Successful treatment of autoimmune chronic idiopathic urticaria with intravenous cyclophosphamide

doi:10.1016/S1081-1206(10)61941-2

Annals of Allergy, Asthma & Immunology

Volume 89, Issue 2, August 2002, Pages 212-214

https://doi.org/10.1016/S1081-1206(10)61941-2 Get rights and content

Background

A 45-year-old woman presented with a 20-year history of chronic idiopathic urticaria (CIU) unresponsive to H₁- and H₂-antagonists and combinations of other anti-inflammatory agents but controlled with daily prednisone (35 mg) for more than 13 years. Intracutaneous testing to autologous serum revealed an 8 × 10-mm wheal/flare reaction consistent with the presence of anti-FcɛRIα autoantibodies. These autoantibodies have been reported to be present in >45% of patients with CIU. Their functional role in the pathogenesis of CIU remains poorly understood.

Objective

Because of the therapeutic refractory nature of this patient's CIU requiring high doses of corticosteroids, it was decided to initiate treatment with intravenous cyclophosphamide (CTX) in an attempt to eradicate autoantibody-producing B-lymphocyte clones. This therapeutic approach has been previously successful in other autoantibody-mediated disorders such as type II acquired angioedema and factor VIII deficiency.

Results

Initial treatment consisted of 500 mg CTX intravenously followed by increases of 100 mg every 2 weeks, with the maximum dose reaching 1,500 mg once a month, which represents approximately 20% of the dose administered during systemic cancer chemotherapy. Within 7 months there was a complete clinical remission and prednisone was discontinued. Repeat intracutaneous testing to autologous serum was negative, consistent with an abrogated autoantibody response. The patient has not experienced a recurrence of CIU at the time of this report.

Conclusion

This index case suggests that intravenous CTX may be effective in alleviating autoantibody-associated CIU in corticosteroid-dependent patients refractory to conventional therapies.

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Further studies should evaluate this and whether markers of poor response to antihistamines and/or omalizumab such as a high baseline urticaria activity score over 7 days and a combination of elevated IgG-anti-TPO and low total IgE can also predict good response to cyclosporine treatment. Case reports of patients with antihistamine-resistant CSU and positive markers for autoimmunity, for example, positive ASST and/or basophil test results, suggested efficacy of plasmapheresis, rituximab (anti-CD20), IVIG, methotrexate, cyclophosphamide,93 and mycophenolate mofetil (reviewed in Holm et al94 and Combalia et al95). Most novel therapies under development are expected to work for both endotypes, type I and type IIb, although some can be expected to work better in one than the other.
Chronic spontaneous urticaria (CSU) is a debilitating mast cell–driven disease characterized by recurrent wheals and/or angioedema. Substantial progress has been made in dissecting the 2 main autoimmune mechanisms that drive the pathogenesis of CSU. Type I autoimmune (autoallergic) CSU is associated with IgE antibodies against autoantigens, for example, thyroid peroxidase and IL-24. Type IIb autoimmune CSU is mediated by autoantibodies that activate mast cells, for example, via IgE and FcεRI, and is present in less than 10% of patients with CSU when strict criteria are used, that is, triple positivity of autologous serum skin test, immunoassays for IgG autoantibodies, and basophil activation tests. A subpopulation of patients with CSU has both types. Type IIb autoimmune CSU is characterized by higher disease severity, concomitant autoimmune diseases, low levels of total IgE, elevated levels of IgG-anti–thyroid peroxidase, basopenia, eosinopenia, poor response to antihistamines and to omalizumab, and a good response to cyclosporine. Novel targeted therapies for CSU are under development such as ligelizumab, an anti-IgE, fenebrutinib and remibrutinib, Bruton's tyrosine kinase inhibitors, and dupilumab, an anti–IL-4Rα. Further studies should investigate the overlap between autoallergic and type IIb autoimmune CSU, optimize the diagnosis of both autoimmune endotypes using easy-to-perform, noninvasive, and inexpensive markers, and assess differences in response to therapy.
Nonbullous skin diseases: Alopecia areata, vitiligo, psoriasis, and urticaria
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Vitiligo and alopecia areata are two common disfiguring autoimmune conditions, caused by an immune attack operated by cytotoxic CD8+ T cells on the hair follicle bulb (in AA) and on mature epidermal melanocytes (in vitiligo). The most common type of AA is patchy alopecia of the scalp, having the best prognosis, while the most common vitiligo type presents as non-segmental depigmeted macules of the skin, appearing in a more or less symmetric pattern. Psoriasis is an immune/inflammatory disease, characterized by erythematous scaly plaques with variable skin involvement, associated with significant morbidity and with a decrease in quality of life. Psoriasis is caused by a dysregulated immune response with increased production of IL-23 and Th1- and Th17-type cytokines. Chronic urticaria represents a relatively common type of urticaria, one of the most disturbing problems that dermatologists can see in the clinical practice, characterized by recurrent pruritic hives that can affect any part of the skin. It has a complex multifactorial causation, with the precise trigger identification in individual patients usually not possible.
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Intravenous and oral cyclophosphamide have demonstrated efficacy in several case reports with patients with CU and demonstrated superiority to antihistamines in a small parallel group study. Doses have varied between 500 to 1500 mg intravenously every 2 to 4 weeks80 and 50 to 100 mg orally daily.81,82 Originally approved for the treatment of severe allergic asthma, omalizumab is a recombinant humanized IgG monoclonal antibody against serum IgE,20 and has recently been approved for the treatment of patients with CU who are unresponsive to H1 antihistamines.
Second-generation antihistamines are considered first-line agents in the treatment of chronic urticaria because of their safety and efficacy profile. Some patients require higher doses of H₁ antihistamines alone or in combination with other classes of medications, including H₂ antihistamines, leukotriene receptor antagonists, or first-generation H₁ antihistamines. One major therapeutic advance has been omalizumab, a humanized monoclonal anti–immunoglobulin E that was recently approved by the US Food and Drug Administration for the treatment of chronic urticaria that is unresponsive to H₁ antagonists. In addition, the second article in this continuing medical education series outlines several evidence-based alternative treatments for urticaria and the differences in recommendations between 2 major consensus groups (the European Academy of Allergy and Clinical Immunology/World Allergy Organization and the American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force).
Treatment of chronic spontaneous urticaria: Immunomodulatory approaches
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This paper summarizes and reviews the mechanisms of action and data concerning efficacy of recommended treatments as well as other treatments that have been tested, independently of the outcomes, in the management of chronic spontaneous urticaria. Due to the central role of mast cells, basophils and histamine in the pathophysiology of this disease, H₁-antihistamines remain the first-line treatment. However, current knowledge about this complex disease, also recognizes an important role for T lymphocytes, B lymphocytes, and autoantibodies. Implications of these others mediators thus provide further targets for treatment. Indeed, agents previously used to treat other autoimmune and inflammatory diseases, have demonstrated efficacy in chronic spontaneous urticaria and are therefore potential therapeutic alternatives for antihistamine unresponsive patients.
Association between chronic idiopathic urticaria and hypertension A population-based retrospective cohort study
2016, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
Research has revealed an association between CIU and autoimmunity.2,12,13 A previous case report described the successful treatment of CIU with intravenous cyclophosphamide.14 In addition, several studies have reported that oral cyclosporine is effective in treating CIU patients, and the results provide further evidence to support the CIU autoimmune pathogenetic hypothesis.15–19
Chronic idiopathic urticaria (CIU) is defined as urticaria that is not caused by external triggers. The pathogenesis of CIU remains unknown. A previous study investigated whether hypertension is associated with extended duration of CIU.
To investigate the possible association between CIU and hypertension.
We performed a population-based retrospective cohort study of 2,460 patients with CIU and 9,840 age-, sex-, and index year–matched comparison patients, using the National Health Insurance of Taiwan database. The median follow-up periods were 7.13 years for the CIU cohort and 7.20 years for the non-CIU cohort. The distributions by sex and age were similar for both cohorts.
The CIU cohort had a 1.37-fold (95% CI, 1.22–1.53) greater risk of developing subsequent hypertension than the non-CIU cohort after adjusting for sex, age, comorbidities, and nonsedating antihistamine use.
This nationwide retrospective cohort study found that CIU is associated with a higher future risk of hypertension after adjusting for sex, age, comorbidities, and nonsedating antihistamine use. The detailed pathophysiologic mechanisms require further clarification in prospective studies.

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CASE REPORTSuccessful treatment of autoimmune chronic idiopathic urticaria with intravenous cyclophosphamide

Background

Objective

Results

Conclusion

J Allergy Clin Immunol

J Allergy Clin Immunol

Dermatol Clin

J Invest Dermatol

Chronic urticaria: mechanism and treatment

Allergy Asthma Proc

Angioneurotic edema with acquired C1-inhibitor deficiency and autoantibody to C1-inhibitor: response to plasmapheresis and cytotoxic therapy

J Lab Clin Med

CASE REPORT
Successful treatment of autoimmune chronic idiopathic urticaria with intravenous cyclophosphamide