- Email: [email protected]
Clinical outcome and safety of rituximab therapy for pemphigoid diseases
Journal Pre-proof Clinical outcome and safety of rituximab therapy for pemphigoid diseases Napatra Tovanabutra, M.D., Aimee S. Payne, M.D., Ph.D. PII:
S0190-9622(19)33113-5
DOI:
https://doi.org/10.1016/j.jaad.2019.11.023
Reference:
YMJD 14005
To appear in:
Journal of the American Academy of Dermatology
Received Date: 13 August 2019 Revised Date:
2 November 2019
Accepted Date: 8 November 2019
Please cite this article as: Tovanabutra N, Payne AS, Clinical outcome and safety of rituximab therapy for pemphigoid diseases, Journal of the American Academy of Dermatology (2019), doi: https:// doi.org/10.1016/j.jaad.2019.11.023. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
Article type: Research Letter Title: Clinical outcome and safety of rituximab therapy for pemphigoid diseases Napatra Tovanabutra M.D.1,2, Aimee S. Payne M.D., Ph.D.1 1
Department of Dermatology, University of Pennsylvania, Philadelphia, PA Department of Internal Medicine, Division of Dermatology, Chiang Mai University, Chiang Mai, Thailand
2
Corresponding author: Aimee S. Payne, M.D., Ph.D. 421 Curie Blvd 1009 Biomedical Research Building Philadelphia, PA 19104 Email: [email protected] Manuscript word count: 504 References: 2 Figures: 1 Tables: 1 Supplemental material: Mendeley Funding source: This work was supported by Faculty of Medicine, Chiang Mai University, Thailand. Conflict of Interest: ASP is a co-founder and equity holder in Cabaletta Bio, Inc., focused on targeted immunotherapy of pemphigus. She is an inventor on patents licensed by Novartis and Cabaletta Bio for cellular immunotherapy of autoimmune diseases and has previously served as a consultant for Syntimmune, Inc. These organizations had no involvement in the research reported in this study. NT has no conflict of interests.
The term “pemphigoid” encompasses a group of subepidermal autoimmune blistering diseases, including bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA), and others. Fatal complications can occur from disease or its therapy. Rituximab (RTX) is FDA-approved for pemphigus vulgaris (PV), but its role in pemphigoid is unclear due to the relative paucity of reported cases. This retrospective case series included all (n=38) pemphigoid patients at the University of Pennsylvania followed at least 1 year after RTX or until death (patient demographics, Supplemental Table S1). Outcomes followed consensus definitions1,2 (Supplemental Methods/Table S2). The primary endpoint was complete remission (CR). Secondary endpoints were CR off therapy (CROT), corticosteroid dose, relapse, serious adverse events (SAEs), and autoantibody titers. RTX outcomes are detailed in Table 1/Supplemental Table S3. Overall, 29/38 (76%) pemphigoid patients achieved CR after a median of 1 RTX cycle, with a median time to CR of 14.3 months (95% CI 9.7-44.1). Considering the more rigorous endpoint of CROT, 15/38 (39%) patients achieved CROT after a median of 2 RTX cycles. No substantive difference in CR/CROT rates was observed among pemphigoid subtypes. CR/CROT was achieved by 53%/27% versus 52%/9% of patients who received RA-dose (n=15) versus lymphoma-dose (n=23) for the first RTX cycle (p>.99/p=0.19). Median prednisone dose decreased from 20 to 3.5 mg/day (p<.001) and 20 to 4.5 mg/day (p=.001) in BP and non-BP patients (Figure 1). Longitudinal autoantibody titers were available for 13 BP patients. Median antiBP180 titer decreased from 100.2 to 11.9 U/ml twelve months after RTX (p<0.05), suggesting that anti-BP180 antibodies are predominantly produced by short-lived plasma cells (Supplemental Figure S1).
17/29 (59%) patients relapsed a median of 6.2 months after achieving CR (Supplemental Figure S2A). Surprisingly, BP patients exhibited a 4.8-fold hazard ratio for relapse (95% CI 1.34-17.4; p=0.007) (Supplemental Figure S2B), perhaps because minimal therapy was tapered in 67% of BP versus 17% of non-BP patients, and relapses occurred in 8/9 pemphigoid patients (89%) who tapered doses of minimal therapy compared to 3/9 (33%) who maintained minimal therapy doses (p<0.05). Additional RTX cycles were prescribed to improve outcome or treat relapse (Supplemental Table S3). 100% who relapsed after achieving CR (n=8) and 54% who received RTX to improve response (n=13) attained CR after the second RTX cycle, indicating that outcomes are significantly different based on the indication for re-treatment (p=0.02). Of 7 infectious SAEs in 5 patients (13%), 5 occurred in patients receiving concomitant prednisone ≥7.5 mg/day and/or adjunctive immunosuppressives (Supplemental Table S4). Two deaths (primary CNS lymphoma, heart failure) were deemed unrelated to RTX. Collectively, these data indicate RTX is effective in inducing CR/CROT in 76%/39% of pemphigoid patients, and suggest that its primary therapeutic benefit is its steroid-sparing effect. No dose-based difference in RTX efficacy is observed. Relapse after achieving initial CR occurs in the majority (59%) of patients, but might be reduced through maintenance therapy with low-dose prednisone or dapsone. These data guide clinical expectations for the use of RTX in pemphigoid and may help to inform the design and endpoints of future prospective clinical trials.
Acknowledgments: The authors would like to thank Donald Tsai, MD, Victoria Werth, MD, and John Stanley, MD for the clinical treatment of patients in this study. This work was supported by the Faculty of Medicine, Chiang Mai University, Thailand. Funding/Sponsor was involved? Design and conduct of the study
Yes___
No_x_
Collection, management, analysis and interpretation of data
Yes___
No_x_
Preparation, review, or approval of the manuscript
Yes___
No_x_
Decision to submit the manuscript for publication
Yes___
No_x_
ASP is a co-founder and equity holder in Cabaletta Bio, Inc., focused on targeted immunotherapy of pemphigus. She is an inventor on patents licensed by Novartis and Cabaletta Bio for cellular immunotherapy of autoimmune diseases and has previously served as a consultant for Syntimmune, Inc. These organizations had no involvement in the research reported in this study. NT has no conflict of interests. Author Contributions: Napatra Tovanabutra and Aimee S. Payne 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: Napatra Tovanabutra and Aimee S. Payne. Acquisition, analysis, and interpretation of data: Napatra Tovanabutra and Aimee S. Payne. Drafting of the manuscript: Napatra Tovanabutra and Aimee S. Payne. Critical revision of the manuscript for important intellectual content: Napatra Tovanabutra and Aimee S. Payne. Statistical analysis: Napatra Tovanabutra and Aimee S. Payne. Obtained funding: N/A Administrative, technical, or material support: Aimee S. Payne. Study supervision: Aimee S. Payne.
References 1.
2.
Murrell DF, Daniel BS, Joly P, et al. Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts. Journal of the American Academy of Dermatology. 2012;66(3):479-485. Murrell DF, Marinovic B, Caux F, et al. Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts. Journal of the American Academy of Dermatology. 2015;72(1):168-174.
Figure legend. Figure 1. RTX is an effective steroid-sparing therapy in pemphigoid. Significant reduction in daily prednisone dose 12 months after the first cycle of RTX in patients with BP and other pemphigoid diseases. *, p≤.05; **, p≤.01; ***, p≤.001; ns, not significant compared to baseline values.
Table 1. Treatment parameters and outcomes. Cycle 1
Cycle 2
Cycle 3
Cycle 4
Overall best response 38
Number of patients 38 21 11 4 Pemphigoid subtype BP 21 11 6 2 21 MMP 9 3 2 2 9 Other pemphigoid 8 7 3 0 8 Dose Lymphoma 23 16 9 4 54 RA 15 5 2 0 22 Purpose of treatment Improve outcome 13 3 2 18 Treat relapse after 18 8 8 2 achieving CR Clinical outcome Any remission 31 (82%) 25 (66%) 16 (76%) 8 (73%) 3 (75%) Complete remission 29 (76%) 20 (53%) 15 (71%) 8 (73%) 2 (50%) CROT 6 11 6 1 15 (38%) CRMT 14 4 2 1 14 (37%) Partial remission 5 (13%) 1 (5%) 0 (0%) 1 (25%) 2 (5%) PROT 1 0 0 0 0 (0%) PRMT 4 1 0 1 2 (5%) Nonresponders 13 (34%) 5 (24%) 3 (27%) 1 (25%) 7 (18%) Relapse after 14/20 10/15 5/7 0/2 17/29 (59%) achieving CR (70%) (67%) (71%)a (0%) Median time to 6.2 relapse after CR 4.7 7.1 15.4 (months) Median time from 14.6 14.6 8.6 (range, previous cycle, (range, (range, 6.35.2-54.8) months 6.5-26.5) 17.1) Abbreviations: BP, bullous pemphigoid; MMP, mucous membrane pemphigoid; CR, complete remission; CROT, complete remission off minimal therapy; CRMT, complete remission on minimal therapy; PROT, partial remission off minimal therapy; PRMT, partial remission on minimal therapy. a 1 patient in CRMT was excluded due to receiving another rituximab cycle to improve outcome
S0190-9622(19)33113-5
DOI:
https://doi.org/10.1016/j.jaad.2019.11.023
Reference:
YMJD 14005
To appear in:
Journal of the American Academy of Dermatology
Received Date: 13 August 2019 Revised Date:
2 November 2019
Accepted Date: 8 November 2019
Please cite this article as: Tovanabutra N, Payne AS, Clinical outcome and safety of rituximab therapy for pemphigoid diseases, Journal of the American Academy of Dermatology (2019), doi: https:// doi.org/10.1016/j.jaad.2019.11.023. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
Article type: Research Letter Title: Clinical outcome and safety of rituximab therapy for pemphigoid diseases Napatra Tovanabutra M.D.1,2, Aimee S. Payne M.D., Ph.D.1 1
Department of Dermatology, University of Pennsylvania, Philadelphia, PA Department of Internal Medicine, Division of Dermatology, Chiang Mai University, Chiang Mai, Thailand
2
Corresponding author: Aimee S. Payne, M.D., Ph.D. 421 Curie Blvd 1009 Biomedical Research Building Philadelphia, PA 19104 Email: [email protected] Manuscript word count: 504 References: 2 Figures: 1 Tables: 1 Supplemental material: Mendeley Funding source: This work was supported by Faculty of Medicine, Chiang Mai University, Thailand. Conflict of Interest: ASP is a co-founder and equity holder in Cabaletta Bio, Inc., focused on targeted immunotherapy of pemphigus. She is an inventor on patents licensed by Novartis and Cabaletta Bio for cellular immunotherapy of autoimmune diseases and has previously served as a consultant for Syntimmune, Inc. These organizations had no involvement in the research reported in this study. NT has no conflict of interests.
The term “pemphigoid” encompasses a group of subepidermal autoimmune blistering diseases, including bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA), and others. Fatal complications can occur from disease or its therapy. Rituximab (RTX) is FDA-approved for pemphigus vulgaris (PV), but its role in pemphigoid is unclear due to the relative paucity of reported cases. This retrospective case series included all (n=38) pemphigoid patients at the University of Pennsylvania followed at least 1 year after RTX or until death (patient demographics, Supplemental Table S1). Outcomes followed consensus definitions1,2 (Supplemental Methods/Table S2). The primary endpoint was complete remission (CR). Secondary endpoints were CR off therapy (CROT), corticosteroid dose, relapse, serious adverse events (SAEs), and autoantibody titers. RTX outcomes are detailed in Table 1/Supplemental Table S3. Overall, 29/38 (76%) pemphigoid patients achieved CR after a median of 1 RTX cycle, with a median time to CR of 14.3 months (95% CI 9.7-44.1). Considering the more rigorous endpoint of CROT, 15/38 (39%) patients achieved CROT after a median of 2 RTX cycles. No substantive difference in CR/CROT rates was observed among pemphigoid subtypes. CR/CROT was achieved by 53%/27% versus 52%/9% of patients who received RA-dose (n=15) versus lymphoma-dose (n=23) for the first RTX cycle (p>.99/p=0.19). Median prednisone dose decreased from 20 to 3.5 mg/day (p<.001) and 20 to 4.5 mg/day (p=.001) in BP and non-BP patients (Figure 1). Longitudinal autoantibody titers were available for 13 BP patients. Median antiBP180 titer decreased from 100.2 to 11.9 U/ml twelve months after RTX (p<0.05), suggesting that anti-BP180 antibodies are predominantly produced by short-lived plasma cells (Supplemental Figure S1).
17/29 (59%) patients relapsed a median of 6.2 months after achieving CR (Supplemental Figure S2A). Surprisingly, BP patients exhibited a 4.8-fold hazard ratio for relapse (95% CI 1.34-17.4; p=0.007) (Supplemental Figure S2B), perhaps because minimal therapy was tapered in 67% of BP versus 17% of non-BP patients, and relapses occurred in 8/9 pemphigoid patients (89%) who tapered doses of minimal therapy compared to 3/9 (33%) who maintained minimal therapy doses (p<0.05). Additional RTX cycles were prescribed to improve outcome or treat relapse (Supplemental Table S3). 100% who relapsed after achieving CR (n=8) and 54% who received RTX to improve response (n=13) attained CR after the second RTX cycle, indicating that outcomes are significantly different based on the indication for re-treatment (p=0.02). Of 7 infectious SAEs in 5 patients (13%), 5 occurred in patients receiving concomitant prednisone ≥7.5 mg/day and/or adjunctive immunosuppressives (Supplemental Table S4). Two deaths (primary CNS lymphoma, heart failure) were deemed unrelated to RTX. Collectively, these data indicate RTX is effective in inducing CR/CROT in 76%/39% of pemphigoid patients, and suggest that its primary therapeutic benefit is its steroid-sparing effect. No dose-based difference in RTX efficacy is observed. Relapse after achieving initial CR occurs in the majority (59%) of patients, but might be reduced through maintenance therapy with low-dose prednisone or dapsone. These data guide clinical expectations for the use of RTX in pemphigoid and may help to inform the design and endpoints of future prospective clinical trials.
Acknowledgments: The authors would like to thank Donald Tsai, MD, Victoria Werth, MD, and John Stanley, MD for the clinical treatment of patients in this study. This work was supported by the Faculty of Medicine, Chiang Mai University, Thailand. Funding/Sponsor was involved? Design and conduct of the study
Yes___
No_x_
Collection, management, analysis and interpretation of data
Yes___
No_x_
Preparation, review, or approval of the manuscript
Yes___
No_x_
Decision to submit the manuscript for publication
Yes___
No_x_
ASP is a co-founder and equity holder in Cabaletta Bio, Inc., focused on targeted immunotherapy of pemphigus. She is an inventor on patents licensed by Novartis and Cabaletta Bio for cellular immunotherapy of autoimmune diseases and has previously served as a consultant for Syntimmune, Inc. These organizations had no involvement in the research reported in this study. NT has no conflict of interests. Author Contributions: Napatra Tovanabutra and Aimee S. Payne 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: Napatra Tovanabutra and Aimee S. Payne. Acquisition, analysis, and interpretation of data: Napatra Tovanabutra and Aimee S. Payne. Drafting of the manuscript: Napatra Tovanabutra and Aimee S. Payne. Critical revision of the manuscript for important intellectual content: Napatra Tovanabutra and Aimee S. Payne. Statistical analysis: Napatra Tovanabutra and Aimee S. Payne. Obtained funding: N/A Administrative, technical, or material support: Aimee S. Payne. Study supervision: Aimee S. Payne.
References 1.
2.
Murrell DF, Daniel BS, Joly P, et al. Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts. Journal of the American Academy of Dermatology. 2012;66(3):479-485. Murrell DF, Marinovic B, Caux F, et al. Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts. Journal of the American Academy of Dermatology. 2015;72(1):168-174.
Figure legend. Figure 1. RTX is an effective steroid-sparing therapy in pemphigoid. Significant reduction in daily prednisone dose 12 months after the first cycle of RTX in patients with BP and other pemphigoid diseases. *, p≤.05; **, p≤.01; ***, p≤.001; ns, not significant compared to baseline values.
Table 1. Treatment parameters and outcomes. Cycle 1
Cycle 2
Cycle 3
Cycle 4
Overall best response 38
Number of patients 38 21 11 4 Pemphigoid subtype BP 21 11 6 2 21 MMP 9 3 2 2 9 Other pemphigoid 8 7 3 0 8 Dose Lymphoma 23 16 9 4 54 RA 15 5 2 0 22 Purpose of treatment Improve outcome 13 3 2 18 Treat relapse after 18 8 8 2 achieving CR Clinical outcome Any remission 31 (82%) 25 (66%) 16 (76%) 8 (73%) 3 (75%) Complete remission 29 (76%) 20 (53%) 15 (71%) 8 (73%) 2 (50%) CROT 6 11 6 1 15 (38%) CRMT 14 4 2 1 14 (37%) Partial remission 5 (13%) 1 (5%) 0 (0%) 1 (25%) 2 (5%) PROT 1 0 0 0 0 (0%) PRMT 4 1 0 1 2 (5%) Nonresponders 13 (34%) 5 (24%) 3 (27%) 1 (25%) 7 (18%) Relapse after 14/20 10/15 5/7 0/2 17/29 (59%) achieving CR (70%) (67%) (71%)a (0%) Median time to 6.2 relapse after CR 4.7 7.1 15.4 (months) Median time from 14.6 14.6 8.6 (range, previous cycle, (range, (range, 6.35.2-54.8) months 6.5-26.5) 17.1) Abbreviations: BP, bullous pemphigoid; MMP, mucous membrane pemphigoid; CR, complete remission; CROT, complete remission off minimal therapy; CRMT, complete remission on minimal therapy; PROT, partial remission off minimal therapy; PRMT, partial remission on minimal therapy. a 1 patient in CRMT was excluded due to receiving another rituximab cycle to improve outcome