Olumiant ® (baricitinib)

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Olumiant® (baricitinib): What are the post marketing safety findings?

Post approval studies are being conducted to further characterise the safety profile of baricitinib in patients with rheumatoid arthritis (RA). Below finds some information regarding the post marketing data of baricitinib in RA.


Postmarketing Studies of Baricitinib

Rationale for Postmarketing Studies

Postmarketing studies allow the exploration of specific adverse events of interest in a clinical trial or real-world population with a large sample size.1 These studies are designed to more closely reflect routine care and permit broader generalization of study results to patients and/or clinics that may not typically participate in clinical trials.2

Safety information collected in patients treated with baricitinib in the clinical trial development programs include:

  • 3770 patients with rheumatoid arthritis (RA) treated up to a maximum of 9.3 years3
  • 2636 patients with atopic dermatitis treated up to a maximum of 3.9 years, and4
  • 1303 patients with alopecia areata treated up to a maximum of 3.1 years.5

In addition, several postapproval studies are being conducted to further characterize the safety profile of baricitinib in patients with RA. These include prospective and retrospective observational studies, involving administrative claims databases and some well-established RA registries.2,6-10

Retrospective Observational Study

B023 Study Design

B023, a multi-database, observational retrospective cohort study, was initiated to compare the safety of baricitinib with tumor necrosis factor inhibitors (TNFi) for risk of venous thromboembolism (VTE), major adverse cardiovascular events (MACE), and serious infection in patients with rheumatoid arthritis (RA) in routine care. A meta-analysis was used to combine results across 14 real-world data sources, including 3 disease registries, 8 administrative claims databases, and 3 national healthcare systems, in Europe, the United States, and Japan.8

Study Population

The study population included adults who were new users of baricitinib (4 mg, 2 mg) or TNFi (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) or biosimilars. New users were defined as patients without prior use of baricitinib or TNFi during the 6-months before and including the cohort entry date. Cohort entry was the date of first dispensing of baricitinib or TNFi during the study period.8

Patients were observed until the first of:

  • outcome of interest (VTE, MACE, serious infection, or hospitalized TB)
  • discontinuation of study medication
  • switching to another RA medication (including to another TNFi in the TNFi cohort)
  • initiation of a concomitant b/tsDMARD
  • disenrollment from the registry or insurance plan leading to loss to follow-up, (up to 45-day gaps in medical or pharmacy enrollment will be allowed), and
  • death (where available).8

Data Analysis

Since patients cannot be randomized to treatment, propensity score matching was used to create comparison groups with a balanced distribution of baseline risk factors.2,11

Propensity score models were created for each individual outcome (VTE, MACE, and serious infection). Each patient from the baricitinib group was then matched 1:1 for each outcome with a patient from the TNFi group based on similar propensity scores. Patients without a match were excluded from analyses.8

The variables included in the propensity score models were risk factors specific to each outcome, including 

  • patient demographics
  • medical history including comorbidities and prescription medication use, and
  • RA disease treatments over the past 6 months.8

Analyses were conducted separately for each outcome. Modified Poisson regression was used for meta-analysis to estimate an overall incidence rate ratio (IRR), for comparing events in baricitinib and TNFi treatment cohorts. The IRR was used instead of hazard ratios to allow for inclusion of data from all sources, even from those sources with low or no events in either or both cohorts.8

For all comparative analyses, baricitinib was the treatment of interest and the TNFi cohort was the reference group.8

Study Limitations

Since the B023 study is based on data that recorded real-world treatment decisions and patients were not randomized to treatment, there is the potential for bias due to confounding.8

Several risk factors known to be associated with the outcomes evaluated in this study are partially complete or unavailable.8


Of 9013 eligible patients treated with baricitinib, 7606 (84%) were propensity score-matched 1:1 with patients treated with TNFi and contributed

  • 5879 person-years of baricitinib exposure, and
  • 6512 person-years of TNFi exposure.8

After propensity score matching, there was little to no difference in the prevalence of measured risk factors between treatment cohorts for each outcome analyzed. 8

Primary Objective: Risk of Venous Thromboembolism

Across all data sources, 97 patients experienced a VTE, 56 of whom were treated with baricitinib. On average, patients were followed for 9 months of baricitinib treatment and 10 months of TNFi treatment.8

The overall IRR of VTE was statistically significantly elevated for baricitinib vs TNFi (IRR=1.51; 95% CI, 1.10 to 2.08).8

Secondary Objectives

A total of 93 patients experienced MACE, 54 of whom were treated with baricitinib. The overall mean follow-up was 8 months for baricitinib-treated patients and 10 months for TNFi-treated patients.8

The overall IRR of MACE was numerically but not significantly greater for baricitinib vs TNFi (IRR=1.54; 95% CI, 0.93 to 2.54).8

Of the 321 patients who experienced serious infection, 176 were treated with baricitinib over a mean follow-up period of 10 months for baricitinib-treated patients and 11 months for TNFi-treated patients.8

The overall IRR of serious infection was numerically but not significantly greater for baricitinib vs TNFi (IRR=1.36; 95% CI, 0.86 to 2.13).8

Ongoing Postmarketing Required Studies RA-BRIDGE and RA-BRANCH

Two randomized, controlled, open-label, phase 3b/4 studies, RA-BRIDGE (NCT03915964) and RA-BRANCH (NCT04086745), are evaluating the safety of high- and low-dose baricitinib compared to adalimumab or etanercept in patients with rheumatoid arthritis who had an inadequate response or intolerance to at least one DMARD. The outcome measures are the time from first dose of study treatment to the first

  • venous thromboembolism (primary endpoint)
  • arterial thromboembolic event
  • major adverse cerebro-cardiovascular event
  • malignancy, excluding nonmelanoma skin cancer
  • opportunistic infection, and
  • serious infection.9,10

In RA-BRIDGE and RA-BRANCH, patients had at least 1 of the following baseline characteristics:

  • documented evidence of a prior venous thromboembolism
  • aged at least 60 years
  • body mass index (BMI) ≥30 kg/m², or
  • aged 50 to less than 60 years and have a BMI 25 to <30 kg/m2.9,10

RA-BRIDGE includes an estimated enrollment of 2600 participants from sites in the United States and outside the United States.9

RA-BRANCH is currently recruiting patients in the United States. The estimated enrollment will be 1300 patients.10

As the study design is a time to event study, the estimated primary completion for both studies is 2025 but may be longer if events occur at a lower rate than estimated.9,10

Other JAK Inhibitor Postmarketing Required Studies of Impact

The safety of tofacitinib compared to adalimumab or etanercept in patients with RA who had inadequate response to methotrexate (MTX) was evaluated in an open-label phase 3b/4 study, ORAL Surveillance (NCT02092467), with respect to incidence rates of MACE and malignancies (excluding non-melanoma skin cancer [NMSC]). Other safety events, including serious infection, opportunistic infection, VTE, arterial thromboembolism, NMSC, and hepatic events, were collected and evaluated in the study.12,13

In ORAL Surveillance, patients were 50 years or older and had to have at least one cardiovascular risk factor, including current cigarette smoker, hypertension, high-density lipoprotein cholesterol <40 mg/dL, diabetes mellitus, history of coronary artery disease, family history of premature coronary heart disease or extraarticular RA.12,13

A total 4362 patients were randomized and

  • 1455 received tofacitinib 5 mg twice daily
  • 1456 received tofacitinib 10 mg twice daily, and
  • 1451 received a TNFi.12

During a median follow-up of 4 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses than with a TNFi. The incidence for

  • MACE was 3.4% (98 patients) for combined tofacitinib doses vs 2.5% (37 patients) for TNFi (HR=1.33; [95% CI, 0.91 to 1.94]), and
  • cancer was 4.2% (122 patients) for combined tofacitinib doses vs 2.9% (42 patients) for TNFi (HR=1.48; [95% CI, 1.04 to 2.09]).12

Noninferiority of tofacitinib was not shown.12

Other Publications of Interest

In addition to the studies discussed above, a literature search has been conducted and identified the following publications of interest

  • Khosrow-Khavar F, Kim SC, Lee H, et al. Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study. Ann Rheum Dis. 2022;81(6):798-804. https://doi.org/10.1136/annrheumdis-2021-221915
  • Hoisnard L, Vegas LP, Dray-Spira R, et al. Risk of major adverse cardiovascular and venous thromboembolism events in patients with rheumatoid arthritis exposed to JAK inhibitors versus adalimumab: a nationwide cohort study. Ann Rheum Dis. Published online October 5, 2022. https://doi.org/10.1136/ard-2022-222824
  • Takagi M, Atsumi T, Matsuno H, et al. Safety and effectiveness of baricitinib for rheumatoid arthritis in Japanese clinical practice: 24-week results of all-case post-marketing surveillance. Mod Rheumatol. Published online August 6, 2022. https://doi.org/10.1093/mr/roac089

Safety Profile of Baricitinib Related to Postmarketing Findings

Please see local labeling for your country specific information on this topic.

Warnings and Precautions

Major Adverse Cardiovascular Events

In a large randomized active-controlled study of another Janus kinase (JAK) inhibitor (tofacitinib), a higher rate of MACE, including myocardial infarction, stroke and cardiovascular (CV) death, have been observed compared with TNF blockers in RA patients 50 years and older with at least one CV risk factor. In a retrospective observational study of baricitinib in RA patients, a higher rate of MACE was observed compared to patients treated with TNF blockers.2,12  

Baricitinib should be used with caution in patients with risk factors for MACE.2

Venous Thromboembolism

Cases of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib.14

Baricitinib should be used with caution in patients with risk factors for DVT/PE, such as

  • older age,
  • obesity,
  • a medical history of DVT/PE, or
  • patients undergoing surgery and immobilisation.14

If clinical features of DVT/PE occur, treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.14


The risk of malignancies including lymphoma is increased in patients with rheumatoid arthritis. Immunomodulatory medicinal products may increase the risk of malignancies including lymphoma. The clinical data are insufficient to assess the potential incidence of malignancies following exposure to baricitinib. Long-term safety evaluations are ongoing.14

Lymphoma and other malignancies have been reported in patients receiving baricitinib. In a large randomized active-controlled study with another JAK inhibitor (tofacitinib) in RA patients 50 years and older, a higher rate of malignancy (excluding NMSC) was observed compared to patients treated with TNF blockers.2,12

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with baricitinib.2


1Suvarna V. Phase IV of drug development. Perspect Clin Res. 2010;1(2):57-60. https://www.picronline.org/text.asp?2010/1/2/57/71852

2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3Taylor PC, Takeuchi T, Burmester GR, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. 2022;81(3):335-343. https://doi.org/10.1136/annrheumdis-2021-221276

4Bieber T, Katoh N, Simpson EL, et al. Safety of baricitinib for the treatment of atopic dermatitis over a median of 1.6 and up to 3.9 years treatment: an updated integrated analysis of 8 clinical trials. Poster presented at: 31st Annual European Academy of Dermatology and Venereology Congress; September 7-10, 2022; Milan, Italy.

5King B, Mostaghimi A, Shimomura Y, et al. Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials. Br J Dermatol. Published online November 11, 2022. https://academic.oup.com/bjd/advance-article/doi/10.1093/bjd/ljac059/6821292

6Alten R, Burmester GR, Matucci-Cerinic M, et al. A multinational, prospective, observational study in patients with rheumatoid arthritis receiving baricitinib, targeted synthetic or biologic disease-modifying therapies (RA-BE-REAL) – study design and baseline characteristics. Ann Rheum Dis. 2021;80(suppl 1):1157. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2035

7Hernández-Cruz B, Rosas J, Díaz-Torné C, et al. Real-world treatment patterns and clinical outcomes of baricitinib in rheumatoid arthritis patients in Spain: results of a multicenter, observational study in routine clinical practice (the ORBIT-RA Study). Rheumatol Ther. 2022;9(2):589-608. https://doi.org/10.1007/s40744-021-00423-8

8Salinas CA, Louder A, Polinski J, et al. Evaluation of VTE, MACE, and serious infections among patients with RA treated with baricitinib compared to TNFi: a multi-database study of patients in routine care using disease registries and claims databases. Rheumatol Ther. Published online November 13, 2022. https://doi.org/10.1007/s40744-022-00505-1

9A study of baricitinib (LY3009104) in participants with rheumatoid arthritis (RA-BRIDGE). ClinicalTrials.gov identifier: NCT03915964. Updated June 10, 2021. Accessed March 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03915964

10A study of baricitinib in participants with rheumatoid arthritis (RA-BRANCH). ClinicalTrials.gov identifier: NCT04086745. Updated April 19, 2022. Accessed March 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04086745

11Kuss O, Blettner M, Börgermann J. Propensity score: an alternative method of analyzing treatment effects. Dtsch Arztebl Int. 2016;113(35-36):597-603. https://dx.doi.org/10.3238%2Farztebl.2016.0597

12Ytterberg SR, Bhatt DL, Mikuls TR, et al; ORAL Surveillance Investigators. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-326. http://dx.doi.org/10.1056/NEJMoa2109927

13Safety study of tofacitinib versus tumor necrosis factor (TNF) inhibitor in subjects with rheumatoid arthritis. Clinicaltrials.gov identifier: NCT02092467. Updated August 17, 2021. Accessed March 2, 2022. https://www.clinicaltrials.gov/ct2/show/NCT02092467

14Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

Date of Last Review: 18 November 2022

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