Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib

Kevin L. Winthrop; Gil Y. Melmed; Séverine Vermeire; Millie D. Long; Gary Chan; Ronald D. Pedersen; Nervin Lawendy; Andrew J. Thorpe; Chudy I. Nduaka; Chinyu Su

doi:10.1093/ibd/izy131

Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib

Kevin L. Winthrop, Gil Y. Melmed, Séverine Vermeire, Millie D. Long, Gary Chan, Ronald D. Pedersen, Nervin Lawendy, Andrew J. Thorpe, Chudy I. Nduaka, Chinyu Su

Ophthalmology

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib. Methods: HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models. Results: Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3-6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14-5.19) over a mean (range) of 509.1 (1-1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77-17.08); Asian patients, 6.49 (3.55-10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5.38 (3.86-7.29); and patients using tofacitinib 10 mg twice daily, 4.25 (3.18-5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors. Conclusions: In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612).

Original language	English (US)
Pages (from-to)	2258-2265
Number of pages	8
Journal	Inflammatory Bowel Diseases
Volume	24
Issue number	10
DOIs	https://doi.org/10.1093/ibd/izy131
State	Published - Oct 2018

Keywords

Herpes zoster
Janus kinase
Safety
Shingles
Tofacitinib
Ulcerative colitis

ASJC Scopus subject areas

Immunology and Allergy
Gastroenterology

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10.1093/ibd/izy131

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Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib. / Winthrop, Kevin L.; Melmed, Gil Y.; Vermeire, Séverine; Long, Millie D.; Chan, Gary; Pedersen, Ronald D.; Lawendy, Nervin; Thorpe, Andrew J.; Nduaka, Chudy I.; Su, Chinyu.

In: Inflammatory Bowel Diseases, Vol. 24, No. 10, 10.2018, p. 2258-2265.

Research output: Contribution to journal › Article › peer-review

@article{31d96b4be51f42c8a38742da44b01fa7,

title = "Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib",

abstract = "Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib. Methods: HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models. Results: Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3-6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14-5.19) over a mean (range) of 509.1 (1-1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77-17.08); Asian patients, 6.49 (3.55-10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5.38 (3.86-7.29); and patients using tofacitinib 10 mg twice daily, 4.25 (3.18-5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors. Conclusions: In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612).",

keywords = "Herpes zoster, Janus kinase, Safety, Shingles, Tofacitinib, Ulcerative colitis",

author = "Winthrop, {Kevin L.} and Melmed, {Gil Y.} and S{\'e}verine Vermeire and Long, {Millie D.} and Gary Chan and Pedersen, {Ronald D.} and Nervin Lawendy and Thorpe, {Andrew J.} and Nduaka, {Chudy I.} and Chinyu Su",

note = "Funding Information: From the *Oregon Health & Science University, Portland, Oregon; †Cedars-Sinai Medical Center, Los Angeles, California; ‡Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; §Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina; ‖Pfizer Inc., Collegeville, Pennsylvania Conflicts of interest: K.W. has received consulting and investigator fees from Pfizer Inc. G.M. has received consulting fees from AbbVie, Boehringer Ingelheim, Celgene, Genentech, Janssen, Pfizer Inc., Samsung Bioepis, Takeda, and UCB; and has received support for research from Prometheus Labs. S.V. has received grant support from AbbVie, MSD, and Takeda; has received speaker fees from AbbVie, MSD, Takeda, Ferring, Dr Falk Pharma, Hospira, and Tillots; and has received consulting fees from AbbVie, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer Inc., Galapagos, Mundipharma, Hospira, Celgene, Second Genome, and Janssen. M.L. has received consulting fees from AbbVie, UCB, Pfizer, Takeda, and Target Funding Information: Pharmasolutions; and has received research support from Takeda. G.C., R.P., N.L., A.T., C.N., and C.S. are employees and stockholders of Pfizer Inc. Supported by: Pfizer Inc. Address correspondence to: Kevin L. Winthrop, MD, MPH, CEI/OHSU, 3375 SW Terwilliger Blvd, Portland, OR 97239 (winthrop@ohsu.edu). Funding Information: Medical writing support under the guidance of the authors was provided by Sandrine M. Dupr{\'e}, PhD, at CMC Connect, a division of Complete Medical Communications Ltd, Manchester, UK and was funded by Pfizer Inc, New York, NY, USA in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med. 2015;163:461–464).",

year = "2018",

month = oct,

doi = "10.1093/ibd/izy131",

language = "English (US)",

volume = "24",

pages = "2258--2265",

journal = "Inflammatory Bowel Diseases",

issn = "1078-0998",

publisher = "John Wiley and Sons Inc.",

number = "10",

}

TY - JOUR

T1 - Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib

AU - Winthrop, Kevin L.

AU - Melmed, Gil Y.

AU - Vermeire, Séverine

AU - Long, Millie D.

AU - Chan, Gary

AU - Pedersen, Ronald D.

AU - Lawendy, Nervin

AU - Thorpe, Andrew J.

AU - Nduaka, Chudy I.

AU - Su, Chinyu

N1 - Funding Information: From the *Oregon Health & Science University, Portland, Oregon; †Cedars-Sinai Medical Center, Los Angeles, California; ‡Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; §Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina; ‖Pfizer Inc., Collegeville, Pennsylvania Conflicts of interest: K.W. has received consulting and investigator fees from Pfizer Inc. G.M. has received consulting fees from AbbVie, Boehringer Ingelheim, Celgene, Genentech, Janssen, Pfizer Inc., Samsung Bioepis, Takeda, and UCB; and has received support for research from Prometheus Labs. S.V. has received grant support from AbbVie, MSD, and Takeda; has received speaker fees from AbbVie, MSD, Takeda, Ferring, Dr Falk Pharma, Hospira, and Tillots; and has received consulting fees from AbbVie, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer Inc., Galapagos, Mundipharma, Hospira, Celgene, Second Genome, and Janssen. M.L. has received consulting fees from AbbVie, UCB, Pfizer, Takeda, and Target Funding Information: Pharmasolutions; and has received research support from Takeda. G.C., R.P., N.L., A.T., C.N., and C.S. are employees and stockholders of Pfizer Inc. Supported by: Pfizer Inc. Address correspondence to: Kevin L. Winthrop, MD, MPH, CEI/OHSU, 3375 SW Terwilliger Blvd, Portland, OR 97239 (winthrop@ohsu.edu). Funding Information: Medical writing support under the guidance of the authors was provided by Sandrine M. Dupré, PhD, at CMC Connect, a division of Complete Medical Communications Ltd, Manchester, UK and was funded by Pfizer Inc, New York, NY, USA in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med. 2015;163:461–464).

PY - 2018/10

Y1 - 2018/10

N2 - Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib. Methods: HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models. Results: Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3-6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14-5.19) over a mean (range) of 509.1 (1-1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77-17.08); Asian patients, 6.49 (3.55-10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5.38 (3.86-7.29); and patients using tofacitinib 10 mg twice daily, 4.25 (3.18-5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors. Conclusions: In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612).

AB - Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib. Methods: HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models. Results: Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3-6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14-5.19) over a mean (range) of 509.1 (1-1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77-17.08); Asian patients, 6.49 (3.55-10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5.38 (3.86-7.29); and patients using tofacitinib 10 mg twice daily, 4.25 (3.18-5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors. Conclusions: In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612).

KW - Herpes zoster

KW - Janus kinase

KW - Safety

KW - Shingles

KW - Tofacitinib

KW - Ulcerative colitis

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U2 - 10.1093/ibd/izy131

DO - 10.1093/ibd/izy131

M3 - Article

C2 - 29850873

AN - SCOPUS:85054921937

VL - 24

SP - 2258

EP - 2265

JO - Inflammatory Bowel Diseases

JF - Inflammatory Bowel Diseases

SN - 1078-0998

IS - 10

ER -