predicting a positive outcome. METHODS: 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.

RESULTS:
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. CONCLUSION:

Cyclosporine is an effective treatment for CU, and a history of hives, shorter duration of

Methotrexate
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

chronic urticaria.

Perez A, Woods A, Grattan CE. Source St John's Institute of Dermatology, St Thomas' Hospital, London SE1 7EH, UK. Abstract 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 functional autoantibodies. 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 years) remission. 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, Mller-Brenne T. Source - Department of Dermatology, University Medical Center Mainz, Mainz, Germany. Abstract OBJECTIVE: To assess the efficacy and safety of high-dose IVIG as a treatment option in patients with therapy-resistant CSU. METHODS: 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. RESULTS: 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. CONCLUSION: High-dose IVIG represents an important therapeutic option in patients with severe CSU.

 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. Abstract 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 urticaria.

Is there anything new round the corner?

Omalizumab
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 basophils.
Patients with autoimmune urticaria due to autoantibodies

directed against FcR1 or IgE itself should benefit from treatment with Omalizumab since there would be a sufficient FcR1 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) responded well to omalizumab (Spectoret al. Ann Allergy 2007; 99: 190-03)

Three patients with unselected treatment resistant CU all

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

fever,cryopyrins) Urticarial dermatitis (wheals desquamate)

Conclusion
Chronic urticaria is a disabling condition and patients

deserve adequate treatment, beyond playing roulette with the latest antihistamines. Dont waste time on unproven and ineffective treatments and allergy tests. Dont be afraid of trying off label dosages of low sedation antihistamines -before going on to second and third line treatments. Follow a stepwise approach. When all else has failed revisit the diagnosis.

THANK YOU