HOME      CME/CNE INFORMATION      PROGRAM DIRECTORS      NEWSLETTER ARCHIVE      EDIT PROFILE      RECOMMEND TO A COLLEAGUE
  April 2012: Volume 3, Issue 7

Alternative Treatments for Antihistamine-Resistant Chronic Urticaria

In this Issue...


The treatment of patients with chronic idiopathic urticaria resistant to antihistamines can be challenging. Chronic urticaria is defined as intermittent (at least 3 times per week) or continuous hives that last for ≥6 weeks. Although systemic oral corticosteroids may be a reasonable short-term treatment option for controlling active hives, long-term use of these agents should be avoided because of their numerous side effects.

In this issue, we review 5 alternative immunomodulating therapies for patients with chronic idiopathic urticaria. I have selected these particular articles because they reflect my treatment choices for patients with chronic idiopathic urticaria who are resistant to antihistamines.
   LEARNING OBJECTIVES
  After participating in this activity, the participant will demonstrate the ability to:

  Describe the risks and benefits associated with prescribing dapsone for patients with antihistamine-resistant chronic idiopathic urticaria
  Discuss the use of low-dose cyclosporine A for the treatment of antihistamine-resistant chronic urticaria
  Explain the mechanism of action of omalizumab
  IMPORTANT CME/CNE INFORMATION
Program Begins Below
 accreditation statements
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Centers Commission on Accreditation.

The Institute for Johns Hopkins Nursing and the American Nurses Credentialing Center do not endorse the use of any commercial products discussed or displayed in conjunction with this educational activity.


credit designations
Physicians
Newsletter: The Johns Hopkins University School of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses
Newsletter: This 1.0 contact hour Educational Activity is provided by the Institute for Johns Hopkins Nursing. Each Newsletter carries a maximum of 1.0 contact hours or a total of 3 contact hours for the six podcasts in this program.


Launch Date
This program launched on October 11, 2011 and is published bi-monthly; activities expire 2 years from the date of publication.

Post-test
To take the post-test for eMedicalDermatology Review you will need to visit the Johns Hopkins University School of Medicine's CME website or the Institute for Johns Hopkins Nursing. If you have already registered for another Hopkins CME program at these sites, simply enter the requested information when prompted. Otherwise, complete the registration form to begin the testing process. A passing grade of 70% or higher on the post test/evaluation is required to receive CME/CNE credit.

There are no fees or prerequisites.


PLANNER disclosure
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of financial relationships with industry from any individual in a position to control the content of a CME activity sponsored by OCME. Members of the Planning Committee are required to disclose all relationships regardless of their relevance to the content of the activity. The Program Directors reported the following:
Susan Matra Rabizadeh, MD, MBA discloses that she serves on the advisory board and is receiving an honorarium from Allergan.
Mark Lebwohl, MD discloses that he has received grants for clinical research from Can-Fite Biopharma and Clinuvel. He also disclosed that he has worked as a consultant for and receiving honorarium from Abgenomics, Allos, Amgen, Astellas, DermaGenoma, DermiPsor, Ethicon, Genentech, GlaxoSmithKline-Stiefel, Glenmark Pharmaceuticals, HelixBioMedix, Janssen Ortho Biotech, LEO Pharmaceuticals, Novartis, Nycomed, Onset Therapeutics, Pfizer, Valeant Pharmaceuticals.
No other planners have indicated that they have any financial interests or relationships with a commercial entity.
Guest Author Disclosures

Statement of Responsibility
The Johns Hopkins University School of Medicine takes responsibility for the content, quality and scientific integrity of this CME activity.

intended audience
This activity has been developed for dermatologists, nurses, dermasurgeons, dermatopathologists, pediatric dermatologists, Immunodermatologists, wound care specialists and allied healthcare providers.
 Confidentiality Disclaimer for CME Conference Attendees
I certify that I am attending a Johns Hopkins University School of Medicine CME activity for accredited training and/or educational purposes.

I understand that while I am attending in this capacity, I may be exposed to “protected health information,” as that term is defined and used in Hopkins policies and in the federal HIPAA privacy regulations (the “Privacy Regulations”). Protected health information is information about a person's health or treatment that identifies the person.

I pledge and agree to use and disclose any of this protected health information only for the training and/or educational purposes of my visit and to keep the information confidential.

I understand that I may direct to the Johns Hopkins Privacy Officer any questions I have about my obligations under this Confidentiality Pledge or under any of the Hopkins policies and procedures and applicable laws and regulations related to confidentiality. The contact information is: Johns Hopkins Privacy Officer, telephone: 410-735-6509, e-mail: HIPAA@jhmi.edu.

“The Office of Continuing Medical Education at the Johns Hopkins University School of Medicine, as provider of this activity, has relayed information with the CME attendees/participants and certifies that the visitor is attending for training, education and/or observation purposes only.”

For CME Questions, please contact the CME Office at (410) 955-2959 or e-mail cmenet@jhmi.edu.

Johns Hopkins University School of Medicine
Office of Continuing Medical Education
Turner 20/720 Rutland Avenue
Baltimore, Maryland 21205-2195

Reviewed & Approved by:
General Counsel, Johns Hopkins Medicine (4/1/03)

Updated 4/09


internet cme policy
The Office of Continuing Medical Education (CME) at the Johns Hopkins University School of Medicine is committed to protecting the privacy of its members and customers. Johns Hopkins University SOM CME maintains its Internet site as an information resource and service for physicians, other health professionals and the public.

Continuing Medical Education at the Johns Hopkins University School of Medicine will keep your personal and credit information confidential when you participate in a CME Internet-based program. Your information will never be given to anyone outside the Johns Hopkins University School of Medicine's CME program. CME collects only the information necessary to provide you with the services that you request.


Disclaimer Statement
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings and adverse effects before administering pharmacologic therapy to patients.

hardware & software requirements
PC: Internet Explorer (v6 or greater), or Firefox
MAC: Safari


To participate in additional CME activities presented by the Johns Hopkins University School of Medicine Continuing Medical Education Office, please visit www.hopkinscme.edu

   IN THIS ISSUE
  COMMENTARY from our Guest Author
  Dapsone for the Treatment of Chronic Idiopathic Urticaria
  Methotrexate for the Treatment of Chronic Urticaria
  Cyclosporine Use in Patients with Chronic Urticaria
  Intravenous Immunoglobulin Therapy in Patients with Chronic Urticaria
  Omalizumab for the Treatment of Chronic Idiopathic Urticaria
 Program Directors

Bernard A. Cohen, MD
Professor of Pediatrics and Dermatology and Director of Pediatric Dermatology,
Johns Hopkins Children’s Center
Baltimore, MD

Susan Matra Rabizadeh, MD, MBA
Department of Dermatology
Cedars-Sinai Medical Group
Beverly Hills, CA

Mark Lebwohl, MD
Professor and Chairman
Department of Dermatology
The Mount Sinai School of Medicine
New York, NY

Elizabeth Sloand, PhD, CRNP
Assistant Professor of Pediatric Nursing
The Johns Hopkins University
School of Nursing
Baltimore, MD
   GUEST AUTHOR OF THE MONTH
 Commentary & Reviews:
Michael D. Tharp, MD
The Clark W. Finnerud, MD, Professor and Chair
Department of Dermatology
Rush University Medical Center
Chicago, Illinois

   
 Guest Faculty Disclosure

Michael Tharp, MD discloses that he has no financial relationship with commercial supporters.

Unlabeled/Unapproved Uses

The author has indicated there will be references to unlabeled or unapproved uses of drugs or products in this presentation, including biologics, colchicine, cyclosporine, dapsone, doxycycline, H2 antihistamine, hydroxychloroquine, methotrexate, montelukast, nicotinamide, prednisone and omalizumab

Program Directors’ Disclosures
 Program Information
CE Info
Accreditation
Credit Designations
Intended Audience
Learning Objectives
Internet CME/CNE Policy
Faculty Disclosure
Disclaimer Statement

Length of Activity
1 hour
1 contact hour Nurses

Release Date

April 27, 2012

Expiration Date

April 26, 2014



 TO COMPLETE THE
POST-TEST


Step 1.
Please read the newsletter.

Step 2.
See the Post-test link at the end of the newsletter.

Step 3.
Follow the instructions to access the post-test.

   COMMENTARY

It has been estimated that chronic urticaria affects from 0.6 to 5% of the population at some time during their life (1,2---Gaig et al, Jiamton et al). This disorder is more common in adults than in children, and middle-aged females are affected nearly 4 times more frequently than males.3 Recent studies have shown that between 30% and 50% of patients with chronic idiopathic urticaria have circulating immunoglobulin G (IgG) antibodies to the high-affinity IgE receptor (FcεRI) or IgE.2 It has been postulated that these auto-antibodies may bind to FcεRI on mast cells and basophils, causing the release of histamine and other mediators. To date, however, little evidence demonstrates that the presence of these autoreactive antibodies in patients with chronic idiopathic urticaria predicts a response to antihistamines or to most other treatments.4

Currently, the treatment of chronic idiopathic urticaria focuses on the use of 1 or more first- or second- generation H1 antihistamines or combined H1 and H2 antihistamines. Although approximately 25% of patients with chronic idiopathic urticaria are resistant or poorly responsive to these agents,3 >90% of patients with chronic urticaria referred to my university practice have failed antihistamine therapy. Thus, years ago, it became imperative to explore other options for the treatment of antihistamine-resistant patients with chronic urticaria. Systemic oral corticosteroids may be a short-term option for the treatment of active hives, but their association with numerous side effects renders their long-term use inadvisable.

Inspired by a 1969 study by Jones and colleagues,5 in which the histologic changes in 24 patients with chronic urticaria were categorized, we began to examine the cellular infiltrates in lesional skin biopsies from our antihistamine-resistant patients with chronic idiopathic urticaria. Biopsies of lesional skin demonstrated a 3-fold increase in neutrophils (with no evidence of vasculitis) compared with skin biopsies from patients with chronic urticaria responsive to antihistamines. As a result, we treated these neutrophil-rich urticaria patients with colchicine in combination with antihistamines, with 5 of the 7 patients achieving a complete response.6 In subsequent years, I also have treated colchicine-resistant chronic urticaria patients with dapsone in combination with H1 antihistamines (usually fexofenadine 360 mg every morning and cetirizine 10 to 30 mg at bedtime.) The study by Engin and Özdemir (reviewed in this issue) prospectively investigated the effect of dapsone in antihistamine-resistant patients with chronic idiopathic urticaria. A total of 38 patients were treated with dapsone plus desloratadine, vs 27 patients who received desloratadine alone. Although no significant differences in response were reported between the 2 treatment groups during the active phase of the study, 9 of 38 dapsone-treated patients were hive-free after 6 months, whereas none of the 27 patients in the antihistamine-only treatment group experienced hive resolution. In contrast to this study, my experience has been that most antihistamine-resistant patients with chronic idiopathic urticaria require higher dapsone doses (100 to 150 mg/day) for disease control. As a result, many patients develop a mild to moderate anemia despite a normal glucose-6-phosphate dehydrogenase (G6PD) level; however, this anemia is well tolerated and rarely results in treatment discontinuation. In a recent evaluation of 23 antihistamine-resistant, dapsone-treated patients with chronic idiopathic urticaria in our clinic, 18 patients experienced full resolution of their hives, 4 achieved a partial response, and only 1 patient failed dapsone treatment. Of the 14 patients who required oral corticosteroids for disease control, all were able to discontinue steroids within weeks to months of initiating dapsone therapy (unpublished data).

Whereas in my experience most antihistamine-resistant patients with urticaria respond to treatment with colchicine or dapsone, for those who do not, I turn next to methotrexate (MTX). In the second review in this issue, Perez and associates evaluated 16 steroid-dependent patients with chronic urticaria who were highly resistant to numerous immunomodulating agents. This chronic urticaria group of patients included several very difficult-to-treat subgroups (delayed pressure urticaria, urticarial vasculitis, and idiopathic angioedema). A total of 16 patients received weekly MTX (5 to 25 mg) and folic acid. Two patients experienced complete hive resolution, with 7 others noting considerable benefit and 3 experiencing some benefit. The average time to onset of action was approximately 10 weeks. The prolonged time to achieve a therapeutic effect may have been due, in part, to the MTX dosing schedule, although the schedule was not detailed in the report. Typically, oral MTX is initiated at a dose of 2.5 mg/week. If the patient's complete blood count (CBC) and liver function tests remain within normal range 1 week later, the MTX dose is increased weekly by 2.5 to 5.0 mg, until either a therapeutic response is observed or bone marrow or liver toxicity is detected. Rarely have I exceeded an MTX dose of 25 mg/week and observed a therapeutic effect.

Cyclosporine A (CsA) has been reported to be effective for the treatment of chronic urticaria. In the retrospective study by Hollander and coworkers (reviewed in this issue), CsA was used to treat 68 antihistamine-resistant adult patients with chronic urticaria. Many of these patients required systemic corticosteroids for disease control. Overall, 78% of the CsA-treated patients achieved a complete remission (defined as ≤1 day of hives per month), with a mean time to clinical response of 4 weeks. A total of 71% of patients were able to discontinue CsA after achieving a complete remission for at least 6 months. Since the mean CsA dose required for hive control was only 1.63 mg/kg/day, side effects were minimal, related mostly to hypertension and elevated creatinine levels. Only 4 patients discontinued treatment because of medication-related problems. The interesting aspect of this report was the CsA dosing schedule. Instead of treatment being initiated at the usual dose of 2 to 5 mg/kg/day, patients in this study were started on a CsA dose of 1 mg/kg/day, which was increased depending on their clinical response. Positive predictive factors for good clinical response to medication included a prior history of hives, hives for a shorter duration (average, 55 weeks), and a positive chronic urticaria index indicative of circulating anti-FcεRI autoantibodies.

Intravenous immunoglobulin (IVIg) also has been used to treat a limited number of patients with chronic urticaria who are resistant to antihistamines, as well as to other immunomodulating agents. In another publication reviewed in this issue, Mitzel-Kaoukhov and collaborators evaluated 6 patients with oral corticosteroid–dependent chronic spontaneous urticaria who were treated with high-dose (2 g/kg) IVIg over 2 days, with infusions repeated every 4 to 6 weeks. Of the 6 patients assessed, 5 achieved a complete response after 2 to 4 cycles of IVIg, with 1 patient becoming hive-free after a single infusion. Patients who responded remained disease-free for 10 to 24 months in follow-up. The sixth patient experienced a partial response to treatment. Interestingly, this patient had had the longest duration of active urticaria (11 years) and was the only individual with a negative autologous serum skin test. Although infusion reactions can occur with the use of IVIg, the greatest limitation with this treatment is its expense. Fortunately, the number of patients with chronic urticaria who fail other immunomodulating treatments is rare, but this and other reports (7,8) indicate that IVIg may be an effective treatment for this patient group.

Omalizumab blocks the binding of IgE to FcεRI on mast cells and basophils, resulting in inhibition of mediator release and downregulation of FcεRI expression.9 In the last review in this issue, Saini and colleagues conducted a prospective, double-blind, dose-ranging study in 90 patients with chronic idiopathic urticaria resistant to recommended doses of antihistamines. Patients were randomized to a single injection of 1 of 3 omalizumab doses (75 mg, 300 mg, or 600 mg) or placebo. Individuals treated with the 300-mg or 600-mg dose of omalizumab experienced a significant reduction in hive activity compared with placebo (P<.001 and P=.047, respectively). The 300-mg treatment group experienced the greatest improvement, with two-thirds of this response occurring within the first week. Overall, 36% of patients in the 300-mg treatment group experienced 100% improvement from baseline, vs 28.6% and 4.4% in the 600-mg and 75-mg groups, respectively. Omalizumab was well tolerated, with limited side effects reported among patients, most of which were considered to be unrelated to treatment. In contrast to the treatment of patients with asthma, the dosing of omalizumab in this study was based on weight, without consideration of IgE levels. This was justified by the fact that most patients with chronic idiopathic urticaria have low or lower IgE levels than do those with asthma. Although this study demonstrates the potential effectiveness of omalizumab therapy for some patients with chronic urticaria, the cost of this agent and the ability to obtain insurance approval limit its usefulness.

Some investigators have recommended the use of leukotriene antagonists for the treatment of chronic urticaria. 10,11 I have not included these agents in this review, however, since I personally feel they are of limited value, except in cases of sensitivity to food additives, aspirin, or nonsteroidal anti-inflammatory drugs.710,11

It is worth recalling that urticaria is a skin reaction pattern rather than a single disease, and, as such, there are undoubtedly many causes of chronic urticaria that are likely to occur through different immune mechanisms. Currently, a thorough understanding of these causes and their immune mechanisms remains unclear. Thus, we are forced to use immunomodulating agents with broad effects, in the hopes of eliminating hive activity. Since the treatments reviewed in this issue all have the ability to alter immune reactions/responses, they all offer potential therapeutic benefits for antihistamine-resistant patients with chronic idiopathic urticaria. As more specific immunosuppressive agents are developed, in particular the biologics, they may provide us not only with improved treatments for chronic idiopathic urticaria, but they may also help to unravel the varied immune mechanisms responsible for the disorder.

Commentary References

1. Gaig P, Olona M Munoz LD, Dominquez FJ et al. Epidemiology of urticaria in Spain. J Investi allergol clin Immunol 2004; 14: 214-220.
2. Jiamton s Swad-Ampiraks P, Kulthanan K, Suthipinittharm P. Urticaria and angioedema in Siriraj medical students. J med Assoc Thai. 2003; 86: 74-81.
3. Najib U, Bajwa ZH, Ostro MG, Sheikh J . A retrospective review of clinical presentation, thyroid autoimmunity, laboratory characteristics, and therapies used in patients with chronic idiopathic urticaria. Ann Allergy Asthma and Immunol. 2009;103(6):496-501.
4. Sabroe RA, Fiebiger E, Francis DM, et al. Classification of anti-FcεRI and anti-IgE autoantibodies in chronic idiopathic urticaria and correlation with disease activity. J Allergy Clin Immunol. 2002;110(3):492-499.
5. Jones RR, Bhogal B, Dash A, Schifferli J. Urticaria and vasculitis: a continuum of histological and immunopathological changes. Br J Dermatol. 1983;108(6):695-703.
6. Zavadak D, Tharp MD. Chronic urticaria as a manifestation of the late phase reaction. Immunol Allergy Clin North Am. 1995;1(4):745-759.
7. O'Donnell BF, Barr RM, Black AK, Fancis DM et al. Intravenous immunoglobulin in autoimmune chronic urticaria. Br J Dermatol. 1998; 138: 101-106.
8. Spector s. Tan R. Effect of omalizumab on patients with chronic urticaria. Ann Allergy Asthma Immunol 2007; 99: 190-93
9. MacGlashan DW Jr, Bochner BS, Adelman DC, et al. Down-regulation of FcεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol. 1997;158(3):1438-1445.
10. Morgan M, Khan DA. Therapeutic alternatives for chronic urticaria: an evidence-based review, part 1. Ann Allergy Asthma Immunol. 2008;100(5):403-411; quiz 412-414, 468.
11. Di Lorenzo G, D'Alcamo A, Rizzo M, et al. Leukotriene receptor antagonists in monotherapy or in combination with antihistamines in the treatment of chronic urticaria: a systematic review. J Asthma Allergy. 2008;2:9-16.
back to top



   Dapsone for the Treatment of Chronic Idiopathic Urticaria
Engin B, Ozdemir M. Prospective randomized non-blinded clinical trial on the use of dapsone plus antihistamine vs. antihistamine in patients with chronic idiopathic urticaria. J Eur Acad Dermatol Venereol. 2008,22(4): 481-486.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
 View journal abstract   View full article
Elgin and Ozdemir evaluated the effectiveness and safety of dapsone for the treatment of 65 patients with severe daily or nearly daily chronic idiopathic urticaria. Of the 65 patients studied, 16 required prednisone for disease control. All patients received autologous intradermal serum skin testing prior to treatment initiation.

Patients were diagnosed with idiopathic disease after exhaustive blood testing. Routine CBC and G6PD levels also were determined prior to initiating therapy with either dapsone 50 mg plus desloratadine 10 mg daily (active treatment group) or desloratadine 10 mg/day alone (control group). Patients took their medication on a daily basis, regardless of the absence or presence of hives, and were followed for 3 months after completion of the study.

Urticaria activity score (UAS) was recorded by each patient daily with use of the following scoring system:



Daily scores were added to provide the weekly score. A 10-cm visual analog scale (VAS) was used to record overall disease severity, which ranged from none (0) to severe (10).

A total of 65 patients completed the study. The mean reduction in UAS from baseline at 3 months was 7.00 (95% confidence interval [CI], 6.92 to 7.08) in the active treatment group vs 5.77 (95% CI, 5.47 to 6.08) in the control group. The mean reduction in VAS at 3 months was 2.58 (95% CI, 2.33 to 2.83) in the active treatment group vs 2.55 (95% CI, 2.38 to 2.73) in the control group. No significant difference was reported between the scores in the 2 treatment groups from baseline to the end of the study. Three months after treatment discontinuation, 9 patients in the active treatment group attained a complete resolution of their hives, 27 achieved a partial response, and 2 had no response. Of the 9 complete responders, 5 remained hive-free for at least 6 months. In contrast, none of the individuals in the control group experienced a complete response. There was no correlation between autologous serum skin test positivity and severity of hives or response to treatments.

Three patients discontinued the study—2 in the active treatment group because of nausea and lack of response to treatment, and 1 in the control group who experienced complete clearing. Side effects were otherwise mild in the remainder of the patients, which included nausea in 5 of 38 patients in the active treatment group. No hematologic abnormalities were recorded in the dapsone-treated group.

This study suggests that dapsone in combination with an H1 antihistamine may induce a lasting therapeutic effect in some patients with chronic idiopathic urticaria that is not seen with the use of antihistamines alone.

back to top



   Methotrexate for the Treatment of Chronic Urticaria
Perez A, Woods A, Grattan CEH. Methotrexate: a useful steroid-sparing agent in recalcitrant chronic urticaria. Br J Dermatol. 2010;162(1):191-194.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
 View journal abstract   View full article
Perez and coworkers conducted a retrospective analysis of 16 patients with chronic, steroid-dependent urticaria treated with methotrexate (MTX). Of the 16 patients evaluated, 7 had chronic idiopathic urticaria, 3 had delayed pressure urticaria, 4 had urticarial vasculitis, and 2 had idiopathic angioedema. The mean duration of urticaria/ angioedema was 48.5 months. A total of 11 patients were tested for the presence of autoreactive IgE/FcεRIα antibodies by either the basophil histamine release assay or the autologous serum skin test.

All patients had failed combined antihistamine therapy, as well as ≥1 of the following: montelukast (n=12), colchicine (n=4), hydroxychloroquine (n=6), sulfasalazine or dapsone (n=7), IVIg (n=3), azathioprine (n=9), and/or cyclosporine (n=14). In addition, all participants required daily prednisone (10 to 60 mg) for disease control. Patients were treated with weekly MTX and folic acid (5 mg)

Of the 16 patients, 12 responded to MTX (5 to 25 mg/week), with 3 showing some benefit, 7 considerable benefit, and 2 cleared. Two patients were able to discontinue oral corticosteroids and 7 others to reduce their dose. Four of 8 responders and 3 of 3 nonresponders had detectable IgE/FcεRI autoantibodies. An MTX dose of 10 to 15 mg/week was required to induce a steroid-sparing effect, but higher doses (20 to 25 mg/week) were required in 2 patients to maintain disease control. Time to an observed therapeutic effect was approximately 10 weeks. Overall, 4 patients (1 each with chronic urticaria, chronic urticaria with angioedema, angioedema, and urticarial vasculitis) were unresponsive to MTX doses of 25 to 30 mg/week.

MTX is likely to act through both T-cell–dependent and T-cell–independent mechanisms, which may be involved in chronic urticaria. Although this study is limited by its small sample size and retrospective design, it is clear that there is a subset of treatment-resistant patients with chronic urticaria who are responsive to MTX. This response, however, does not appear to correlate with the presence of functional autoantibodies.
back to top



   Cyclosporine Use in Patients with Chronic Urticaria
Hollander SM, Joo SS, Wedner HJ. Factors that predict the success of cyclosporine treatment for chronic urticaria. Ann Allergy Asthma Immunol. 2011;107(6):523-528.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
 View journal abstract   View full article
Hollander and associates conducted a retrospective analysis of chronic urticaria patients treated with cyclosporine A (CsA). A total of 106 adult patients with chronic urticaria resistant to combined antihistamine therapy met the study inclusion criteria; however, only 68 of these individuals completed CsA treatment. Of the CsA-treated patients, 78% were female and 81% were white. The average duration of hives was 25 months. Overall, 82% of the CsA-treated patients also received oral corticosteroids, with 73% of those individuals achieving hive control.

Patients were started on CsA 1 mg/kg/day, with the dose increased by 25 to 50 mg every 2 to 4 weeks, until either a complete remission was achieved or a CsA trough level of 100 to 200 ng/mL was observed. Patients were evaluated on a monthly basis.

Of the 68 CsA-treated patients, 53 (78%) attained a complete remission with a mean dose of 1.63 mg/kg/day. On average, a positive response to treatment was observed within 1 month, and the mean time to complete remission was 20.5 weeks. Of the responding patients, 42% had undetectable CsA trough levels. Of the 68 patients treated with CsA, 15 attained only a partial response and 4 achieved no response. A total of 71% of the patients were able to discontinue CsA after remaining hive-free for 6 months. Only 4 patients discontinued CsA therapy due to adverse effects.

At a mean follow-up of 60 months, 7 patients experienced recurrence of their hives, with all responding to re-treatment. Of these 7 patients, 3 required daily CsA for disease control. Factors predictive of a positive response to CsA treatment included a shorter duration of urticaria (55.2 weeks vs 259.63 weeks in incomplete responders; P=.03), a prior history of urticaria (P=.03), and the presence of autoreactive antibodies (positive Chronic Urticaria [CU] Index; P=.05). Age, response to steroids, presence of antithyroid antibodies, and a positive autologous serum skin test did not predict a positive CsA response.

Although this study was limited by its retrospective design, lack of a control group, and nonstandardized protocol for evaluating patients, it did confirm the effectiveness of CsA for the treatment of chronic urticaria. Whereas other reports (Barlow et al., Kessel and Toubi) have used higher CsA doses (2 to 5 mg/kg/day), this study demonstrated that much lower doses of the agent can be an effective and safe treatment for patients with chronic urticaria. Although 93% of patients with a positive CU index achieved a response to CsA, 60% of those who were CU Index–negative also improved on CsA therapy, indicating that the effect of the agent may be independent of autoreactive anti-IgE antibodies.

References

1. Barlow RJ, Black AK, Greaves MW. Treatment of severe chronic urticaria with cyclosporine-A. Eur J Dermatol 1993; 3:273-275.
2. Kessel A.,Toubi E. Cyclosporine-A in severe chronic urticaria: the option for long-term therapy. Allergy 2010; 65: 1478-1482.
back to top





















   Intravenous Immunoglobulin Therapy in Patients with Chronic Urticaria
Mitzel-Kaoukhov H, Staubach, P, Müller-Brenne T. Effect of high-dose intravenous immunoglobulin treatment in therapy-resistant chronic spontaneous urticaria. Ann Allergy Asthma Immunol. 2010;104(3):253-258.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
 View journal abstract   View full article
Mitzel-Kaoukhov and associates conducted a retrospective study of 6 patients with severe chronic urticaria and episodic angioedema treated with intravenous immunoglobulin (IVIg). All patients required daily systemic corticosteroids for hive control, and each had a history of being poorly responsive to antihistamines, dapsone, and/or cyclosporine. The mean duration of disease activity was 5.2 years (range, 1 to 11 years). Patients received an exhaustive evaluation to exclude other causes of urticaria. Of the 6 patients investigated, 4 had a positive autologous serum skin test. Patients were treated with an IVIg dose of 2 g/kg over 2 days every 4 to 6 wks. The total number of treatments ranged from 3 to 11, depending on the patient's response and individual insurance coverage. Urticaria activity was assessed using an urticaria assessment scoring system, in which wheals and itch were each rated on a scale of 0 to 3, with a maximum score of 6.

Of the 6 patients assessed, 5 attained a complete response to treatment. One patient achieved a complete resolution of hives after only 1 infusion. The remaining 4 patients required between 4 and 11 IVIg infusions to achieve a complete response, with all remaining hive-free for 10 to 24 months posttreatment. The sixth patient experienced a decrease in his urticaria activity score from 5 to 3 and was the only patient with a negative autologous serum skin test. Adverse effects were minimal, including headache and exacerbation of preexisting hypertension.

This analysis is limited by its retrospective design, small sample size, and lack of a control group. Nevertheless, 5 of 6 patients with extremely difficult-to-control chronic urticaria were completely responsive to high-dose IVIg in a relatively short period of time. This effect appeared to result in long-lasting disease remissions.
back to top





















   Omalizumab for the Treatment of Chronic Idiopathic Urticaria
Saini S, Rosen KE, Hsieh H-J, et al. A randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine-refractory chronic idiopathic urticaria. J Allergy Clin Immunol. 2011;128(3):567-573.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
 View journal abstract   View full article
The objective of this study by Saini and coworkers was to evaluate the efficacy and safety of omalizumab for the treatment of patients with chronic idiopathic urticaria, and to establish an optimal therapeutic dose. Omalizumab is a recombinant monoclonal antibody approved for the treatment of moderate to severe, persistent asthma. It blocks the binding of IgE to FcεRI, resulting in reduced mediator release from mast cells and basophils, and decreased IgE receptor expression. Patients enrolled in the study were required to have an urticaria activity score (UAS) of ≥4 for wheals and itch (maximum possible score of 6) and a weekly UAS score (UAS7) of ≥12. Some patients required immunomodulating agents for disease control. A total of 90 patients were randomized in the study and were stratified, according to weight, to 1 of 3 omalizamub treatment groups (75, 300, or 600 mg) or placebo. IgE antibodies were not determined for dosing, since it was believed that they were not significantly elevated in most patients. Patients received a single omalizumab injection and were followed weekly for 4 weeks. Diphenhydramine (50 to 75 mg/day) was permitted as a rescue medication during and after the treatment period, but all other urticaria treatments were discontinued for at least 3 months prior to study enrollment.

Of the 90 enrolled patients, 71 completed the study. Nine patients discontinued before the end of the treatment period. Additionally, 19 other patients left the study after the treatment period: 6 each from the placebo and omalizumab 75-mg groups, 2 from the omalizumab 300-mg group, and 5 from the omalizumab 600-mg group. Compared with baseline, both the omalizumab 300-mg and omalizumab 600-mg groups experienced a significant decrease in mean UAS7 at week 4 vs placebo (P<.001 and P=.047, respectively). The change from baseline in the 75-mg group did not differ from that in the placebo group. The onset of a therapeutic effect for omalizumab in the 2 responding groups occurred within 1 week. The 300-mg group demonstrated the most dramatic response over 4 weeks, with the greatest improvement occurring within the first week. No significant difference in treatment response between the 300-mg and 600-mg groups was observed. Overall, 36% of patients in the 300-mg group attained 100% improvement from baseline, vs 28.6% and 4.4% in the 600-mg and 75-mg groups, respectively.

Omalizumab was well tolerated with few side effects (upper respiratory tract infection, headache, nasopharyngitis, and dysmenorrhea) reported among patients, which were not considered to be drug related. This study is limited by its sample size and number of treatment groups; however, compared with placebo, a single 300-mg omalizumab injection was associated with a significant reduction in the number of hives and itching in patients with chronic idiopathic urticaria (P<.001). The frequency of omalizumab dosing was not part of this study and will need to be established.
back to top













 COMPLETE THE
POST-TEST


Step 1.
Click on the appropriate link below. This will take you to the post-test.

Step 2.
If you have participated in a Johns Hopkins on-line course, login. Otherwise, please register.

Step 3.
Complete the post-test and course evaluation.

Step 4.
Print out your certificate.



2012 JHUSOM, IJHN and eMedicalDermatology Review

Presented by JHUSOM and IJHN in collaboration with DKBmed.