Durable Remission of PemphigusWith a Fixed-Dose Rituximab Protocol

Giovanni W Putra11 2013 281

• Pemphigus and pemphigoid– rare group of potentially fatal dermatologic diseases – Caused by autoantibodies against adhesion

molecules of the epidermal and dermoepidermal junction.

– Require long-term systemic treatment with corticosteroids and other immunosuppressive agents

– The therapy can cause serious adverse effects, morbidity, and even mortality

Rituximab • Chimeric murine/human monoclonal antibody

that recognizes the B-lymphocyte surface protein CD20

• Rituximab has increasingly been reported to be effective in several autoimmune diseases, including autoimmune bullous dermatoses.

• optimal dosage regimen and predictor of response are unknown

• The objective of this study was to present our experience (clinical responses, relapse time) with rituximab therapy using the fixed-dose protocol in autoimmune bullous dermatoses.

Methods

• Study setting– Retrospective single-center study of all patients

with autoimmune bullous disease examined at Sunnybrook Health Sciences Centre, University of Toronto

– Received rituximab • 01 May 06 – 30 August 12

METHODS

• Patients – Data were collected retrospectively from the

medical records of patients with pemphigus diseases who had received rituximab.

– Initial indications for rituximab treatment • severe relapsing or recalcitrant disease that was

refractory to treatment • contraindication to the use of corticosteroids or other

immunosuppressive therapy.

Methods

• Treatment protocol– Rituximab was administered using a fixed-dose

modification of the RA protocol (1 gr iv on days 1 and 15, administered 6 months or more after induction if clinically warranted)

Assessment of Response to Treatment

Response to treatment was determined according to the definitions of an international consensus statement.• Complete remission off therapy (CR)

– The absence of new or established lesions while the patient is not receiving any systemic therapy for at least 2 months.

• Complete remission on therapy (CROT) – The absence of new or established lesions while the patient

is receiving minimal therapy. • Partial remission off therapy (PR)

– The presence of transient new lesions that heal within 1 week without treatment while the patient is not receiving any systemic therapy for at least 2 months.

• Partial remission on minimal therapy (PROT)– The presence of transient new lesions that heal

within 1 week while the patient is receiving minimal therapy

• Relapse/flare – The appearance of 3 or more new lesions each

month that do not heal spontaneously within 1 week or the extension of established lesions in a patient who has achieved disease control.

Outcome Measures

• Response to treatment• Times to relapse• Adverse reactions.

• The primary end points were time to failure and complete remission with or without treatment.

• Secondary end points included adverse events, long-term follow-up, and the number of treatment cycles received.

Charasteristic No (%)

Sex : Male 37 (40)

Female 55 (60)

Age at diagnosis, median (range) 43 (13-77)

Diagnosis : Pemphigus Vulgaris 84 (91)

Pemphigus Foliaceus 8 (9)

Site : Mucosal only 20 (22)

Mucocutaneous only 61 (66)

Cutaneous only 11 (12)

Previous treatment

Corticosteroids 90 (98)

Azathioprine 58 (63)

Characteristics of 92 Patients

Mycophenolate mofetil 48 (52)

Mycophenolate sodium 17 (18)

Intravenous immuglobulin 34 (37)

Cylosporine 2 (2)

Cylophosphamide 9 (10)

Methotrexate 9 (10)

Gold 3 (3)

Dapsone 9 (10)

Colchicine 2 (2)

Other 7 (8)

Duration of disease before first rituximab cycle, median (range ), mo

24 (0-256)

Age at time of first rituximab cycle, median (range), y

47 (17-77)

Response to Theraphy

No No. of Patients

(%)

Time since previous cycle, median

Remission CR/CROT

Concomitant corticosteroids

Concomitant immunosuppresive Therapies

Relapse

1 92 (100) … 74 (80) 63 (68) 64 (70) 56 (61)

2 54 (59) 12 (5-47) 50 (93) 18 (33) 21 (39) 23 (43)

3 22 (24) 10 (1-20) 21 (95) 4 (18) 7 (32) 6 (27)

4 7 (8) 8 (4-10) 7 (100) 1 (14) 1 (14) 3 (43)

Treatment

• Adjuvant treatment had shorter time of relapse (mean, 12 months) compare with no adjuvant treatment (mean, 40.6 months)

Relapse

• 36 patients (39%) who received just 1 rituximab cycle did not experience relapse.

• Status at 6 months after initiation of treatment cycles demonstrated that there was a significantly lower proportion of relapses after the second and third cycles compared with the first cycle (P < .05)

Adverse Effects of Treatment

• 8 occurrences (9%) of rash/pruritus• 5 occurrences (5%) of throat irritation• 2 episodes (2%) of chest tightness• 1 of headache (1%)• 1 of dizziness (1%)• 1 of hypotension (1%)

Most (61%) reactions occurred during the first treatment cycle.

Response to Treatment

• 64 patients (70%) CR• 26 patients (28%) CROT• 1 patient (1%) PR• 1 patient (1%) PROT

• Death 2 patients

Discussion

• Our results show that the fixed-dose modified RA protocol is effective in the treatment of pemphigus disorders. – 1/3 achieving complete remission, median time to

relapse was 15 months, 36 patients (39%) never experienced relapse

• Rituximab was well tolerated

• There is increasing evidence that rituximab may be useful as a first-line therapy.

• Lunardon, observed that rituximab therapy early in the course of disease is significantly more likely to lead to complete disease remission with no or minimal therapy.

• Patients who received adjuvant rituximab therapy had a shorter time to relapse. – The patients may have more severe disease– There may be a hypothetical effect of sustained

immunosuppression on immuno surveillance, permitting the subsequent development of an abnormal B-cell repertoire

– The patients may represent a group that for unknown reasons has abnormal barriers to B-cell maturation.

• The optimal dosing regimen for rituximab in autoimmune disorders has yet to be determined

• Rituximab has provided a major advance for patients who can gain access to it, it can be curative.

• Confirmation of the efficacy of rituximab in patients with pemphigus is required in larger and controlled trials.

• Issues remain regarding the financial constraints and funding by health payers for rituximab.

• Modification of rituximab dosage, low-dose maintenance therapy, and possibly even use as first-line therapy may be solutions to avoid the expense of long-term corticosteroid and immunosuppressive agents

Conclusions

• Rituximab is an effective therapy for severe or refractory autoimmune bullous diseases.

• The modified, fixed-dose RA protocol for rituximab was efficacious and well tolerated inpatients with pemphigus.

• Rituximab appears to be a safe therapeutic option with minimal serious adverse effects.

• Our results add further validity to the evaluation of rituximab as first line treatment of autoimmune bullous disorders.