Publications

Highlights of 2021

Please click the links below to go to the CSF review of each paper

McInnes IB

I’m sure we’d all hoped that this year would be a return to normal but, in the midst of the challenges we’ve faced with COVID-19, the rheumatology community has continued to deliver excellent publications, and we’ve covered many of these on the CSF. Here are my highlights from 2021's publications: Points to Consider for the Treatment of Immune-Mediated Inflammatory Diseases With Janus Kinase Inhibitors: A Co...

Keywords:

• Review

Sélectivité des JAK et implications pour l'inhibition clinique de la signalisation pharmacodynamique des cytokines par le filgotinib, l'upadacitinib, le tofacitinib et le baricitinib

Ann Rheum Dis. 2021 Mar 19:annrheumdis-2020-219012. Epub ahead of print. DOI: 10.1136/annrheumdis-2020-219012

Traves PG,

Murray B,

Campigotto F,

Galien R,

Meng A,

Di Paolo JA

The first study to combine in vitro inhibition of cytokine responses in whole blood with clinical pharmacokinetics of individual JAKinibs to model daily cytokine-mediated pharmacodynamic profiles in healthy individuals and patients with RA, has demonstrated that JAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type.Traves and colleagues have observed that JAKinibs have unique, differential effects on specific cytokine signalling pathways, dependent on cytokine stimulus, ST...

Keywords:

• JAK,
• Basic Science,
• MOA

Caractérisation Préclinique de l'Itacitinib (INCB039110), un Nouvel Inhibiteur Sélectif de JAK1, Pour le Traitement des Maladies Inflammatoires

European Journal of Pharmacology. 2020 Oct 15;885:173505. doi: 10.1016/j.ejphar.2020.173505

Covington M,

He X,

Scuron M,

Li J,

Collins R,

Juvekar A,

Shin N,

Favata M,

Gallagher K,

Sarah S,

Xue CB,

Peel M,

Burke K,

Oliver J,

Fay B,

Yao W,

Huang T,

Scherle P,

Diamond S,

Newton R,

Zhang Y,

Smith

Itacitinib is an orally active JAK inhibitor and effectively delayed disease onset, reduced symptom severity, and accelerated recovery of inflammatory diseases in mouse models. Covington M et al demonstrated itacitinib’s high selectivity for JAK 1, its inhibition on IL-2 induced T cell proliferation and JAK/STAT signalling, its ability to also inhibit of the JAK/STAT pathway in response to IL-6 stimulation, and its effect on rat adjuvant induced arthritis model. The study used recombinant enzym...

Keywords:

• JAK,
• Itacitinib

Inhibition Préférentielle de JAK1 Par Rapport à JAK3 par l'Upadacitinib : Analyses Exposition-Réponse des Données Ex Vivo de 2 Essais Cliniques de Phase 1 et Comparaison Avec le 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

Une Revue Systématique et une Méta-Analyse du Risque d'Infections avec les Petites Molécules, Inhibiteurs de JAK dans la Polyarthrite Rhumatoïde

Rheumatology (Oxford) 2019;58(10):1755–66

Bechman K,

Subesinghe S,

Norton S,

Atzeni F,

Galli M,

Cope AP,

Winthrop KL,

Galloway JB

Absolute serious infection rates were low. However, across the JAKinibs, the incidence of HZ is higher than expected for the population. While the risk was numerically greatest with BARI, indirect comparisons between the drugs did not demonstrate any significant difference in risk. How JAKinibs increase the risk of HZ reactivation is unclear, but how different JAKs interact in the immune response suggest that there may be differences in safety profiles between JAKinib drugs, underpinned by their...

Keywords:

• Safety,
• Review

Efficacité et modélisation pharmacodynamique de l'évobrutinib, inhibiteur de BTK, dans les modèles de maladie auto-immune

J Immunol 2019;202:2888–2906. DOI: 10.4049/jimmunol.1800583

Haselmayer P,

Camps M,

Liu-Bujalski L,

Nguyen N,

Morandi F,

Head J,

O’Mahony A,

Zimmerli SC,

Bruns L,

Bender AT,

Schroeder P,

Grenningloh

BTK is involved in both adaptive and innate immune responses and mediates signalling of several immune receptors of relevance to RA and SLE pathogenesis. Targeting BTK is a promising approach therefore for autoimmune disorders with aberrant B cell responses. Evobrutinib is a novel, highly specific, and irreversible BTK inhibitor. In vivo and animal models showed that evobrutinib modulated B cell and innate immune cell activation, was efficacious, and prevented joint damage. The potency of evobru...

Keywords:

• BTK,
• Evobrutinib,
• Preclinical

Revue systématique et méta-analyse du risque d'infection avec les inhibiteurs JAK à petite molécule dans la polyarthrite rhumatoïde

Rheumatology (Oxford). DOI: 10.1093/rheumatology/kez087

Bechman K,

Subesinghe S,

Norton S,

Atzeni F,

Galli M,

Cope AP,

Winthrop KL,

Galloway JB

How JAKinibs increase the risk of HZ reactivation is unclear. Roles of different JAKs in the immune response may suggest differences in safety profiles between drugs, underpinned by their differential JAK selectivity profiles. The authors undertook a systematic review and meta-analysis to evaluate SI and opportunistic indicator infections including HZ in RA Phase II/III clinic trials with JAKinibs. A literature review of RCT of TOF (5 mg BID), BARI (4 mg OD) and UPA (15 mg OD) was conducted. A p...

Keywords:

• JAK,
• Safety,
• Meta analysis,
• Infections

Influence de l'Âge et de l'Insuffisance Rénale sur la Pharmacocinétique à l'État Stable du Filgotinib, un Inhibiteur Sélectif de JAK1

Br J Clin Pharmacol 2018 Dec;84(12):2779-2789. DOI:10.1111/bcp.13726

Namour F,

Fagard L,

Van der AA,

Harrison P,

Xin Y,

Tasset C

Age and renal impairment (RI) had limited impact on the pharmacokinetics (PK) of filgotinib (FIL) but, in subjects with severe RI, exposure to the FIL metabolite was increased. FIL is a selective JAK1 inhibitor that is extensively, rapidly and proportionately absorbed after oral dosing from 50–200mg. Its major metabolite has a similar JAK1 selectivity profile but with reduced potency. In humans, exposure to the metabolite is higher by approximately 16–20 fold compared with the parent FIL. FIL an...

Keywords:

• JAK,
• Filgotinib,
• PK/PD

JAK Inhibition as a Therapeutic Strategy for Immune and Inflammatory Diseases

Nat Rev Drug Discov 2017;16:843–62 DOI: 10.1038/nrd.2017.201

Schwartz DM,

Kanno Y,

Villarino A,

Ward M,

Gadina M,

O’Shea JJ

Janus kinases (JAKs) are essential mediators of downstream signaling pathways in many inflammatory and autoimmune diseases. This review summarizes current clinical data on first- and second-generation JAK inhibitors (jakinibs) and discusses their use for the treatment of immune and inflammatory conditions.First generation jakinibs such as tofacitinib, baricitinib, and ruxolitinib, non-selectively inhibit JAK-dependent pro-inflammatory cytokines, which are major contributors to immunopathology. T...

Keywords:

• JAK,
• Review

Pathogenetic Insights from the Treatment of Rheumatoid Arthritis

Lancet 2017;389:2328–37 DOI 10.1016/S0140-6736(17)31472-1

McInnes I,

Schett G

This review paper examines the understanding gained from looking at the effects of specific immune interventions in the treatment of RA.The introduction of novel IL-6 agents has provided the ideal opportunity to explore the distinct effect of cytokine inhibition, as opposed to receptor inhibition, at the molecular level. Mechanistic insights into TNF could also be obtained in the future with advanced molecular and informatics approaches, and future biopsy studies will be important to explore the...

Keywords:

• Basic Science,
• Review