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Table 1.  Characteristics of 11 Patients With Rituximab Alone as Maintenance Therapy
Characteristics of 11 Patients With Rituximab Alone as Maintenance Therapy
Table 2.  Serum Anti–Dsg 1 and 3 Autoantibody Levels in 11 Patients Before and After Rituximab Alone as Maintenance Therapya
Serum Anti–Dsg 1 and 3 Autoantibody Levels in 11 Patients Before and After Rituximab Alone as Maintenance Therapya
1.
Hertl  M, Jedlickova  H, Karpati  S,  et al.  Pemphigus: S2 guideline for diagnosis and treatment—guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV).  J Eur Acad Dermatol Venereol. 2015;29(3):405-414.PubMedGoogle ScholarCrossref
2.
Joly  P, Mouquet  H, Roujeau  J-C,  et al.  A single cycle of rituximab for the treatment of severe pemphigus.  N Engl J Med. 2007;357(6):545-552.PubMedGoogle ScholarCrossref
3.
Lunardon  L, Tsai  KJ, Propert  KJ,  et al.  Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients.  Arch Dermatol. 2012;148(9):1031-1036.PubMedGoogle ScholarCrossref
4.
Wang  HH, Liu  CW, Li  YC, Huang  YC.  Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens.  Acta Derm Venereol. 2015;95(8):928-932.PubMedGoogle ScholarCrossref
5.
Joly  P, Maho-Vaillant  M, Prost-Squarcioni  C,  et al; French Study Group on Autoimmune Bullous Skin Diseases.  First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.  Lancet. 2017;389(10083):2031-2040.PubMedGoogle ScholarCrossref
6.
Cianchini  G, Lupi  F, Masini  C, Corona  R, Puddu  P, De Pità  O.  Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with long-term follow-up.  J Am Acad Dermatol. 2012;67(4):617-622.PubMedGoogle ScholarCrossref
Research Letter
March 2018

Rituximab as Single Long-term Maintenance Therapy in Patients With Difficult-to-Treat Pemphigus

Author Affiliations
  • 1Department of Dermatology, Reims University Hospital, Reims, France
  • 2Department of Dermatology, Assistance Publique des Hôpitaux de Paris, Henri Mondor Hospital, Créteil, France
  • 3Epidemiology in Dermatology and Evaluation of Therapeutics, Unit 7379, University Paris Est, Créteil, France
  • 4Laboratory of Dermatology, Unit 7319, University of Reims Champagne-Ardenne, Reims, France
JAMA Dermatol. 2018;154(3):363-365. doi:10.1001/jamadermatol.2017.5176

Pemphigus is a rare, chronic, relapsing, and potentially life-threatening autoimmune bullous dermatosis. European guidelines recommend administration of systemic corticosteroids as a first-line therapy.1 According to its previously published efficacy as a corticosteroid-sparing agent in refractory disease, rituximab, an anti-CD20 monoclonal antibody, is recommended as a second- or third-line therapy.1-4 A French randomized clinical trial demonstrated that rituximab is effective and well tolerated as a first-line therapy, enabling a marked decrease in cumulative dose and duration of co-administered corticosteroid.5 However, whether rituximab can be administered alone as a maintenance therapy for prevention of relapse to pemphigus remains unclear. We report our experience with rituximab used as a single, long-term maintenance therapy in 11 patients with severe, difficult-to-treat pemphigus.

Methods

This single-center, retrospective case-series study was conducted in our autoimmune bullous diseases reference center. We identified all consecutive patients from January 1 to December 31, 2014, with a confirmed diagnosis of pemphigus vulgaris or foliaceus treated with at least 1 cycle of rituximab for corticosteroid dependence, corticosteroid resistance, or adverse events. Among those, we included patients who received additional cycles of rituximab as a single maintenance therapy (ie, without any other treatment, such as a corticosteroid) and with a follow-up of 12 or more months after the first maintenance cycle. From patient medical records, we collected clinical data, rituximab administration regimens, follow-up information, and enzyme-linked immunosorbent assay results of serum autoantibody levels specific to desmoglein 1 and 3. The date of the last follow-up was August 31, 2017. This study was approved by the Reims University Hospital institutional review board, and all patients provided oral informed consent.

Results

Among 27 patients who received at least 1 cycle of rituximab, 11 patients (41%; 5 women; median [range] age, 42 [35-72] years; all white individuals) received maintenance therapy. All were in complete remission and not taking any corticosteroid at the time of the first maintenance rituximab infusion (Table 1). The maintenance therapy regimen consisted of a single rituximab infusion (1 g) given every 6 months (but in some cases decreasing after 18 months to once yearly), with a median (range) duration of 33 (24-67) months, and the median (range) number of infusions was 6 (5-12) (Table 1). During maintenance therapy, all 11 patients remained in complete remission and no adverse events were observed. However, 5 patients experienced grade 3 or 4 adverse events (1 patient had sepsis; 2, diabetes; 1, hypertension; and 2, endocrine disorders) between the initial cycle and the first rituximab maintenance infusion. At their last follow-up visit (median [range], 78 [42-147] months after the first cycle of rituximab), all 11 patients remained in complete remission, with 10 patients having discontinued rituximab maintenance therapy. Serum anti–desmoglein 1 and 3 antibody levels, which had been high before rituximab treatment, decreased markedly and remained below 14 U/mL during rituximab maintenance therapy (Table 2).

Discussion

The results of this case series indicated that rituximab can be used as single maintenance therapy, without a systemic corticosteroid, with good efficacy and tolerance in patients having severe pemphigus requiring long-term therapy for prevention of relapse. This study supplements a previous one showing the efficacy of rituximab alone in the treatment of relapse to pemphigus initially controlled with a combination of rituximab and corticosteroid.6 We found that treatment with rituximab alone, even at a low dose, not only prevented relapse but also maintained complete remission with a better benefit to risk ratio than treatment with corticosteroids. The maintenance therapy was shown to be effective for preventing relapse despite shortcomings inherent in retrospective studies (eg, heterogeneity of patient pemphigus history and variable length of rituximab maintenance therapy), highlighting the feasibility of such an approach. A progressive decrease in serum anti-desmoglein autoantibody levels to less than 14 U/mL occurred in all cases along with clinical complete remission even after maintenance therapy cessation.

Practical questions remain about the rituximab treatment regimen, including the optimal dose (500 mg or 1 g), frequency of administration (every 6 months or 1 year), and immunologic criteria enabling treatment withdrawal (negative direct immunofluorescence results or low serum autoantibody levels), and the cost-effectiveness of this maintenance therapy in patients with pemphigus. The criteria we used to discontinue rituximab maintenance therapy were persistent complete clinical remission and serum anti–desmoglein 1 and 3 autoantibody levels less than 14 U/mL for at least 1 year. Further prospective studies are warranted to identify patients for treatment with maintenance rituximab therapy and to optimize long-term management of difficult-to-treat pemphigus.

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Article Information

Corresponding Author: Philippe Bernard, MD, PhD, Department of Dermatology, Reims University Hospital, General Koenig Ave, 51092 Reims, France (pbernard@chu-reims.fr).

Accepted for Publication: October 20, 2017.

Published Online: January 3, 2018. doi:10.1001/jamadermatol.2017.5176

Author Contributions: Drs Bernard and Sanchez had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Sanchez, Ingen-Housz-Oro, Bernard.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Sanchez, Ingen-Housz-Oro, Bernard.

Critical revision of the manuscript for important intellectual content: Chosidow, Antonicelli, Bernard.

Statistical analysis: Sanchez.

Study supervision: Bernard.

Conflict of Interest Disclosures: None reported.

References
1.
Hertl  M, Jedlickova  H, Karpati  S,  et al.  Pemphigus: S2 guideline for diagnosis and treatment—guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV).  J Eur Acad Dermatol Venereol. 2015;29(3):405-414.PubMedGoogle ScholarCrossref
2.
Joly  P, Mouquet  H, Roujeau  J-C,  et al.  A single cycle of rituximab for the treatment of severe pemphigus.  N Engl J Med. 2007;357(6):545-552.PubMedGoogle ScholarCrossref
3.
Lunardon  L, Tsai  KJ, Propert  KJ,  et al.  Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients.  Arch Dermatol. 2012;148(9):1031-1036.PubMedGoogle ScholarCrossref
4.
Wang  HH, Liu  CW, Li  YC, Huang  YC.  Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens.  Acta Derm Venereol. 2015;95(8):928-932.PubMedGoogle ScholarCrossref
5.
Joly  P, Maho-Vaillant  M, Prost-Squarcioni  C,  et al; French Study Group on Autoimmune Bullous Skin Diseases.  First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.  Lancet. 2017;389(10083):2031-2040.PubMedGoogle ScholarCrossref
6.
Cianchini  G, Lupi  F, Masini  C, Corona  R, Puddu  P, De Pità  O.  Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with long-term follow-up.  J Am Acad Dermatol. 2012;67(4):617-622.PubMedGoogle ScholarCrossref
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