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

Abstract

This case-series study of 11 patients with severe, difficult-to-treat pemphigus examines whether rituximab alone can be used long-term as maintenance therapy for prevention of relapse.

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. 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. 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. 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).

Table 1. Characteristics of 11 Patients With Rituximab Alone as Maintenance Therapy.

Patient No./ Pemphigus Type	Time From Diagnosis to First Rituximab Cycle, mo	Reason for First Rituximab Cycle	Duration of Corticosteroid Therapy After First Rituximab Cycle, mo	Time From Diagnosis to Maintenance Therapy With Rituximab Alone, mo	Rituximab Maintenance Therapy Cycles, No.	Total Duration of Rituximab Alone Maintenance Therapy, mo	Clinical Status at Last Follow-up	Duration of Follow-up After First Rituximab Cycle, mo
1/PV	194	CDD	1	201	6	30	CRoff	43
2/PV	24	CDD, AE	74	104	12	67	CROT	147
3/PV	33	CDD, AE	66	100	7	41	CRoff	120
4/PV	2	CDD	66	72	3	24	CRoff	106
5/PF	8	CDD +, AE	24	33	6	30	CRoff	84
6/PV	10	CRD, + AE	2	21	6	48	CRoff	78
7/PV	8	CDD	36	44	6	33	CRoff	82
8/PF	26	CDD, AE	2	32	5	25	CRoff	43
9/PV	2	CRD	13	20	5	30	CRoff	64
10/PV	2	CDD	12	13	5	26	CRoff	56
11/PV	4	CDD, AE	2	11	6	34	CROT	42

Abbreviations: AE, adverse event; CDD, corticosteroid-dependent disease; CRD, corticosteroid-refractory disease; CRoff, complete remission off therapy, including rituximab; CROT, complete remission on maintenance therapy with rituximab alone; PF, pemphigus foliaceus; PV, pemphigus vulgaris.

Table 2. Serum Anti–Dsg 1 and 3 Autoantibody Levels in 11 Patients Before and After Rituximab Alone as Maintenance Therapy^a.

Patient No.	At Diagnosis, U/mL		Before First Rituximab Cycle, U/mL		At Onset of Rituximab Alone Maintenance Therapy, U/mL		At Last Follow-up, U/mL
	Anti-Dsg1	Anti-Dsg3	Anti-Dsg1	Anti-Dsg3	Anti-Dsg1	Anti-Dsg3	Anti-Dsg1	Anti-Dsg3
1	ND	ND	Neg	64	Neg	Neg	Neg	Neg
2	ND	ND	ND	ND	Neg	69	Neg	Neg
3	Neg	181	Neg	205	Neg	32	Neg	14
4	65	76	83	35	Neg	Neg	Neg	Neg
5	ND	ND	124	Neg	Neg	Neg	Neg	Neg
6	Neg	101	Neg	94	Neg	Neg	Neg	Neg
7	37	95	26	Neg	Neg	Neg	ND	ND
8	285	36	166	Neg	19	Neg	Neg	Neg
9	202	166	33	94	Neg	Neg	Neg	Neg
10	41	142	50	76	Neg	44	Neg	Neg
11	Neg	163	Neg	179	Neg	Neg	Neg	Neg

Abbreviations: Dsg, desmoglein; ND, not determined; Neg, negative (ie, <14 U/mL).

^aSerum levels determined using enzyme-linked immunosorbent assay kits (MBL International Corporation). In all patients, serum anti–Dsg 1 and 3 autoantibody levels were negative before the last rituximab infusion.

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. 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.