A randomized double-blind trial of intravenous immunoglobulin for pemphigus

doi:10.1016/j.jaad.2008.09.052

Journal of the American Academy of Dermatology

Volume 60, Issue 4, April 2009, Pages 595-603

https://doi.org/10.1016/j.jaad.2008.09.052 Get rights and content

Background

Pemphigus is a rare life-threatening intractable autoimmune blistering disease caused by IgG autoantibodies to desmogleins. It has been difficult to conduct a double-blind clinical study for pemphigus partly because, in a placebo group, appropriate treatment often must be provided when the disease flares.

Objective

A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of a single cycle of high-dose intravenous immunoglobulin (400, 200, or 0 mg/kg/d) administered over 5 consecutive days in patients relatively resistant to systemic steroids.

Methods

We evaluated efficacy with time to escape from the protocol as a novel primary end point, and pemphigus activity score, antidesmoglein enzyme-linked immunosorbent assay scores, and safety as secondary end points.

Results

We enrolled 61 patients with pemphigus vulgaris or pemphigus foliaceus who did not respond to prednisolone (≥20 mg/d). Time to escape from the protocol was significantly prolonged in the 400-mg group compared with the placebo group (P < .001), and a dose-response relationship among the 3 treatment groups was observed (P < .001). Disease activity and enzyme-linked immunosorbent assay scores were significantly lower in the 400-mg group than in the other groups (P < .05 on day 43, P < .01 on day 85). There was no significant difference in the safety end point among the 3 treatment groups.

Limitation

Prednisolone at 20 mg/d or more may not be high enough to define steroid resistance.

Conclusion

Intravenous immunoglobulin (400 mg/kg/d for 5 d) in a single cycle is an effective and safe treatment for patients with pemphigus who are relatively resistant to systemic steroids. Time to escape from the protocol is a useful indicator for evaluation in randomized, placebo-controlled, double-blind studies of rare and serious diseases.

Section snippets

Patients

This study was conducted in 27 medical institutions in Japan with affiliated dermatologists specialized in autoimmune blistering disease. Patients were given the diagnosis of pemphigus vulgaris (PV) or pemphigus foliaceus (PF) as confirmed based on our national diagnostic criteria as follows: pemphigus was diagnosed when at least one item from every 3 findings, or two items from clinical findings and one item from immunologic findings were satisfied.

1.
Clinical findings
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  Multiple, easily rupturing,

Disposition of patients

The disposition of patients enrolled in the study is shown in Fig 1. A total of 61 patients were treated with the investigational drug (placebo, 20; 200 mg, 20; and 400 mg, 21). All the enrolled patients including 10 patients (placebo, 5; 200 mg, 3; and 400 mg, 2) who were withdrawn from the study according to the requirements in the protocol were included in the analyses. The main reasons for study withdrawal were the evaluator's decision to withdraw the patient and the occurrence of adverse

Discussion

Most clinical research involving a rare disease is based on case reports or data from limited samples obtained in open-label studies. In particular, in life-threatening, serious, and intractable diseases, such as pemphigus, appropriate treatment must be provided in a timely fashion if symptoms are aggravated or unchanged for days. This makes performance of a placebo-controlled, double-blind comparison study infeasible. On the other hand, the efficacy of new drugs for malignant tumors or for

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Taiwanese dermatological association (TDA) consensus for the management of pemphigus
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Pemphigus is an uncommon but life-threatening autoimmune blistering disease characterized by the presence of antibodies against desmogleins. Without effective treatment, pemphigus can result in significant morbidity and mortality. Existing consensus statements on pemphigus management from international medical groups provide varying guidelines, especially on treatment. Thus, on January 4, 2020, a panel of seven dermatology experts from the Taiwanese Dermatological Association (TDA) and one rheumatology expert convened to develop a consensus for the management of pemphigus. These experts with extensive experience in pemphigus management were recommended by their respective teaching hospitals and primary care clinics in Taiwan and by the TDA. The meeting reviewed the available consensus statements from international dermatology groups, including the European Dermatology Forum (EDF), the European Academy of Dermatology and Venereology (EADV), and the International Bullous Diseases Consensus Group. Using these guidelines as a basis for discussion and consensus formulation, these experts formulated their consensus statement that provides practical, concise but comprehensive recommendations as to the diagnosis, treatment, and monitoring of pemphigus patients in Taiwan. This consensus serves as a clinical reference for physicians for the management of pemphigus in Taiwan or wherever it may be applicable.
Intravenous Ig Regulates Anti-Desmoglein 3 IgG Production in B220<sup>–</sup> Antibody-Producing Cells in Mice with Pemphigus Vulgaris
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Intravenous Ig (IVIG) is a treatment option for intractable cases of pemphigus vulgaris (PV), an autoimmune blistering disease caused by autoantibodies against desmoglein 3 (DSG3). To investigate the efficacy of IVIG on autoantibody secretion, we produced PV model mice by adoptive transfer of immunized Dsg3^−/− splenocytes to Rag2^−/− mice. We found that circulating anti-DSG3 IgG ELISA titer decreased in PV model mice after 5 days of treatment with IVIG compared with PBS-treated mice, whereas the F(ab’)₂ fragment did not suppress the anti-DSG3 IgG titer. enzyme-linked immunospot assay revealed that IVIG treatment reduced the frequency of anti-DSG3 antibody–secreting cells in the spleen but not in lymph nodes and bone marrow. Moreover, this reduction was observed only in the splenic B220⁻ fraction but not in the B220⁺ fraction. Furthermore, IVIG decreased the serum levels of anti-DSG3 IgG, even after a significant reduction of its titer, owing to antibody-mediated CD20⁺ B cell depletion. In addition, IVIG suppressed anti-DSG3 IgG production in B220⁻CD138⁺ plasma cells derived from PV model mice ex vivo. These results indicate that IVIG reduced autoantibody production in B220⁻ cells containing plasma cells in PV model mice, and this function may indicate one of the mechanisms of action of IVIG on PV.
Pemphigus and Pemphigoid: From Disease Mechanisms to Druggable Pathways
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Pemphigus and pemphigoid are paradigms for understanding the mechanisms of antibody-mediated autoimmune disease in humans. In pemphigus, IgG4-predominant autoantibodies cause intraepidermal blistering by direct interference with desmoglein interactions and subsequent disruption of desmosomes and signaling pathways. In pemphigoid, IgG1, IgG4, and IgE autoantibodies against basement membrane zone antigens directly interfere with hemidesmosomal adhesion, activating complement and Fc receptor‒mediated effector pathways. Unraveling disease mechanisms in pemphigus and pemphigoid has identified numerous opportunities for clinical trials, which hold promise to identify safer and more effective therapies for these potentially life-threatening diseases.
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IgG replacement therapy (IgRT) has an essential role in minimizing infections and improving the quality of life in patients with immunodeficiency, who would otherwise suffer from recurrent infections. Different preparations of immunoglobulin are available, with intravenous and subcutaneous routes being the main forms of administration. Secondary humoral impairment can result from several diseases or medications, increasing patients’ vulnerability to bacterial infections. In secondary antibody deficiency, despite being more prevalent than inborn errors of immunity, clinical data of IgRT are limited. In this article we discuss the history of the production of immunoglobulin, mechanisms of action, indications, dosage, clinical efficacy and the adverse effects of this treatment.
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Intraepithelial autoimmune blistering dermatoses are a rare group of skin disorders characterized by disruptions of inter-keratinocyte connections within the epidermis through the action of autoantibodies. The second article in this continuing medical education series presents validated disease activity scoring systems, serologic parameters of disease, treatments, and clinical trials for pemphigus and its subtypes.

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: Other investigators in the Pemphigus Study Group are listed in the Appendix.

: Supported by Nihon Pharmaceutical Co Ltd, but no financial support was provided to any individual investigator for performing this trial.

: Disclosure: Drs Amagai, Ikeda, Kitajima, Nishikawa, and Hashimoto report receiving consulting and lecture fees from Nihon Pharmaceutical Co Ltd. Drs Shimizu, Iizuka, Hanada, Aiba, Kaneko, Izaki, Tamaki, Ikezawa, Takigawa, Seishima, Tanaka, Miyachi, Katayama, Horiguchi, Miyagawa, Furukawa, Iwatsuki, Hide, Tokura, Furue, Ihn, Fujiwara, Ogawa, and Hashimoto have no conflicts of interest to declare.

: Presented in part at the Post International Investigative Dermatology Satellite International Meeting on Autoimmune Bullous Diseases at Ohtsu, Japan on May 19, 2008 and the Annual Meeting of the Japanese Dermatological Association at Kyoto, Japan on April 20, 2008.

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Original articleA randomized double-blind trial of intravenous immunoglobulin for pemphigus

Background

Objective

Methods

Results

Limitation

Conclusion

Section snippets

Patients

Disposition of patients

Discussion

High-dosage intravenous gamma globulin: therapeutic failure in pemphigus and pemphigoid

J Am Acad Dermatol

Frequency of adverse events associated with intravenous immunoglobulin therapy in patients with pemphigus or pemphigoid

Ann Pharmacother

High-dose intravenous immunoglobulins for the treatment of autoimmune mucocutaneous blistering diseases: evaluation of its use in 19 cases

J Am Acad Dermatol

Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin

N Engl J Med

Corticosteroid-sparing effect of intravenous immunoglobulin therapy in patients with pemphigus vulgaris

Arch Dermatol

Treatment of pemphigus with intravenous immunoglobulin

J Am Acad Dermatol

Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment

J Am Acad Dermatol

Treatment of severe pemphigus with protein A immunoadsorption, rituximab and intravenous immunoglobulins

Br J Dermatol

History of the establishment and revision of diagnostic criteria, severity index and therapeutic guidelines for pemphigus in Japan

Arch Dermatol Res

Guidelines for the management of pemphigus vulgaris

Br J Dermatol

Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases

Arch Dermatol

Original article
A randomized double-blind trial of intravenous immunoglobulin for pemphigus