A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis

Katie Bechman; Sujith Subesinghe; Sam Norton; Fabiola Atzeni; Massimo Galli; Andrew P Cope; Kevin L Winthrop; James B Galloway

doi:10.1093/rheumatology/kez087

A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis

Katie Bechman, Sujith Subesinghe, Sam Norton, Fabiola Atzeni, Massimo Galli, Andrew P Cope, Kevin L Winthrop, James B Galloway

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Abstract

OBJECTIVES: To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors.

METHODS: We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach.

RESULTS: Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates.

CONCLUSION: The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk.

SYSTEMATIC REVIEW REGISTRATION NUMBER: Prospero 2017 CRD4201707879.

Original language	English
Pages (from-to)	1755-1766
Number of pages	12
Journal	Rheumatology
Volume	58
Issue number	10
Early online date	14 Apr 2019
DOIs	https://doi.org/10.1093/rheumatology/kez087 https://doi.org/10.1093/rheumatology/kez087
Publication status	Published - 14 Apr 2019

Keywords

immunosuppressants
meta-analysis
rheumatoid arthritis
systematic review
viruses

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@article{dc3fe218d83345d1ae183d70cda3a6a2,

title = "A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis",

abstract = "OBJECTIVES: To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors.METHODS: We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach.RESULTS: Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates.CONCLUSION: The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk.SYSTEMATIC REVIEW REGISTRATION NUMBER: Prospero 2017 CRD4201707879.",

keywords = "immunosuppressants, meta-analysis, rheumatoid arthritis, systematic review, viruses",

author = "Katie Bechman and Sujith Subesinghe and Sam Norton and Fabiola Atzeni and Massimo Galli and Cope, {Andrew P} and Winthrop, {Kevin L} and Galloway, {James B}",

note = "{\textcopyright} The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: [email protected].",

year = "2019",

month = apr,

day = "14",

doi = "10.1093/rheumatology/kez087",

language = "English",

volume = "58",

pages = "1755--1766",

journal = "Rheumatology",

issn = "1462-0324",

publisher = "OXFORD UNIV PRESS",

number = "10",

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TY - JOUR

T1 - A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis

AU - Bechman, Katie

AU - Subesinghe, Sujith

AU - Norton, Sam

AU - Atzeni, Fabiola

AU - Galli, Massimo

AU - Cope, Andrew P

AU - Winthrop, Kevin L

AU - Galloway, James B

PY - 2019/4/14

Y1 - 2019/4/14

N2 - OBJECTIVES: To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors.METHODS: We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach.RESULTS: Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates.CONCLUSION: The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk.SYSTEMATIC REVIEW REGISTRATION NUMBER: Prospero 2017 CRD4201707879.

AB - OBJECTIVES: To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors.METHODS: We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach.RESULTS: Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates.CONCLUSION: The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk.SYSTEMATIC REVIEW REGISTRATION NUMBER: Prospero 2017 CRD4201707879.

KW - immunosuppressants

KW - meta-analysis

KW - rheumatoid arthritis

KW - systematic review

KW - viruses

UR - http://www.scopus.com/inward/record.url?scp=85069782886&partnerID=8YFLogxK

U2 - 10.1093/rheumatology/kez087

DO - 10.1093/rheumatology/kez087

M3 - Article

C2 - 30982883

SN - 1462-0324

VL - 58

SP - 1755

EP - 1766

JO - Rheumatology

JF - Rheumatology

IS - 10

ER -

A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis

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