Publications

Tofacitinib and Risk of Malignancy: Results From the Safety of Tofacitinib in Routine Care Patients With Rheumatoid Arthritis (STAR-RA) Study

Arthritis Rheumatol. 2022;74:1648–1659 doi: 10.1002/art.42250

Khosrow-Khavar F,

Desai RJ,

Lee H,

Lee SB,

Kim SC

Large, population-based, real-world cohort of study in patients with RA finds tofacitinib not to be associated with an increased risk of malignancies, in comparison to TNFi agents, although a numerically increased risk of malignancies was observed in older patients with risk factors for cardiovascular disease.

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Malignancy

Short- and longer-term cancer risks with biologic and targeted synthetic disease-modifying antirheumaticdrugs as used against rheumatoid arthritis in clinical practice

Rheumatology (Oxford) 2022 doi: 10.1093/rheumatology/keab570

Huss V,

Bower H,

Wadström H,

Frisell T,

Askling J; ARTIS group

Observational, nationwide cohort study finds no increased risk for cancer overall in RA patients treated with TNFis, anti-CD20 or anti-IL6.

Keywords:

• JAK,
• Safety,
• Malignancy

Cardiovascular and Cancer Risk With Tofacitinib in Rheumatoid Arthritis

N Engl J Med 2022;386:316–26. doi: 10.1056/NEJMc2202778

Ytterberg SR,

Bhatt DL,

Mikuls TR,

Koch GG,

Fleischmann R,

Rivas JL,

Germino R,

Menon S,

Sun Y,

Wang C,

Shapiro AB,

Kanik KS,

Connell CA

In this paper, Ytterberg et al. compare incidence of MACE and cancers (excluding NMSC) with tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi. They found that risk of MACE and cancer were higher with tofacitinib versus TNFi, and did not meet noninferiority criteria.This prospective head-to-head safety trial compared tofacitinib to TNFi, and was required by the FDA after increases in lipid levels and cancers were observed during tofacitinib drug development. ...

Keywords:

• JAK,
• Tofacitinib,
• Safety,
• Malignancy,
• Cardiovascular

Effect of janus kinase inhibitors and methotrexate combination on malignancy in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials

Auto Immun Highlights. 2021;12(1):8.

Solipuram V,

Mohan A,

Patel R,

Ni R.

The combination of JAK inhibitors with MTX is not associated with an increased risk of malignancy when compared to MTX alone. Although long-term studies are needed to confirm this conclusion from short-term studies. Although it is now known that patients with RA are predisposed to an increased risk of malignancy, especially malignant lymphomas, lung cancers and non-melanoma skin cancer, it remains unclear whether the combination therapy is associated with a higher risk.To this end, Solipuram, et...

Keywords:

• JAK,
• Meta analysis,
• Safety,
• Malignancy

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis

Annals of the Rheumatic Diseases 2020;79:760-770

Sepriano A,

Kerschbaumer A,

Smolen JS,

Van Der Heijde D,

Dougados M,

Van Vollenhoven R,

McInnes IB,

Bijlsma JW,

Burmester GR,

De Wit M,

Falzon L,

Landewé R

This SLR informed the 2019 EULAR taskforce updating recommendations for RA management. Overall, no new safety signals were reported. The known safety profile of bDMARDs was confirmed and extended to tsDMARDS. IL-6i associated lower intestinal perforation has been further confirmed, while VTE and PE concerns in JAKi treatment need further evaluation.Previous updates for the EULAR recommendations on RA pharmacological management were conducted in 2016. In this SLR safety of csDMARDs, tsDMARDs, and...

Keywords:

• Safety,
• EULAR

Safety Profile of Baricitinib For the Treatment of Rheumatoid Arthritis Over a Median of 3 Years of Treatment: An Updated Integrated Safety Analysis

Lancet Rheumatol 2020;2:e347–57

Genovese MC,

Smolen JS,

Takeuchi T,

Burmester G,

Brinker D,

Rooney TP,

Zhong J,

Daojun M,

Saifan C,

Cardoso A,

Issa M,

Wu W-S,

Winthrop KL

RA is a chronic, life-long disease requiring long-term treatment. As such, it is important to understand the long-term safety profile of DMARDs. In this analysis, baricitinib maintained a stable safety profile during long-term exposure. This baricitinib safety analysis included integrated data from nine Phase 3, 2, and 1b clinical trials, and one long-term extension, with data up to 360 weeks. 3700 patients were included, with maximum follow-up of almost 7 years – representing an additional 3,54...

Keywords:

• JAK,
• Baricitinib,
• Safety

Preferential Inhibition of JAK1 Relative to JAK3 by Upadacitinib: Exposure-Response Analyses of Ex Vivo Data From 2 Phase 1 Clinical Trials and Comparison to Tofacitinib

Pharmacodynamics. 2020

Mohamed MF,

Beck D,

Camp HS,

Othman AA

Ex vivo pharmacodynamic assay results demonstrated a greater selectivity of UPA on JAK1 versus JAK3 compared to TOF. This analysis conducted ex vivo stimulation of STAT3 phosphorylation by IL-6 as a measure of JAK1 activity and STAT5 phosphorylation by IL-7 as a measure of JAK1/JAK3 activity. Change in pSTAT3 and pSTAT5 were calculated at 1, 6 and 12 hours following drug administration using samples collected from healthy subjects and subjects with RA, from 2 phase 1 studies. Exposure-response m...

Keywords:

• JAK,
• Upadacitinib,
• Tofacitinib,
• Phase 1,
• Malignancy

Safety Profile of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis with Over 1.6 Years Median Time in Treatment: An Integrated Analysis of Phase 2 and 3 Trials

Mod Rheumatol. 2019 Feb 20:1-23. DOI: 10.1080/14397595.2019.1583711

Harigai M,

Takeuchi T,

Smolen JS,

Winthrop KL,

Nishikawa A,

Rooney TP,

Saifan CG,

Issa M,

Isaka Y,

Akashi N,

Ishii T,

Tanaka Y

In this integrated analysis, BARI showed an acceptable safety profile in Japanese patients with up to 3.2 years of exposure. Other than incidences of herpes zoster (HZ), no major differences were noted with BARI safety in Japanese patients with RA, compared to the patients in the integrated database.BARI has previously demonstrated significant clinical efficacy and acceptable safety. Japanese patients who participated in the BARI clinical development programme, were comparable to those from the ...

Keywords:

• JAK,
• Baricitinib,
• Safety,
• Phase 3

Adverse Events, Clinical Considerations and Management Recommendations in Rheumatoid Arthritis Patients Treated with JAK Inhibitors

Exp Rev Clin Immunol 2018 Nov;14(11):945-956. DOI: 10.1080/1744666X.2018.1504678

Atzeni F,

Talotta R,

Nucera V,

Marino F,

Gerratana E,

Sangari D,

Masala IF,

Sarzi-Puttini P

Janus kinase (JAK) inhibitors are efficacious in patients with moderate-to-severe RA and have a favourable safety profile. However adverse events (AE), in particular infections, are associated with the use of JAK inhibitors. This paper reviews the mechanism behind JAK inhibitors, the AEs associated with them, and provides consideration in the management of AEs in clinical practice. Data on two RA approved JAK inhibitors – tofacitinib (TOF) and baricitinib (BARI) – was obtained using PubMed, Medl...

Keywords:

• JAK,
• Safety,
• Review

Lymphoma in the Tofacitinib Rheumatoid Arthritis Clinical Development Program

Arthritis Care Res (Hoboken). 2018 May;70(5):685-694. doi: 10.1002/acr.23421

Mariette X,

Chen C,

Biswas P,

Kwok K,

Boy MG

Analysis of 19 studies involving the use of tofacitinib to treat RA showed that lymphoma incidence rate and type were consistent with expectations in the RA population as a whole, and did not increase with tofacitinib exposure time.Previous research has suggested that there is a link between the likelihood of developing malignant tumours and RA. Previously, it has been unclear whether the increased rates seen are due to the use of immunomodulatory therapies, such as tofacitinib, which are used a...

Keywords:

• JAK,
• Tofacitinib,
• Phase 2,
• Phase 3,
• Malignancy