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Delayed response of oral pemphigus vulgaris to rituximab treatment

European Journal of Dermatology. Volume 16, Number 3, 266-70, May-June 2006, Therapy

Summary

Author(s) : Andrea Niedermeier, Petra Wörl, Sandra Barth, Gerold Schuler, Michael Hertl , Universitätsklinikum Gießen und Marburg, Klinik für Dermatologie und Allergologie, Standort Marburg, Deutschhausstr. 9, 35037 Marburg, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Dermatologische Klinik mit Poliklinik, Hartmannstr. 14, 91052 Erlangen.

Summary : Rituximab is a monoclonal antibody directed against the CD20 antigen of B cells, which has been developed for the treatment of lymphomas and has been successfully used in the treatment of recalcitrant pemphigus vulgaris. Here, we report on a 26-year-old patient with an 18 month history of pemphigus vulgaris of the oral mucosa where treatment with rituximab led to a delayed but sustained therapeutic response. This case is of interest since most of the previous reports have described a more rapid clinical improvement of refractory pemphigus by rituximab treatment. The delayed clinical response to rituximab of the present case may be explained by the persistence of long-lived plasma cells that continued to produce pathogenic autoantibodies against desmoglein 3.

Keywords : IVIG, intravenous immunoglobulins, PF, pemphigus foliaceus, PV, pemphigus vulgaris

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ARTICLE

Auteur(s) : Andrea Niedermeier¹, Petra Wörl², Sandra Barth², Gerold Schuler², Michael Hertl¹

¹Universitätsklinikum Gießen und Marburg, Klinik für Dermatologie und Allergologie, Standort Marburg, Deutschhausstr. 9, 35037 Marburg
²Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Dermatologische Klinik mit Poliklinik, Hartmannstr. 14, 91052 Erlangen

accepté le 24 Janvier 2006

Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and mucous membranes associated with the production of IgG autoantibodies directed against distinct cell-cell adhesion molecules of desmosomes, i.e. desmogleins (Dsg) 1 and 3 [1-3]. Until recently, the therapeutic armament in pemphigus consisted of systemic corticosteroids, usually in the form of oral prednisone, combined with immunosuppressive agents, e.g. azathioprine, mycophenolate mofetil or cyclophosphamide. In severe cases, unresponsive to systemic glucocorticosteroids and immunosuppressives, immunoadsorption has evolved as an additional option to achieve an immediate reduction of the titers of circulating autoantibodies [4]. High-dose intravenous immunoglobulin was another option for therapy resistant disease [5]. Recently, several case reports showed that rituximab was a successful treatment for pemphigus unresponsive to other therapeutic options (table 1) [6-16]. Rituximab is a genetically engineered monoclonal Ab with human IgG₁ constant regions and murine light and heavy-chain variable regions specific for CD20, which is located on pre-B, mature B lymphocytes and most B-cell neoplasms [17, 18]. After binding to membrane-bound CD20, rituximab mediates lysis via both complement-dependent and antibody-dependent cellular cytotoxicity, resulting in rapid depletion of peripheral B cells. Recovery begins after 6-9 months and B-cell counts return to normal within 9-12 months. The drug is well tolerated with toxicity mainly related to rare allergic reactions (and tumour lysis syndrome when used in malignancy). Rituximab was initially developed for the treatment of lymphoma and was the first monoclonal antibody approved for the treatment of cancer in 1997 [19]. Since then, more than 300,000 patients with relapsed or refractory, low-grade or follicular non-Hodgkin lymphoma (NHL) have been treated [20]. Despite the lack of official approval, rituximab has been successfully used to treat various refractory autoimmune diseases. In addition to pemphigus vulgaris and foliaceous, these include idiopathic thrombocytopenic purpura [21], autoimmune haemolytic anaemia [22], rheumatoid arthritis [23], systemic lupus erythematosus [24, 25], myasthenia gravis [26], Wegener’s granulomatosis [27-29], Sjögren’s syndrome [30, 31], dermatomyositis [32, 33] and paraneoplastic pemphigus [34, 35]. Initially, there were two papers reporting the successful treatment of the underlying B-cell-malignancy with rituximab in paraneoplastic pemphigus, that showed a nearly vs. total clearance of the mucocutaneous lesions within two and six months respectively [34, 35].

Case report

(Table 1)A 26-year-old patient was referred to our department for the treatment of recalcitrant PV. Clinically, chronic gingivitis and blisters that appeared at several sites of the oral mucosa led to the diagnosis of PV, which was then confirmed by histology and immunohistochemistry. The patient then received prednisolone (initially 80 mg/day) in conjunction with cyclophosphamide (50 mg/day) and azathioprine (100 mg/day). Later on, plasmapheresis, which was performed three times per month, did not lead to an improvement of the condition. When the patient presented in our department she showed extensive ulcerations and erosions of the soft palate, the uvula, the buccal mucosa and the lateral aspect of the tongue (figure 1). No signs of cutaneous involvement were visible. Immunosuppressive treatment was changed to mycophenolate mofetil 3 g/day in conjunction with prednisolone 30 mg/day and treatment with 4 cycles of rituximab (375 mg/m² body surface area) in weekly intervals was started. Treatment with mycophenolate mofetil and prednisolone was continued after completion of the rituximab cycles. Three months later there was no clinical improvement and the patient still presented with persistent ulcers on the buccal mucosa and on the soft palate. Ten months after initiation of rituximab administration the patient showed marked improvement of the erosions on the buccal mucosa. After a further two months the buccal mucosa was almost completely cleared of lesions and only on the lateral aspect of the tongue was a residual erosion visible (figure 1B). During this period prednisolone was tapered from 30 mg/day to 5 mg/day and mycophenolate mofetil from 3 to 2 g/day (Table 2). Flowcytometric analysis of the lymphocyte subsets showed that shortly after therapy and more than seven months later, CD19 positive peripheral B cells were completely depleted. By ELISA, IgG antibodies targeting Dsg3, the autoantigen of PV, were initially detected at elevated titers and showed a remarkable decrease within 6 weeks (figure 2). Eventually, fifteen months after completion of rituximab treatment, the patient showed a complete regression of the oral erosions accompanied by the absence of anti-Dsg3 antibodies despite the recovery of peripheral CD20+ B cells (figure 2). Currently, her immunosuppressive baseline therapy consists of mycophenolate mofetil 2 g/day (table 2). As reported previously [36], total IgG levels were not affected by rituximab treatment.
Table 1 Synopsis of recent reports on the efficacy of rituximab in the treatment of recalcitrant pemphigus

Disease	pts	Sex/Age (y)	Du (y)	Extent of disease Before R treatment	Previous treatments	Medication at onset of R treatment	Medication after R treatment	Rem after R treat-ment (w)	CR/PR	Dosage	Ref.
PV	1	F 29	< 3	80% of the BSA	P, MP, AZA, CP, PL, IVIG	IVIG, P 1 mg/kg/d MMF	CP 2 mg/kg/d P 1 mg/kg/d	19	PR	6 × 375 mg/m²	[6]
PV	1	F 54	13	No description	P, AZA, MMF	P 30 mg/d	P 5 mg/d	≤ 4	CR	4 × 375 mg/m²	[7]
PV	1	M 54	nd	Scalp, face and feet	P, AZA, MMF, IVIG, CP, PL	P (up to 2 mg/kg/d) MMF (up to 3 g/d)	P 15 mg/d MMF red. + disc. after 4 m	≤ 4	CR	4 × 375 mg/m²	[8]
PV	1	F 53	11	Chest and thighs	P, MTX, CP	MP 60 mg/d CP 100 mg/d	Treatment red.	16	CR	4 × 375 mg/m²	[9]
PF	1	F 56	2.5	Trunk, head, arms	MP, AZA, CYC, P, CP, DEXA	DEXA pulse 100 mg for 3 d in 4-6 w intervals	No treatment	6	CR	4 × 375 mg/m²	[10]
PV	3	F 34	14	I course: oral mucosa genitalia, 30% of the BSA II course: oral mucosa, genitalia	P, AZA, IVIG, CYC, MMF, gold, D, MTX	I course: P 0,6 mg/kg/d CP i.v. 500 mg/m²/m II course: P 1 mg/kg/d, AZA 100 mg/d	I course: P 0.3 mg/kg/d II course: P 1 mg/kg/d, AZA 100 mg/d	I course: 16, persisted for 5 m, II course: 3	PR	2 × (4 × 375 mg/m²⁾	[11]
		F 42	5	I course: oropharyngeal,, laryngeal, genital mucosa, entire integument II course: eyes, oropharynx, genitalia, body	P, MTX, AZA, CYC, MMF, IVIG, extracorporeal photopheresis	I course: CYC 150 mg/d + MP boluses 500 mg/d for 3 d, P 2 mg/kg/d II course: P 25 mg/d, CYC 150 mg/d, MMF 3 g/d	I course: CYC 150 mg/d + MP boluses 500 mg/d for 3 d; P red. from w 10 II course: P 25 mg/d	I course: 16 II course: 7	CR	2 × (4 × 375 mg/m²)
		M 20	2	Entire scalp, face and >50% of the trunk	P, D, MP, MMF, gold, IVIG, PL	P 1 mg/kg/d	P 1 mg/kg/d, 0.5 mg/kg/d after 6 m	16	CR	4 × 375 mg/m²
PV	1	M 39	nd	Oral, pharyngeal, anal mucosa, 70% of the BSA	P, AZA, PL	P 2 mg/kg/d	P red.	6	CR	4 × 375 mg/m²	[12]
PV	3	M 51	nd	30% of the BSA	P, MTX, D, MIN, AZA, MMF, IVIG, CP	P 30 – 60 mg/d CP 2.5 mg/kg/d	CP 2.5 mg/kg/d P red. P, CP disc. at 9 +10 m after R	≤ 4	CR	4 × 375 mg/m²	[13]
		M 37	4	10 – 15% of the BSA	CP, P, PL, D, IVIG	CP 2 mg/kg/d IVIG every 6 w P 10-20 mg/d	CP 2 mg/kg/d P 10-20 mg/d	20	CR	4 × 375 mg/m²
		F 47	1	Oral mucosa, scalp, neck	AZA, MMF, IVIG, CP	I course: CP 1.6 mg/kg/d II course: CP 1.4 mg/kg/d	I course: CP 1.6 mg/kg/d II course: CP 1.2-0.5 mg/kg/d	44	PR	2 × (4 × 375 mg/m²)
PV	1	F 55	13	Chest, back, axillae and inguinal areas	MP, AZA, CP, MTX, MMF, IVIG	MP 8 mg/d	MP 6 mg/d	10	CR	4 × 375 mg/m²	[14]
PV	5	F 60	8	Oral mucosa, larynx	P, MMF, AZA	MMF 2 g/d P 25 mg/d	MMF 0,5 g/d	< 15	CR	4 × 375 mg/m²	[15]
PV		F 26	3	Oral and genital mucosa	P, MMF, AZA, MTX	MTX 30 mg/w P 20 mg/d	MTX 10 mg/w P 5 mg/d	< 20	PR	4 × 375 mg/m²
PV		F 27	3	Oral mucosa	P, MMF, AZA, MTX, Etanercept	MTX 20 mg/w P 20 mg/d	MTX 20 mg/w P 5 mg/d	< 10	PR	4 × 375 mg/m²
PF		M 67	6	Scalp, face, chest, back	P, AZA, MMF	MMF 2 g/d P 20 mg/d	No treatment	< 20	CR	4 × 375 mg/m²
PV		F 57	14	Scalp, entire trunk, arms, oral mucosa	P, AZA, MMF	MMF 2 g/d P 10 mg/d	P 1 mg/d	< 10	CR	4 × 375 mg/m²
PV	1	F 37	4	Trunk, vagina, mouth	P, AZA, MMF, CYC, CP, IVIG, MP pulses	P 14 mg/d MMF 4 g/d MP 1 g/d for 3 d	P 4 mg/d	12 impr. 47 CR	CR	4 × 375 mg/m² + 375 mg/m² every 3 m	[16]

Table 2 Clinical course of the patient

Days after R	Clinical findings	Medication	anti-Dsg 3 IgG (PIV)
1	Large erosions on the buccal mucosa,	MMF 3 g/d	178
uvula, palate	P 30 mg/d
45	Extensive erosions on the soft plate and	MMF 3 g/d	177
the buccal mucosa	P 30 mg/d
109	Erosions on the right buccal mucosa	MMF 3 g/d	40
and the right side of the soft palate	P 20 mg/d
280	Erosions on the right and left buccal mucosa	MMF 2 g/d	8 (negative)
P 5 mg/d
359	Residual erosions on the lateral aspect of the tongue	MMF 2g/d	19 (negative)
464	Complete remission, occasionally blisters on the mucous membranes	MMF 2g/d	11 (negative)

Discussion

In pemphigus, B cell clones secreting Dsg antibodies seem crucial in the development of the disease. Therefore, it was supposed that therapeutic depletion of B cells would be an effective treatment of the disease. In our patient, complete B cell depletion was achieved after the fourth cycle of rituximab and persisted for more than three months. However, Dsg3 specific IgG autoantibodies were still detectable more than three months after completion of rituximab treatment. The observed presence of Dsg3-specific antibodies despite rituximab treatment implies the persistence of autoantibody-producing long-lived plasma cells. These may secrete antibodies for a long time in the absence of detectable memory cells [37]. Long-lived plasma cells do not express CD20 and thus are not affected by rituximab treatment [38].

There is a body of case reports on the effect of rituximab treatment in refractory pemphigus table 1[6-16]. Established immunosuppressive treatments failed in all reported patients. Based on the described efficacy of rituximab in refractory PV [6-8] and pemphigus foliaceous [10], we performed treatment with rituximab in a young patient with refractory mucosal dominant PV. Total levels of serum IgG (and IgA) were unchanged in our patient, which is in line with previous reports [36]. In contrast to most previous reports, praising rituximab as a highly promising treatment for PV [6-14], our results suggest more caution with regard to the outcome of the treatment. It took about ten months until our patient, who presented with oral lesions only, showed marked clinical improvement. Noteworthy, even after 12 months, the patient presented with residual erosions at the lateral aspect of the tongue despite decreasing autoantibody titers. One might argue that the slow clinical improvement of PV in the present patient is unrelated to rituximab treatment and rather due to treatment with mycophenolate mofetil. However, the lack of response to a broad range of immunosuppressants including mycophenolate mofetil over more than five months prior to rituximab treatment strongly suggests that rituximab finally led to the observed clinical improvement.

In a case described by Salopek [6] a PV patient initially presented with oral ulcers and then developed extensive blisters and erosions involving more than 10% of the body surface area. After rituximab treatment, this patient showed 95% re-epithelialization of the body surface area. From the report it is not clear whether there were persistent mucosal lesions. One of the three patients treated by Morrison still had mild oral disease 9 months after completion of therapy [13]. Two of the three patients observed by Dupuy [11] had persistent significant mucosal lesions after therapy.

Based on the observations that rituximab may be less effective in the treatment of mucosal PV than in the treatment of cutaneous PV and PF, further studies are necessary to show whether rituximab exerts its therapeutic effect only by reduction of pathologic autoantibodies or by additional mechanisms of action. For now, one has to be aware when treating with rituximab, that the long-term consequences of prolonged B cell depletion with regard to infections and tumour development are not yet fully understood.

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