Rituximab in the Treatment of Patients With Bullous Pemphigoid

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00286325
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 8
• Location: 1
• Arm: 1
• Duration (Months): 60
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will determine the safety of treatment of bullous pemphigoid in patients resistant to therapy with systemic corticosteroids, with rituximab plus systemic corticosteroids.

Condition or Disease	Intervention/Treatment	Phase
Bullous Pemphigoid	Drug: Rituximab	Phase 1/Phase 2

Detailed Description

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized clinically by the presence of severely itchy, tense blisters located over the trunk and extremities. BP is the most common of the autoimmune blistering diseases with an incidence of approximately 10 per 1,000,000 population(1;2). In addition, BP occurs more frequently in the elderly. Routine histopathology reveals a sub-epidermal blister most often with large numbers of eosinophils. Direct immunofluorescence of the skin of patients with BP reveals a linear band of C3 and IgG at the basement membrane zone. Examination of the sera of patients shows the presence of a circulating anti-basement membrane zone autoantibody. This antibody has been found to be directed against a 180 kd protein of the basement membrane zone type XVII collagen (BPAg2) and against a 230 kd protein (BPAg1) found in the epidermal hemi-desmosome(3;4).

BP is a severe disease most often requiring therapy with high dose systemic corticosteroids (0.75 - 1.0 mg/kg/day) often for months(5). In addition, relapses are common and the additional use of immunosuppressive drugs such as azathioprine, methotrexate, cyclosporine A and others are needed to minimize the dose of systemic corticosteroids. The 1-year mortality of BP has been estimated to range from 10 - 30%(1;6). Currently treatment of patients with BP consists of initial use of systemic corticosteroids (0.75 - 1.0 mg/kg/day). Control of symptoms and new blister formation is most often achieved within 1 month and systemic corticosteroids are then tapered. As many as 33 - 50% of patients may not be able to be tapered to clinically acceptable levels of systemic corticosteroids, requiring the addition of systemic immunosuppression often with azathioprine. Approximately 66% of patients require long term treatment with immunosuppressive medication to maintain control of their blistering.(5;7;8) The need for long term systemic corticosteroid therapy often with systemic immunosuppression in an elderly population results in a significant morbidity and mortality in patients with BP. New therapeutic interventions that would potentially allow for the more rapid discontinuation of prednisone, avoidance of systemic immuno- suppression and perhaps earlier clinical relapse would be of substantial benefit to patients with BP. The clinical and laboratory data has demonstrated that BP is an autoantibody mediated blistering disease. Taken together these observations suggest that the use of anti-CD20 antibody (Rituxan) may be useful in the treatment of patients with BP. We have previously treated a patient with BP and graft versus host disease with anti-CD20 and anti-CD25 and were able to achieve clinical and serological remission within 4 weeks of initiation of therapy(9). In addition, others and we have successfully utilized Rituxan for the treatment of pemphigus vulgaris, another autoantibody mediated, autoimmune blistering disease(10-15)

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Rituximab in the Treatment of Patients With Bullous Pemphigoid
• Study Start Date: Mar 1, 2005
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Rituximab Open label study all subjects treated with rituximab	Drug: Rituximab; Infusion of 1000 mg of rituximab on day 0 and day 14; Other Names: rituxan

Outcome Measures

Primary Outcome Measures

1. Primary Safety Endpoint [1 year]

   The primary safety endpoint is the occurrence of treatment emergent adverse events including infections, infusion reactions and disease progression. These were determined by clinical evaluation and laboratory questions. Disease progression is defined as development of new blisters despite therapy. These are reported as the number of participants with a study related SAE.

Secondary Outcome Measures

1. Number of Days to Cessation of New Blister [1 year]

   The first study visit in which patient reported and was confirmed to have no new blister or lesion formation .

2. Systemic Corticosteroid Dose of 25% of Starting Dose or 10 mg/Day by Week 24 [24 weeks]

   Subject systemic corticosteroid dosage at week 24 was 25% of starting dose or 10 mg/day of prednisone or less

3. IgG Anti Bullous Pemphigoid (BP) 180 Measured in Units by ELISA at Week 24. [Week 0 and at 24 weeks]

   IgG antibodies against BP 180 measured in units (by ELISA) for each participant at week 0 compared to value at week 24,

4. B Cell Number at Week 24 [Week 0 and at 24 weeks]

   Peripheral blood B cell number at week 24 compared to B cell number at week 0

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with autoimmune blistering skin diseases with clinical, histologic and immunological criteria confirming the diagnosis of bullous pemphigoid

• Ongoing disease activity on 17.5 mg/day of prednisone or more

Exclusion Criteria:

• Current use of other immunosuppressive therapy such as azathioprine, cytoxan or mycophenolate mofetil within the last 4 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University
• Genentech, Inc.

Investigators

• Principal Investigator: Russell Hall, III, MD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Anolik JH, Campbell D, Felgar RE, Young F, Sanz I, Rosenblatt J, Looney RJ. The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 2003 Feb;48(2):455-9.
• Bernard P, Bedane C, Bonnetblanc JM. Anti-BP180 autoantibodies as a marker of poor prognosis in bullous pemphigoid: a cohort analysis of 94 elderly patients. Br J Dermatol. 1997 May;136(5):694-8.
• Cooper HL, Healy E, Theaker JM, Friedmann PS. Treatment of resistant pemphigus vulgaris with an anti-CD20 monoclonal antibody (Rituximab). Clin Exp Dermatol. 2003 Jul;28(4):366-8.
• Diaz LA, Ratrie H 3rd, Saunders WS, Futamura S, Squiquera HL, Anhalt GJ, Giudice GJ. Isolation of a human epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome. J Clin Invest. 1990 Oct;86(4):1088-94.
• Dupuy A, Viguier M, Bédane C, Cordoliani F, Blaise S, Aucouturier F, Bonnetblanc JM, Morel P, Dubertret L, Bachelez H. Treatment of refractory pemphigus vulgaris with rituximab (anti-CD20 monoclonal antibody). Arch Dermatol. 2004 Jan;140(1):91-6.
• Gault MH, Purchase L. Would decreased aluminum ingestion reduce the incidence of Alzheimer's disease? CMAJ. 1992 Sep 15;147(6):845-7.
• Giudice GJ, Liu Z, Diaz LA. An animal model of bullous pemphigoid: what can it teach us? Proc Assoc Am Physicians. 1995 Jul;107(2):237-41. Review.
• Goebeler M, Herzog S, Bröcker EB, Zillikens D. Rapid response of treatment-resistant pemphigus foliaceus to the anti-CD20 antibody rituximab. Br J Dermatol. 2003 Oct;149(4):899-901.
• Gupta N, Kavuru S, Patel D, Janson D, Driscoll N, Ahmed S, Rai KR. Rituximab-based chemotherapy for steroid-refractory autoimmune hemolytic anemia of chronic lymphocytic leukemia. Leukemia. 2002 Oct;16(10):2092-5.
• Herrmann G, Hunzelmann N, Engert A. Treatment of pemphigus vulgaris with anti-CD20 monoclonal antibody (rituximab). Br J Dermatol. 2003 Mar;148(3):602-3.
• Khumalo NP, Murrell DF, Wojnarowska F, Kirtschig G. A systematic review of treatments for bullous pemphigoid. Arch Dermatol. 2002 Mar;138(3):385-9. Review.
• Korman NJ. Bullous pemphigoid. The latest in diagnosis, prognosis, and therapy. Arch Dermatol. 1998 Sep;134(9):1137-41. Review.
• Leandro MJ, Edwards JC, Cambridge G. Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis. 2002 Oct;61(10):883-8.
• Liu Z, Diaz LA, Troy JL, Taylor AF, Emery DJ, Fairley JA, Giudice GJ. A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. J Clin Invest. 1993 Nov;92(5):2480-8.
• Maloney DG, Grillo-López AJ, Bodkin DJ, White CA, Liles TM, Royston I, Varns C, Rosenberg J, Levy R. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol. 1997 Oct;15(10):3266-74.
• McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33.
• Nousari HC, Anhalt GJ. Pemphigus and bullous pemphigoid. Lancet. 1999 Aug 21;354(9179):667-72. Review.
• Pestronk A, Florence J, Miller T, Choksi R, Al-Lozi MT, Levine TD. Treatment of IgM antibody associated polyneuropathies using rituximab. J Neurol Neurosurg Psychiatry. 2003 Apr;74(4):485-9.
• Piro LD, White CA, Grillo-López AJ, Janakiraman N, Saven A, Beck TM, Varns C, Shuey S, Czuczman M, Lynch JW, Kolitz JE, Jain V. Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1999 Jun;10(6):655-61.
• Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994 Jan 15;83(2):435-45.
• Roujeau JC, Lok C, Bastuji-Garin S, Mhalla S, Enginger V, Bernard P. High risk of death in elderly patients with extensive bullous pemphigoid. Arch Dermatol. 1998 Apr;134(4):465-9.
• Rzany B, Partscht K, Jung M, Kippes W, Mecking D, Baima B, Prudlo C, Pawelczyk B, Messmer EM, Schuhmann M, Sinkgraven R, Büchner L, Büdinger L, Pfeiffer C, Sticherling M, Hertl M, Kaiser HW, Meurer M, Zillikens D, Messer G. Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age. Arch Dermatol. 2002 Jul;138(7):903-8.
• Salopek TG, Logsetty S, Tredget EE. Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder. J Am Acad Dermatol. 2002 Nov;47(5):785-8.
• Stanley JR, Hawley-Nelson P, Yuspa SH, Shevach EM, Katz SI. Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia. Cell. 1981 Jun;24(3):897-903.
• Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood. 2001 Aug 15;98(4):952-7.
• Stasi R, Stipa E, Forte V, Meo P, Amadori S. Variable patterns of response to rituximab treatment in adults with chronic idiopathic thrombocytopenic purpura. Blood. 2002 May 15;99(10):3872-3.
• Szabolcs P, Reese M, Yancey KB, Hall RP, Kurtzberg J. Combination treatment of bullous pemphigoid with anti-CD20 and anti-CD25 antibodies in a patient with chronic graft-versus-host disease. Bone Marrow Transplant. 2002 Sep;30(5):327-9.
• Venning VA, Wojnarowska F. Lack of predictive factors for the clinical course of bullous pemphigoid. J Am Acad Dermatol. 1992 Apr;26(4):585-9.
• Wojnarowska F, Kirtschig G, Highet AS, Venning VA, Khumalo NP; British Association of Dermatologists. Guidelines for the management of bullous pemphigoid. Br J Dermatol. 2002 Aug;147(2):214-21.
• Zaja F, Iacona I, Masolini P, Russo D, Sperotto A, Prosdocimo S, Patriarca F, de Vita S, Regazzi M, Baccarani M, Fanin R. B-cell depletion with rituximab as treatment for immune hemolytic anemia and chronic thrombocytopenia. Haematologica. 2002 Feb;87(2):189-95. Erratum in: Haematologica 2002 Mar;87(3):336.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00286325
• Other Study ID Numbers: Pro00013763
• First Posted: Feb 3, 2006
• Last Update Posted: Apr 11, 2013
• Last Verified: Sep 1, 2012

• Additional relevant MeSH terms: Pemphigoid, Bullous; Rituximab

Study Results

Participant Flow

Recruitment Details	Patients with bullous pemphigoid were recruited in dermatology clinics from 2005 - 2009.
Pre-assignment Detail	Patient were screened for appropriate diagnosis, disease activity, prednisone dosage before entry into the study

Arm/Group Title	Treated
Arm/Group Description	Open label study subjects all treated with rituximab
Period Title: Overall Study
STARTED	8
COMPLETED	8
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treated
Arm/Group Description	Open label study subjects all treated with rituximab
Overall Participants	8
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 62.5%
>=65 years	3 37.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (9.7)
Sex: Female, Male (Count of Participants)
Female	6 75%
Male	2 25%
Region of Enrollment (participants) [Number]
United States	8 100%

Outcome Measures

1. Secondary Outcome

Title	Number of Days to Cessation of New Blister
Description	The first study visit in which patient reported and was confirmed to have no new blister or lesion formation .
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Excluded subject with diagnosis of epidermolysis bullosa acquisita , made after study entry.

Arm/Group Title	Treated
Arm/Group Description	Open label study subjects all treated with rituximab
Measure Participants	7
Median (Full Range) [Days]	57

2. Primary Outcome

Title	Primary Safety Endpoint
Description	The primary safety endpoint is the occurrence of treatment emergent adverse events including infections, infusion reactions and disease progression. These were determined by clinical evaluation and laboratory questions. Disease progression is defined as development of new blisters despite therapy. These are reported as the number of participants with a study related SAE.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The safety analysis was performed on all subjects

Arm/Group Title	Treated
Arm/Group Description	Open label study subjects all treated with rituximab
Measure Participants	8
Treatment emergent adverse events	0 0%
Infusion reactions	0 0%
Disease Progression	1 12.5%

3. Secondary Outcome

Title	Systemic Corticosteroid Dose of 25% of Starting Dose or 10 mg/Day by Week 24
Description	Subject systemic corticosteroid dosage at week 24 was 25% of starting dose or 10 mg/day of prednisone or less
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Excluded subject with epidermolysis bullosa acquisita diagnosed after study entry.

Arm/Group Title	Treated
Arm/Group Description	Open label study subjects all treated with rituximab
Measure Participants	7
Number [participants]	7 87.5%

4. Secondary Outcome

Title	IgG Anti Bullous Pemphigoid (BP) 180 Measured in Units by ELISA at Week 24.
Description	IgG antibodies against BP 180 measured in units (by ELISA) for each participant at week 0 compared to value at week 24,
Time Frame	Week 0 and at 24 weeks

Outcome Measure Data

Analysis Population Description

Excluded subject with diagnosis of epidermolysis bullosa acquisita made after study entry, excluded one subject with no circulating antibodies measured at either time point.

Arm/Group Title	Treated
Arm/Group Description	Open label study subjects all treated with rituximab
Measure Participants	6
Median (Full Range) [Elisa Units]	40.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treated
	Comments	Wilcoxon comparing week zero antibody value in units to week 24 antibody value in units
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0156
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	B Cell Number at Week 24
Description	Peripheral blood B cell number at week 24 compared to B cell number at week 0
Time Frame	Week 0 and at 24 weeks

Outcome Measure Data

Analysis Population Description

excluded subject with epidermolysis bullosa acquisita diagnosed after study entry

Arm/Group Title	Treated
Arm/Group Description	Open label study subjects all treated with rituximab
Measure Participants	7
Median (Full Range) [B cells per microliter]	3.99

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treated
	Comments	Comparison of B cell number at week 0 to b cell number in participants at week 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0078
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	Adverse events related or possibly related to study drug
Arm/Group Title	Treated
Arm/Group Description	Open label study subjects all treated with rituximab
All Cause Mortality
	Treated
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treated
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Other (Not Including Serious) Adverse Events
	Treated
	Affected / at Risk (%)	# Events
Total	0/8 (0%)

Limitations/Caveats

Open label trial of rituximab in the treatment of 7 patients with the autoimmune blistering disease bullous pemphigoid.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.