January 21
Nash P, Kerschbaumer A, Dorner T, Dougados M, Fleischmann RM, Geissler K, McInnes I, Pope JE, van der Heijde D, Stoffer-Marx M, Takeuchi T, Trauner M, Winthrop KL, de Wit M, Aletaha D, Baraliakos X, Boehncke W-H, Emery P, Isaacs JD, Kremer J, Lee EB, et al.
Ann Rheum Dis 2021;80:71–87.
JAKi are approved in various immune-mediated inflammatory diseases. With five JAKi now licensed, this paper reviews key points to consider in their use to assist clinicians, patients, and other stakeholders once the decision is made to commence JAKi. The consensus was developed by a Steering Committee and an expanded Task Force using EULAR standard operating procedures. The committee included patients as well as experts in rheumatology, gastroenterology, haematology, dermatology, and infectious ...
December 20
Kerschbaumer A, Smolen JS, Nash P, Doerner T, Dougados M, Fleischmann R, Geissler K, McInnes IM, Takeuchi T, Trauner M, Winthrop K, de Wit M, Boehncke W-H, Falzon L, van der Heijde D.
RMD Open 2020;6:e001374 doi:10.1136/rmdopen-2020-001374
Trials of JAKi have been conducted in many therapy areas, including rheumatology, dermatology and gastroenterology. In 2019, a task force was set up to create a consensus to guide clinicians on how to use JAKi in clinical practice. This systematic literature review conducted in 2019 support this consensus In line with EULAR’s standardised operating procedures for recommendations, a literature search was conducted in EMBASE, Medline and the Cochrane Library databases. To evaluate the effica...
July 20
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.
Annals of the Rheumatic Diseases 2020;79:760-770
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, a...
Keywords: Safety
Kerschbaumer A, Smolen JS, Dougados M, De Wit M, Primdahl J, McInnes I, Van Der Heijde D, Baraliakos X, Falzon L, Gossec L.
Annals of the Rheumatic Diseases 2020;79:778-786
This SLR reviewed data on pharmacological treatment of PsA. Findings informed the 2019 EULAR taskforce when updating recommendations for PsA management. Overall, no new safety signals were reported. Encouragingly, LTEs of JAKi did not report any venous thromboembolic events or PEs. Efficacy was demonstrated for a range of bDMARD and tsDMARD therapies in various disease domains. Efficacy varied between PsA manifestations and between therapies. Observational data demonstrated efficacy when switchi...
Keywords: Cytokine Signalling, Safety
February 20
Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, McInnes IB, Sepriano A, et al.
Ann Rheum Dis. 2020 Jan 22. pii: annrheumdis-2019-216655.
The EULAR recommendations for the management of RA have become increasingly useful in providing rheumatologists, patients, payers and other stakeholders with the evidence-based guidance and views of experts on the optimal use and sequence of pharmaceutical therapies in patients with RA. Over the course of the last decade, the evolution of the treatment landscape has already required two updates. The release of the new addition updates the 2016 recommendations. An international task force consid...
Keywords: JAK
October 19
Gladman DD, Charles-Schoeman C, McInnes IB, Veale DJ, Thiers B, Nurmohamed M, Graham D, Wang C, Jones T, Wolk R, DeMasi R.
Arthritis Care Res (Hoboken) 2019;71(10):1387–95
Serum lipid level increases at month 3 following TOF treatment in PsA were consistent with observation in RA and psoriasis. The risk of CV disease is higher in people with PsA versus the general population – comparable with the well-documented rates seen in RA and diabetes. The reasons for this are not fully elucidated, but it has been suggested that there is an association between peripheral joint inflammation and lipid dysregulation in PsA. This post hoc analysis of pooled data from ...
Keywords: JAK, Tofacitinib, Clinical, Safety
September 19
McInnes IB, Byers NL, Higgs RE, Lee J, Macias WL, Na S, Ortmann RA, Rocha G, Rooney TP, Wehrman T, Zhang X, Zuckerman SH, Taylor PC.
Arthritis Res Ther. 2019 Aug 2;21(1):183
Different JAKinibs modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signalling pathway throughout the dosing interval. This study aimed to compare the in vitro cellular pharmacology of BARI, TOF and UPA across relevant leukocyte subpopulations, coupled with their in vivo PK, to determine their effects on distinct cytokine pathways. Peripheral blood mononuclear cells from healthy donors were incubated with differen...
Keywords: JAK, Upadacitinib, Preclinical, Selectivity
January 19
Tanaka Y, McInnes IB, Taylor PC, Byers NL, Chen L, de Bono S, Issa M, Macias WL, Rogai V, Rooney TP, Schlichting DE, Zuckerman SH, Emery P.
Arthritis Rheumatol. 2018 Dec;70(12):1923-1932. doi: 10.1002/art.40680
This review shows that changes in lymphocyte subsets were largely within normal reference ranges and were not associated with efficacy or safety end points. BARI is a selective JAK1/JAK2 inhibitor, approved for the treatment of moderate to severe RA. BARI treatment is associated with changes to circulating lymphocyte and lymphocyte subsets, however detailed analyses of these effects, and their relevance to efficacy and safety is lacking. This study investigated the changes in lymphocyte cell s...
Keywords: JAK, Baricitinib, Clinical, Safety
September 18
Taylor PC, Kremer JM, Emery P, Zuckerman SH, Ruotolo G, Zhong J, Chen L, Witt S, Saifan C, Kurzawa M, Otvos JD, Connelly MA, Macias WL, Schlichting DE, Rooney TP, de Bono S, McInnes IB.
Ann Rheum Dis. 2018 Jul;77(7):988-995. DOI 10.1136/annrheumdis-2017-212461
Baricitinib (BARI) was associated with increased lipid levels; baseline statins did not alter these profiles. The introduction of statins during treatment reduced total cholesterol and LDL-C. The use of anti-inflammatory drugs in RA patients has been shown to alter lipid levels and is associated with reduced atherogenic risk. Increases in lipid levels, specifically HDL-C and LDL-C, have been observed in Phase 2 BARI studies1. This study analysed data from seven randomised RA Phase 2/3 studies o...
Keywords: JAK, Baricitinib, Real World, Cardiovascular
July 17
McInnes I, Schett G.
Lancet 2017;389:2328–37 DOI 10.1016/S0140-6736(17)31472-1
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 t...
Keywords: Cytokine Signalling, Preclinical, MOA
December 15
Gabay C, McInnes IB, Kavanaugh A, Tuckwell K, Klearman M, Pulley J, Sattar N.
Ann Rheum Dis. 2015;0:1-7. doi:10.1136/annrheumdis-2015-207872 [Epub ahead of print]
RA patients have increased risk of CVD compared with the general population that is not fully explained by traditional risk factors. This is a post-hoc analysis of data from a clinical trial that compared IL-6 and TNF-α signaling inhibition to compare changes in lipids and lipid-associated CV risk markers in 324 patients treated with TCZ IV q4w or ADA SC q2w for 24 weeks. HDL-SAA and sPLA2 IIA is also measured in an additional subpopulation of 87 and 97 TCZ and ADA patients, respectively. ...
Keywords: IL-6, Tocilizumab, Cardiovascular
January 15
Charles-Schoeman C, Fleischmann R, Davignon J, Schwartz H, Turner S, Beysen C, Milad M, Hellerstein M, Luo Z, Kaplan I, Riese R, Zuckerman A, McInnes IB.
Arthritis Rheumatol. 2015;67(3):616-25.
Active RA is associated with changes in both high- and low-density lipoprotein cholesterol as well as changes in the level and function of several HDL-associated proteins, yet the pathways and mechanisms involved with systemic inflammation altered lipid metabolism have not been determined. In addition, treatments for active RA are known to modify lipid metabolism, such as increasing circulating cholesterol levels. In the clinical development programme, a proportion of tofacitinib-treated patien...
Keywords: Cytokine Signalling, Preclinical, MOA
September 13
Nijjar JS, Tindell A, McInnes ID and Siebert S.
Rheumatology 2013;52:1556–1562 doi:10.1093/rheumatology/ket225
Both the innate and adaptive immune responses are targeted by current RA treatments, but these treatments do not achieve consistent sustained disease remission. Protein kinase inhibitors represent a promising new therapeutic target, owing to their influence on downstream signalling and oral bioavailability. Fostamatinib (R788) has shown ACR20 responses of 67–72% in MTX inadequate responder patients at doses of 100mg bd and 150mg bd. However, the results in biologic non-responder patients w...
Keywords: Cytokine Signalling, Preclinical, MOA
June 13
McInnes IB, Ho-Youn K, Sang-Heon L, et al.
Annals of Rheumatic Diseases 2013; doi:10.1136/annrheumdis-2012-202442
This randomised, placebo-controlled, multicentre phase 2 study evaluated the efficacy and safety of atorvastatin versus placebo in modifying lipids in 111 patients with active rheumatoid arthritis (RA) receiving tofacitinib. All patients took tofacitinib 10 mg twice daily for 12 weeks, and after the first 6 weeks patients were randomised 1:1 to receive either atorvastatin 10 mg once daily (n=50) or matched placebo (n=48) in a double-blind phase for a further 6 weeks. Tofacitinib-induced elevatio...
Keywords: JAK, Tofacitinib, Clinical, Phase 2