The impact of tofacitinib on fatigue, sleep, and health‑related quality of life in patients with rheumatoid arthritis: a post hoc analysis of data from Phase 3 trials

Bartlett SJ, Bingham CO, van Vollenhoven R, Murray C, Gruben D, Gold DA, Cella D.
Arthritis Res Ther. 2022;24(1):83 doi: 10.1186/s13075-022-02724-x

This was an exploratory post hoc analysis of pooled data, from over 2000 patients in three Phase 3 studies of tofacitinib, which demonstrates an association between tofacitinib treatment and significantly greater improvements in fatigue, sleep, and health-related quality of life (HRQoL), compared with placebo. Affecting a large majority of patients with RA, fatigue is a common symptom of the disease and is detrimental to HRQoL. However, the clinical significance of this overwhelming, unpredicta...

Effectiveness of baricitinib and tofacitinib compared with bDMARDs in RA: results from a cohort study using nationwide Swedish register data

Barbulescu A, Askling J, Chatzidionysiou K, Forsblad-d'Elia H, Kastbom A, Lindström U, Turesson C, Frisell T.
Rheumatology (Oxford). 2022. Epub ahead of print doi: 10.1093/rheumatology/keac068

Data from the Swedish Rheumatology Quality Register and Swedish Registries, show a higher treatment retention and overall equivalent or better treatment response on baricitinib, compared with bDMARDs or tofacitinib, but no statistically significant differences between tofacitinib and bDMARDs. In this largest population-based study to date, comparing RA patients initiating baricitinib, tofacitinib or bDMARDs, Barbulescu, et al. help to fill some of the current knowledge gaps surrounding the effic...

Effect of dose adjustments on the efficacy and safety of tofacitinib in patients with rheumatoid arthritis: a post hoc analysis of an open-label, long-term extension study (ORAL Sequel)

Mueller RB, Schulze-Koops H, Furst DE, Cohen SB, Kwok K, Wang L, Killeen T, von Kempis J.
Clin Rheumatol. 2022 Jan 1. Epub ahead of print doi: 10.1007/s10067-021-05908-z

Post-hoc analysis shows that dosing up from tofacitinib 5 to 10 mg BID is associated with improved efficacy for up to 12 months, versus staying on 5 mg BID, and dosing down from 10 to 5 mg BID is not generally associated with a significant loss of efficacy. Although clinical trials have generally shown no significant differences, in terms of efficacy and safety, when switching tofacitinib dose up or down, these per-protocol switches are not directly informative for clinical decision-making in da...

Effect of JAK inhibitors on high- and low-density lipoprotein in patients with rheumatoid arthritis: a systematic review and network meta-analysis

Li N, Gou ZP, Du SQ, Zhu XH, Lin H, Liang XF, Wang YS, Feng P.
Clin Rheumatol. 2022. Epub ahead of print doi: 10.1007/s10067-021-06003-z

Systematic review and network meta-analysis highlight that RA patients who receive recommended doses of the five approved JAK inhibitors (tofacitinib, baricitinib, upadacitinib, filgotinib, and peficitinib) are likely to experience an increase in serum low- and high-density lipoprotein (LDL and HDL) levels. JAK inhibitors have been associated with alterations in levels of LDL and HDL cholesterol, which may lead to dyslipidaemia (an important risk factor for cardiovascular disease). However, the...

Tofacitinib and risk of cardiovascular outcomes: results from the Safety of Tofacitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) study

Khosrow-Khavar F, Kim SC, Lee H, Lee SB, Desai RJ.
Ann Rheum Dis. 2022 Jan 13. Epub ahead of print doi: 10.1136/annrheumdis-2021-221915

Real-world evidence finds no increased risk of CV outcomes with tofacitinib, in comparison with TNFi, in patients with RA. However, an elevated risk of CV outcomes cannot be ruled out in patients with CV risk factors or history of CVD. Recent post-marketing findings from the ‘ORAL Surveillance’ trial have raised concerns that tofacitinib, in comparison with TNFi, may increase the risk of CV disease in patients with RA who are at least 50 years of age and with at least one risk factor...

Cardiovascular and Cancer Risk With Tofacitinib in Rheumatoid Arthritis

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.
N Engl J Med 2022;386:316–26.

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.

Clinical Management of Herpes Zoster in Patients With Rheumatoid Arthritis or Psoriatic Arthritis Receiving Tofacitinib Treatment

Winthrop KL, Curtis JR, Yamaoka K, Lee EB, Hirose T, Rivas JL, Kwok K, Burmester GR.
Rheumatol Ther. 2021. Epub ahead of print. doi: 10.1007/s40744-021-00390-0

This post hoc analysis provides the first detailed description of the management and outcomes of HZ events in tofacitinib RA and PsA clinical studies. While prior studies have characterised the increased HZ risk with JAKinibs, the clinical management of these events has not been detailed. To this end, Winthrop, et al. analysed data from 21 RA and 3 PsA clinical studies to evaluate how HZ events and their sequelae were clinically managed during the RA and PsA tofacitinib clinical development pr...

Incidence Rates of Interstitial Lung Disease Events in Tofacitinib-Treated Rheumatoid Arthritis Patients

Citera G, Mysler E, Madariaga H, Cardiel MH, Castañeda O, Fischer A, Richette P, Chartrand S, Park JK, Strengholt S, Rivas JL, Thorat AV, Girard T, Kwok K, Wang L, Ponce de Leon D.
J Clin Rheumatol. 2021;27(8):e482–e490

This post hoc analysis of pooled data from 21 clinical trials in the tofacitinib clinical trial programme highlights the importance of identifying known risk factors of RA-interstitial lung disease (ILD) in clinical practice. Citera, et al. investigated incidence rates of ILD – an extra-articular manifestation of RA – in patients with RA, receiving tofacitinib 5 or 10 mg BID and sort to identify potential risk factors for ILD in these patients.

Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study

Deodhar A, Sliwinska-Stanczyk P, Xu H, Baraliakos X, Gensler LS, Fleishaker D, Wang L, Wu J, Menon S, Wang C, Dina O, Fallon L, Kanik KS, van der Heijde D.
Ann Rheum Dis. 2021 Apr 27;80(8):1004–13.

A Phase 3 study assesses the efficacy and safety of tofacitinib in adults with active AS. Deodhar, et al. found that ASAS20 and ASAS40 response rate significantly increased with tofacitinib 5 mg BID versus placebo at Week 16, with improvements maintained to Week 48. There were no new safety signals detected over the course of the study.

Tofacitinib in juvenile idiopathic arthritis: a double-blind, placebo-controlled, withdrawal phase 3 randomised trial

Ruperto N, Brunner HI, Synoverska O, Ting TV, Mendoza CA, Spindler A, et al.
Lancet. 2021;398(10315):1984–96

Pivotal trial data show that tofacitinib is an effective treatment in patients with polyarticular course juvenile idiopathic arthritis (pJIA). New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections. To this end, Ruperto, et al. assessed the efficacy and safety of tofacitinib versus placebo in patients with pJIA (N=225). They observed a JIA flare rate at Week 44 of 29% and 53% for tofacitinib and placebo, respectively. Safety results were s...

Efficacy and safety of tofacitinib versus baricitinib in patients with rheumatoid arthritis in real clinical practice: analyses with propensity score-based inverse probability of treatment weighting

Miyazaki Y, Nakano K, Nakayamada S, Kubo S, Inoue Y, Fujino Y, Tanaka Y.
Ann Rheum Dis. 2021;80(9):1130-1136

Propensity score-based inverse probability of treatment weighting shows that efficacy may differ between tofacitinib and baricitinib. Miyazaki, et al. compared the efficacy and safety of the two JAK inhibitors in real-world clinical practice, after reduction to a minimum of the selection bias, using propensity score-based inverse probability of treatment weighting, and adjustment for confounding patient characteristics. They found that tofacitinib may be less effective in patients resistant to m...

Reactivation of hepatitis B virus infection in patients with rheumatoid arthritis receiving tofacitinib

Wang ST, Tseng CW, Hsu CW, Tung CH, Huang KY, Lu MC, Lai NS.
Int J Rheum Dis. 2021. Epub ahead of print

Tofacitinib could induce Hepatitis B virus (HBV) reactivation in RA patients.With previous studies having already demonstrated that RA patients using biologic agents, might experience HBV reactivation leading to acute hepatitis, hyperbilirubinemia, and death, Wang, et al. aimed to investigate HBV reactivation in patients with RA receiving tofacitinib. They found that Hepatitis B surface antigen positive patients receiving tofacitinib have a high incidence rate of HBV reactivation, which could be...

Real‑world evaluation of effectiveness, persistence, and usage patterns of monotherapy and combination therapy tofacitinib in treatment of rheumatoid arthritis in Australia

Bird P, Littlejohn G, Butcher B, Smith T, O'Sullivan C, Witcombe D, Griffiths H.
Clin Rheumatol. 2021. Epub ahead of print doi: 10.1007/s10067-021-05853-x

Real-world evidence suggests that monotherapy and combination therapy tofacitinib is an effective intervention in RA with persistence and effectiveness comparable to bDMARDs. Despite recommendations from EULAR that bDMARDs and tsDMARDs be used in combination with csDMARDs for the treatment of RA, it is estimated that up to a third of patients take their medication as monotherapy. This post hoc analysis of data from the Australian OPAL study by Bird, et al. aimed to describe the real-world eff...

Contribution of a European-Prevalent Variant Near CD83 and an East Asian-Prevalent Variant Near IL17RB to Herpes Zoster Risk in Tofacitinib Treatment: Results of Genome-Wide Association Study Meta-Analyses

Bing N, Zhou H, Chen X, Hirose T, Kochi Y, Tsuchida Y, Ishigaki K, Sumitomo S, Fujio K, Zhang B, Valdez H, Vincent MS, Martin D, Clark JD.
Arthritis Rheumatol. 2021;73(7):1155–66

Genetic analysis of tofacitinib-treated subjects with RA or PsO identified multiple loci associated with increased herpes zoster (HZ) risk. It is well known that HZ risk is elevated in subjects with RA compared with the general population, and that treatment with JAK inhibitors may result in increased risks compared with TNFi and other bDMARD treatments. To this end, Bing, et al. used genome-wide association studies to identify genetic factors associated with an increased risk/faster onset of...

Real-World Comparative Effectiveness and Safety of Tofacitinib and Baricitinib in Patients With Rheumatoid Arthritis

Iwamoto N, Sato S, Kurushima S, Michitsuji T, Nishihata S, Okamoto M, Tsuji Y, Endo Y, Shimizu T, Sumiyoshi R, Suzuki T, Okada A, Koga T, Kawashiri SY, Fujikawa K, Igawa T, Aramaki T, Ichinose K, Tamai M, Nakamura H, Mizokami A, Origuchi T, Ueki Y, Eguchi K, Kawakami A.
Arthritis Res Ther. 2021;23(1):197

In a real-world setting, tofacitinib and baricitinib have comparable continuing efficacies and safety profiles in patients with RA. It is important to determine the differences and similarities of JAK inhibitors in a real-world setting so that the optimal agent can be administered. However, until now, no published data of a direct comparison among these agents in RA have been available. With this in mind, Iwamoto, et al. compared the efficacy and safety of tofacitinib with those of baricitinib ...

Median Time to Pain Improvement and the Impact of Baseline Pain Severity on Pain Response in Patients with Psoriatic Arthritis Treated with Tofacitinib

de Vlam K, Ogdie A, Bushmakin AG, Cappelleri JC, Fleischmann R, Taylor PC, Azevedo V, Fallon L, Woolcott J, Mease PJ.
RMD Open. 2021;7(2):e001609.

Tofacitinib 5 mg twice daily provides clinically meaningful improvements in pain for patients with PsA. Reducing pain is a primary treatment concern for patients with PsA. As such, de Vlam, et al. set out to evaluate the time to pain improvement and the impact of baseline pain severity on pain response in patients with PsA receiving tofacitinib. Using data from the OPAL Broaden and OPAL Beyond trials, they discovered that clinically important improvements in pain were experienced by more patie...

Tofacitinib versus tocilizumab in the treatment of biological-naïve or previous biological-failure patients with methotrexate-refractory active rheumatoid arthritis

Mori S, Urata Y, Yoshitama T, Ueki Y.
RMD Open. 2021;7(2):e001601.

Findings from a multicentre cohort study in Japan provide important information that is expected to aid in determining the position of tofacitinib in the treatment algorithm for RA. Mori S, et al. compared therapeutic outcomes, from real-world registries, at 12 months between tofacitinib-treated and tocilizumab-treated patients to clarify whether tofacitinib should only be considered as an option for patients who have either failed to respond to at least one bDMARD or are MTX-resistant/-intoler...

Comparative efficacy and safety of secukinumab, ixekizumab, and tofacitinib in patients with active psoriatic arthritis showing insufficient response to tumor necrosis factor inhibitors

Song GG, Lee YH.
Int J Clin Pharmacol Ther. 2021. Epub ahead of print.

Bayesian network meta-analysis of randomised controlled trials (RCTs) highlights the effectiveness of secukinumab, ixekizumab, and tofacitinib in patients with psoriatic arthritis (PsA) and an inadequate response to tumour necrosis factor inhibitors (TNFi). There is a current need for therapies with alternative mechanisms of actions to DMARDs and TNFi, for the significant proportion of patients with PsA who insufficiently respond to these therapies. While RCTs for therapies such as secukinum...

Assessment of radiographic progression in patients with rheumatoid arthritis treated with tofacitinib in long-term studies

van der Heijde D, Landewé RBM, Wollenhaupt J, Strengholt S, Terry K, Kwok K, Wang L, Cohen S.
Rheumatology (Oxford). 2021;60(4):1708-1716.

Long-term evaluation of tofacitinib has found limited progression of structural damage in patients with RA treated with tofacitinib for up to 5 years. Similar results were also observed for patients receiving tofacitinib monotherapy or combination therapy for up to 3 years. It is well known that inflammation in RA leads to structural damage over time, and therapies such as DMARDS have the ability to reduce inflammation whilst inhibiting the progression of structural damage. In this study, van...

Risk of venous thromboembolism associated with tofacitinib in patients with rheumatoid arthritis: a population-based cohort study

Desai RJ, Pawar A, Khosrow-Khavar F, Weinblatt ME, Kim SC.
Rheumatology (Oxford). 2021 Mar 22:keab294. Epub ahead of print. DOI: 10.1093/rheumatology/keab294

A population-based cohort study of 87,653 RA patients has found no evidence for an increased risk of venous thromboembolism (VTE) for tofacitinib, versus TNFis, in patients with RA. The introduction of JAKinibs, almost a decade ago, has provided an important oral option for the treatment of RA. However, in recent years, a safety concern, relating to incidence of VTE after treatment, has emerged. Consequently, both the US and European regulatory authorities now recommend caution for use of tofaci...

JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib

Traves PG, Murray B, Campigotto F, Galien R, Meng A, Di Paolo JA.
Ann Rheum Dis. 2021 Mar 19:annrheumdis-2020-219012. Epub ahead of print. DOI: 10.1136/annrheumdis-2020-219012

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, S...

Efeitos de Um Ano de Terapia com Tofacitinib no Metabolismo Ósseo em Artrite Reumatoide

Hamar A, Szekanecz Z, Pusztai A, Czókolyová M, Végh E, Pethő Z, Bodnár N, Gulyás K, Horváth Á, Soós B, Bodoki L, Bhattoa H P, Nagy G, Tajti G, Panyi G, Szekanecz É, Domján A, Hodosi K, Szántó S, Szűcs G, Szamosi S.
Osteoporos Int 2021 Feb 9 DOI 10.1007/s00198-021-05871-0

Thought to be the first study of its kind, Hamar, et al. have demonstrated the effect of one-year tofacitinib treatment on bone mineral density (BMD) in RA patients. While the association between RA and osteoporosis is well known, and evidence indicates that up to 70% of these patients have reduced BMD, little information is available on how the JAK inhibitor tofacitinib affects bone status, areal and volumetric BMD, and bone turnover markers. In this prospective study, 30 patients were asse...

Estudo de Segurança Comparativa Pós-Aprovação de Tofacitinib e Fármacos Biológicos Antirreumáticos Modificadores de Doença: Resultados de 5 anos de um Registro de Artrite Reumatoide Sediado nos Estados Unidos

Kremer JM, Bingham CO 3rd, Cappelli LC, Greenberg JD, Madsen AM, Geier J, Rivas JL, Onofrei AM, Barr CJ, Pappas DA, Litman HJ, Dandreo KJ, Shapiro AB, Connell CA, Kavanaugh A.
ACR Open Rheumatol. 2021 Feb 11.

Analysis from the US Corrona RA registry has provided the longest-term real-world safety data for a JAK inhibitor to date. The analysis showed that the cohorts had similar adverse events, except for higher herpes zoster rates for tofacitinib initiators vs bDMARDs. Kremer JM, et al. analysed adult patients with RA newly initiating tofacitinib, or a bDMARD, to compare incidence rates of MACE, SIEs, HZ, malignancies and death. VTE data were also collected prospectively and assessed descriptively t...

Keywords: JAK, Tofacitinib, Clinical

Tofacitinib em Artrite Psoriásica: Sinais e Sintomas e Qualidade de Vida Relacionada à Saúde em dois Estudos Randomizados de Fase 3

Merola JF, Papp KA, Nash P, Gratacós J, Boehncke W-H, Thaçi D, Graham D, Hsu M-A, Wang C, Wu J, Young P.
J Eur Acad Dermatol Venereol 2020;34:2809–2820.

Considering the multi-domain nature of PsA, effective treatments must demonstrate efficacy across a range of clinical and patient-reported outcomes. Dermatologic symptoms often precede rheumatic manifestations in people with PsA, typically by 10 years. Tofacitinib demonstrated significant improvements across a range of outcomes including burdensome dermatologic symptoms. This post hoc analysis included data from two double-blind, Phase 3 studies in patients with active PsA and an inadequate res...

Keywords: JAK, Tofacitinib, Clinical, Phase 3

Incidência Baseada em Idade (<65 vs ≥65 anos) de Infecções e Infecções Graves com Tofacitinib versus DMARDs biológicos nos Ensaios Clínicos em Artrite Reumatoide nos EUA e no Registro Corrona RA

Winthrop KL, Citera G, Gold D, Henrohn D, Connell CA, Shapiro AB, Shi H, Onofrei AM, Pappas DA, Schulze-Koops H.
Ann Rheum Dis 2020; DOI: 10.1136/annrheumdis-2020-218992

Reports from clinical trials and the US Corrona RA registry showed that serious infection event (SIE) incidence was higher in older versus younger patients with RA receiving 10 mg BID of TOF and ADA, however, SIE risk was similar between age groups with TOF 5 mg BID and ADA. Data were collected from Phase II–IV tofacitinib studies, and the US Corrona RA registry. The clinical data set evaluated patients receiving TOF 5 and 10 mg BID versus TNFi (ADA/ETN) in RA patients aged ≥50 years. ...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor Kos

Tofacitinib e Baricitinib são Capturados por Diferentes Mecanismos de Celulares Determinando a Eficácia de Ambos os Fármacos em AR

Amrhein J, Drynda S, Schlatt L, Karst U, Lohmann C, Ciarimboli G, Bertrand J.
Int. J. Mol. Sci. 2020; 21:6632 DOI: 10.3390/ijms21186632

Amrhein et al examined the different uptake and expulsion mechanisms of BARI and TOF in cellular assays. Different cellular uptake mechanism for BARI and TOF was observed and showed that BARI’s transport was not dependent on organic cation transporters. Results indicated TOF was exported from RASF in a MATE-1 dependent way. TOF might be exported from healthy cells, thereby not inhibiting JAK pathway in these cells The interaction of BARI and TOF with OCTs was investigated using quenching ...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Igor Kos

Incidência de Eventos Tromboembólicos Arteriais e Venosos Reportados nos Programas de Desenvolvimento de Tofacitinib em Artrite Reumatoide, Psoríase e Artrite Psoriática e de Dados de Mundo Real

Mease P, Charles-Schoeman C, Cohen S, Fallon L, Woolcott J, Yun H, Kremer J, Greenberg J, Malley W, Onofrei A, Kanik KS, Graham D, Wang C, Connell C, Valdez H, Hauben M, Hung E, Madsen A, Jones TV, Curtis JR.
Annals of the Rheumatic Diseases 05 August 2020 2020 Nov;79(11):1400-1413. doi: 10.1136/annrheumdis-2019-216761. Epub 2020 Aug 5.

Concerns surrounding increased rates of PE and cardiovascular associated deaths has led to black box warnings when prescribing JAK inhibitors. As such, ongoing investigations regarding cardiovascular and VTE event risks in JAK inhibitor therapies, both clinical and real-world, are vital. Mease and colleagues consider data from clinical tofacitinib development programmes, and the ongoing real-data study A3921133. Conclusions from data analysis state that those with pre-existing cardiovascular and...

Keywords: JAK, Tofacitinib, Cardiovascular

Translated by: Igor Koz

https://drive.google.com/file/d/1kYemQVjGOIePWjcDZX8FCKHAwLmIzByZ/view?usp=sharing

Citera G, Mysler E, Madariaga H, Cardiel M H, Castaneda O, Fischer A, Richette P, Chartrand S, Park J K, Strengholt S, Rivas J L, Thorat A V, Girard T, Kwok K, Wang L.
Journal of Clinical Rheumatology, Aug 2020 doi: 10.1097/RHU.0000000000001552.

This study highlights the importance of accounting for known risk factors of RA-ILD in clinical practice. Interstitial lung disease (ILD) is an extra-articular manifestation of RA. The post-hoc investigated incidence rates of ILD in patients with RA, receiving tofacitinib 5 or 10 mg twice daily, and identified potential risk factors for ILD. This post-hoc analysis comprised a pooled analysis of patients receiving tofacitinib 5 or 10 mg twice daily or placebo from 21 Phase 1-4, and 2 long-term e...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor Koz

Segurança de DMARDs sintéticos e biológicos: uma revisão sistemática de literatura informando a atualização de 2019 das recomendações EULAR para o tratamento da artrite reumatoide

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

Translated by: Igor Koz

Tratamento Farmacológico na Artrite Psoriática: Uma Revisão Sistemática de Literatura para a Atualização das Recomendações EULAR no Tratamento da Artrite Psoriática

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

Translated by: Igor Koz

Segurança e Eficácia de Tofacitinib em Pacientes com Artrite Psoriática Ativa: Análise Provisória de OPAL Balance, um Estudo Aberto de Extensão a Longo Prazo

Nash P, Coates LC, Kivitz AJ, Mease PJ, Gladman DD, Covarrubias-Cobos JA, FitzGerald O, Fleishaker D, Wang C, Wu J, Hsu M, Menon S, Fallon L, Romero AB, Kanik KS.
Rheumatol Ther 2020 doi.org/10.1007/s40744-020-00209-4

This 3-year, open-label, LTE study follows PsA patients previously treated in pivotal studies OPAL Broaden and OPAL Beyond. It demonstrates maintained safety and efficacy of tofacitinib up to 36 and 30 months, respectively. No new safety concerns are highlighted. Previous P3 studies, OPAL Broaden and OPAL Beyond, demonstrated safety and efficacy of 5mg and 10mg tofacitinib BID in PsA. These patients rolled over to OPAL Balance for a period of 36 months. 686 participants were used in this inter...

Keywords: JAK, Tofacitinib, Safety

Translated by: Igor Koz

Retenção do Fármaco com 7 biológicos e tofacitinib em pacientes com artrite reumatóide naive para biológicos eem pacientes que trocaram de biológicos: o estudo de coorte ANSWER

Ebina K, Hirano T, Maeda Y, Yamamoto W, Hashimoto M, Murata K, Takeuchi T, Shiba H, Son Y, Amuro H, Onishi A, Akashi K, Hara R, Katayama M, Yamamoto K, Kumanogoh A, Hirao M.
Arthritis Res Ther 2020;22:142

This paper is based upon a long-term cohort study, namely the ANSWER cohort, an observational multi-centre registry of RA patients in the Kansai district of Japan. Analyses demonstrate a difference in observed drug retention between bDMARDs-naïve and bDMARDs-switched patients. 7 bDMARD treatments were compared in patients with no prior exposure to biologics, with abatacept showing the greatest retention rate. In patients that had switched between these same bDMARDs or to tofacitinib through...

Keywords: JAK, Tofacitinib

Translated by: Igor Koz

Eficiência comparativa de agentes anti-fator de necrose tumoral, biológicos com um modo de ação alternativo e tofacitinib em uma coorte observacional de pacientes com artrite reumatoide na Suíça

Finckh A, Tellenbach C, Herzog L, Scherer A, Moeller B, Ciurea A, von Muehlenen I, Gabay C, Kyburz D, Brulhart L, Müller R, Hasler P, Zufferey P.
RMD Open 2020;6:e001174 doi:10.1136/rmdopen-2020-001174

This nested cohort study found that, in Switzerland, there was a generally limited overall drug maintenance for b/tsDMARD options in RA. Using data from SCQM-RA – a prospective longitudinal registry, overall maintenance (drug survival) was calculated for TNFi, bDMARD-OMA or JAKi in patients with RA. After adjusting for potential confounding factors, there was a higher hazard of drug discontinuation with TNFi compared with tofacitinib; no significant difference was observed between non-TNF ...

Keywords: Cytokine Signalling, Real World, Efficacy

Translated by: Igor Kos

Análise Integrada de Segurança de Tofacitinib em Artrite Psoriásica em Estudos de Fase 3 e de Extensão a Longo Prazo e Comparação com Dados Observacionais de Mundo Real

Burmester GR, Curtis JR, Yun H, FitzGerald O, Winthrop KL, Azevedo VF, Rigby WFC, Kanik KS, Wang C, Biswas P, Jones T, Palmetto N, Hendrikx T, Menon S, Rojo R.
Drug Saf. 2020;43:379-392

Patients with psoriatic arthritis (PsA) had similar safety profile with TOF to that of other systemic therapies in real-world settings, except for the known risk of HZ. Treatment recommendations from EULAR and GRAPPA for patients with PsA vary according to adverse prognostic risk factors, disease manifestations and responsiveness to prior treatment. Safety concerns for most PsA therapies include gastrointestinal AEs, hepatotoxicity, opportunistic infections (OIs) including TB, and SIEs. This s...

Keywords: JAK, Tofacitinib, Real World, Safety

Translated by: Igor Koz

Eficácia e Segurança Relativas de Tofacitinib, Baricitinib, Upadacitinib e Filgotinib em Comparação com Adalimumabe em Pacientes com Artrite Reumatoide Ativa

Lee YH, Song GG.
Z Rheumatol. 2020 DOI: 10.1007/s00393-020-00750-1

This Bayesian network meta-analysis, comparing the relative efficacy and safety of JAK inhibitors, determined BARI 4mg + MTX and UPA 15mg + MTX were the most effective. The analysis included 5451 patients with an inadequate response to MTX and active RA, from four RCTs. Relative effects were converted into a probability allowing each treatment to be ranked. BARI and UPA had significantly higher ACR20 response rates than ADA 40mg + MTX whilst TOF 5mg and FIL 200mg had comparable ACR20 response ...

Keywords: JAK, Baricitinib

Translated by: Igor Koz

Efetividade a Longo Prazo da Vacina Viva Herpes Zoster em Pacientes com Artrite Reumatoide Tratados Posteriormente com Tofacitinib

Winthrop KL, Wouters A, Choy EH, Chen C, Biswas P, Wang L, Soma K, Needle E, Valdez H, Rigby WFC.
Ann Rheum Dis. 2020 10.1136/annrheumdis-2019-216566

The results of ORAL Sequel suggest that the live zoster vaccine (LZV) may not provide adequate long-term protection in patients with RA receiving TOF. This LTE study enrolled 100 patients with RA, 14 weeks post LZV vaccination. Patients received either TOF 5 mg BID, or TOF 10 mg BID in addition to any background csDMARDs. Incidence rates and 95% CIs for HZ post-vaccination were calculated based on time to first event. Short-term varicella zoster vaccine (VZV) specific immunity was evaluated a...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor Koz

Vasculite IgA como Efeito Adverso de Tofactinib em Artrite Reumatoide

Itoh I, Kasuno K, Yamamoto C, Takahashi N, Shimizu H, Ojima T, Hayashi S, Kimura H, Iwano M.
Intern Med. 2020;59(6):817-821

Nephrotoxicity is a key side effect of NSAIDs and DMARDs used to treat RA, while biologics can reportedly cause proliferative glomerulonephritis or crescentic glomerulonephritis. This report reviews a patient on TOF presenting IgA vasculitis as an adverse effect that fully resolved following termination of TOF. Drug induced IgA vasculitis has been previously described for anti-TNFɑ therapies, but this is the first report with JAK inhibitor therapy. This is a case report of a 67-year old woman w...

Keywords: JAK, Tofacitinib, Real World, Safety

Translated by: Igor Koz

Impacto da Inibição de Janus Quinase com Tofacitinib nos Processos Fundamentais de Regeneração Óssea

Gaber T, Brinkman ACK, Pienczikowski J, Diesing K, Damerau A, Pfeiffenberger M, Lang A, Ohrndorf S, Burmester G-R, Buttgereit F, Hoff P.
Int J Mol Sci 2020;21:865

TOF demonstrated a dose-dependent promotion of human mesenchymal stromal cell (hMSC) recruitment under hypoxia, while inhibiting recruitment under normoxia. TOF also dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. As people age, they are more likely to suffer from fractures and delayed bone healing, as well as degenerative joint diseases or osteoporosis. Bone metabolism and fracture healing may be negatively affected by underl...

Keywords: JAK, Tofacitinib, Clinical

Translated by: Igor Koz

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

Mohamed MF, Beck D, Camp HS, Othman AA.
Pharmacodynamics. 2020

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...

Keywords: JAK, Upadacitinib, Preclinical, MOA

Translated by: Igor Kos

Tofacitinib em Combinação com Metotrexato em Pacientes com Artrite Reumatoide: Desfechos Reportados por Pacientes do Estudo de Fase 3 de 24 Meses ORAL Scan

Strand V, van der Heijde D, Tanaka Y, Keystone E, Kremer J, Zerbini C A F, Cardiel M H, Cohen S, Nash P, Song Y-W, Tegzová D, Gruben D, Wallenstein G, Connell C A, Fleischmann R.
Clin Exp Rheumatol . Sep-Oct 2020;38(5):848-857. Epub 2019 Dec 19.

In the ORAL SCAN study, patients receiving TOF 5 mg or 10 mg BID reported significant improvements in patient-reported outcomes at month 3 compared with placebo, which were maintained through 24 months of treatment. RA causes a significant health and socioeconomic burden and affects all aspects of health related quality of life. ORAL Scan included patients with active RA and inadequate response to MTX who were randomised to receive TOF 5 mg or 10 mg BID plus MTX or PBO. This study evaluated the ...

Keywords: JAK, Tofacitinib, Clinical, PRO

Translated by: Igor Koz

Tofacitinib Modula a Resposta Imune in vitro de Células T CD4+ VZV – Específicas em Linfócitos de Pacientes com Artrite Reumatoide

Almanzar A, Kienle F, Schmalzing M, Maas A, Tony H-P, Prelog M.
Rheumatology (Oxford) 2019;58(11):2051–60

TOF significantly modulated the Th1 response to Varicella-zoster-virus (VZV). The poor VZV-specific cellular immune responses in patients with RA may be considered in recommendations regarding appropriate vaccination strategies for enhancing the VZV-specific Th1 response. Previous studies have shown that treatment with JAKinibs increases HZ incidence compared with conventional DMARDs. This cross-sectional in vitro study aimed to investigate the effect of TOF on the VZV-specific T cell immune re...

Keywords: JAK, Tofacitinib, Clinical, Safety

Fatores de Risco para Eventos Cardiovasculares Maiores em Estudos de Extensão a Longo Prazo e de Fase III de Tofacitinib em Pacientes com Artrite Reumatoide

Christina Charles-Schoeman, Ryan DeMasi, Hernan Valdez, Koshika Soma, Lie-Ju Hwang, Mary G Boy, Pinaki Biswas, Iain B McInnes.
Arthritis Rheumatol .2019 Sep;71(9):1450-1459. doi: 10.1002/art.40911. Epub 2019 Aug 6.

Post hoc analyses of the six ORAL studies and two LTE’s suggested that after 24 weeks of TOF treatment, increases in HDL-c and decreases in the TC/HDL-c ratio appeared to be associated with reduced future MACE risk in RA patients. 52 MACE occurred in 4076 patients over 12873 patient-years of exposure. Separate Cox regression models were used to evaluate traditional CV risk factors’ association with time to first MACE at baseline and changes in lipid levels with time to future MACE ...

Keywords: JAK, Tofacitinib, Real World, Cardiovascular

Translated by: Igor Koz

Changes in Lipid Levels and Incidence of Cardiovascular Events Following Tofacitinib Treatment in Patients with Psoriatic Arthritis: A Pooled Analysis Across Phase 3 and Long-Term Extension Studies

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 ...

Resultados de Redução de Dose, Retirada e Reinicio de Tofacitinib em Pacientes com Artrite Reumatoide: Um Estudo Prospectivo Observacional

Mori S, Ueki Y.
Clin Rheumatol. 2019 Aug 9. DOI: 10.1007/s10067-019-04721-z

Following achievement of remission or low disease activity (LDA), a dose reduction strategy of TOF to a 5mg QD dose was preferable to immediate withdrawal of TOF, with lower relapse rates. Clinical remission or LDA early in the disease course is a target for every RA patient. Although maintaining a state of remission or LDA is beneficial to patients, the AEs and costs associated with DMARDs, have significant burdens on patients during life-long RA treatment. This long-term study was performed t...

Keywords: JAK, Tofacitinib, Clinical, Efficacy

Comparação da Regulação da Sinalização de Citoquinas Mediada por Baricitinib, Upadacitinib e Tofacitinib em Subpopulações de Leucócitos Humanos

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

Translated by: Igor

Vacina Viva Zoster em Pacientes com Artrite Reumatoide Tratados com Tofacitinib com ou sem Metotrexate, ou Adalimumab com Metotrexate

Calabrese LH, Abud-Mendoza C, Lindsey SM, Lee SH, Tatulych S, Takiya L, Iikuni N, Soma K, Luo Z, Fleischmann R.
Arthritis Care and Research 2019 DOI: 10.1002/acr.24010

Live zoster vaccine (LZV) was well tolerated, and herpes zoster (HZ) incidence rates were generally similar between treatment groups in vaccinated versus non-vaccinated patients in a subset of RA who received LZV before TOF ± MTX, or ADA + MTX, in ORAL Strategy. It is known that patient with RA are at increased risk of developing HZ though the mechanisms behind this are currently not well understood though therapies, such as TOF, are thought to increase the risk. ACR and EULAR recommend...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor

Uma Revisão Sistemática e Meta-Análise sobre o Risco de Infecções com Moléculas Pequenas Inibidoras de JAK em Artrite Reumatoide

Bechman K, Subesinghe S, Norton S, Atzeni F, Galli M, Cope AP, Winthrop KL, Galloway JB.
Rheumatology (Oxford). DOI: 10.1093/rheumatology/kez087

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...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor

Segurança e Eficácia de Tofacitinib por até 9.5 Anos no Tratamento de Artrite Reumatoide: Resultados Finais de um Estudo de Extensão Global Aberto

Wollenhaupt J, Lee EB, Curtis JR, Silverfield J, Terry K, Soma K, Mojcik C, DeMasi R, Strengholt S, Kwok K, Lazariciu I, Wang L, Cohen S.
Arthritis Res Ther. 2019 Apr 5;21(1):89.

TOF 5 mg and 10mg BID demonstrated a consistent safety profile and sustained efficacy for up to 9.5 years in this open-label LTE ORAL Sequel study. TOF 5 mg and 10 mg BID demonstrated consistent safety (as monotherapy and combination therapy) and efficacy within this open-label LTE study of RA patients. As RA requires long-term treatment, it’s important to assess the long-term efficacy and safety of RA therapies to understand the potential lifelong impact on patient health and quality of ...

Keywords: JAK, Tofacitinib, Clinical, Efficacy

Translated by: Igor

Tuberculose, Hepatite B e Herpes Zoster em Pacientes Tratados com Tofacitinib com Artrite Reumatóide

Zhang Z, Deng W, Wu Q, Sun L.
Immunotherapy. 2019 Mar;11(4):321-333.

The risk of TB and hepatitis B virus (HBV) appears to be no greater with TOF than with bDMARDs. Most cases of TB during TOF studies occurred in regions with high background rate of TB, including east Asian countries. TOF is also associated with a higher rate of herpes zoster (HZ) compared with bDMARDs. DMARDs used to treat RA can increase the risk of infections by causing a degree of immunosuppression. A range of bacterial and viral infections have been observed in association with DMARD thera...

Keywords: JAK, Tofacitinib, Clinical, Safety

Meta-Análise em Rede de Tofacitinib versus Tratamentos Biológicos em Pacientes com Artrite Reumatoide Moderada a Grave

Camean‐Castillo M, Gimeno‐Ballester V, Rios‐Sanchez E, Fenix‐Caballero S, Vázquez‐Real M, Alegre‐del Rey E.
J Clin Pharm Ther. 2019 Jun;44(3):384-396.

This study suggests that many bDMARDs and tsDMARDs can be considered equivalent therapeutic alternatives in bDMARD-naïve RA patients, with inadequate response to csDMARDs. In the absence of randomised controlled trials comparing drugs, indirect comparisons and network meta-analysis may provide information to help select an optimal treatment alternative. In this network meta-analysis, 27 randomized controlled trials were analysed to assess the possibility that some drugs on the market may b...

Keywords: JAK, Tofacitinib, Clinical, Efficacy

Translated by: Igor

Comparações da Replicação Viral da Hepatite C em Pacientes com Artrite Reumatóide Recebendo Tocilizumabe, Abatacepte e Terapia com Tofacitinibe

Chen YM, Huang WN, Liao TL, Chen JP, Yang SS, Chen HH, Hsieh TY, Hung WT, Chen YH, Chen DY.
Ann Rheum Dis. 2019 Jun;78(6):849-850.

Tocilizumab (TCZ), abatacept (ABA) and tofacitinib (TOF) appear to have no major safety concerns for treatment of RA patients with hepatitis C virus (HCV) infections. HCV is an infectious disease which continues to present a major therapeutic challenge for clinicians in treating patients with RA. Previous reports demonstrate that the use of TNF targeted therapies in RA patients with HCV infections appear to have no major safety concerns. During short-term therapy with TCZ and ABA, data has show...

Keywords: JAK, Tofacitinib, Clinical, Safety

Tofacitinib em combinação com o metotrexato em pacientes com artrite reumatóide: eficácia clínica, resultados radiográficos e de segurança do estudo de verificação oral de Fase 3 de 24 meses

van der Heijde D, Strand V, Tanaka Y, Keystone E, Kremer J, Zerbini CAF, Cardiel MH, Stanley Cohen S, Nash P, Song YW, Tegzová D, Gruben D, Wallenstein G, Connell CA, Fleischmann R, ORAL Scan investigators.
Arthritis Rheumatol. 2019 Jun;71(6):878-891

RA patients receiving TOF 5 or 10 mg BID plus MTX showed sustained clinical and radiographic treatment effects through months 12-24. The safety profile was consistent with previous TOF studies. The 12-month data from the ORAL Scan study have been previously reported. This report assesses durability of responses, including structural damage progression, and safety with TOF through 24 months. Patients were randomized 4:4:1:1 to receive TOF 5 or 10 mg BID, or PBO advanced to TOF with stable, ba...

Keywords: JAK, Tofacitinib, Clinical, Safety

A Pooled analysis of the Safety of Tofacitinib as Monotherapy or in Combination with Background Conventional Synthetic Disease-Modifying Antirheumatic Drugs in a Phase 3 Rheumatoid Arthritis Population

Kivitz AJ, Cohen S, Keystone E, van Vollenhoven RF, Haraoui B, Kaine J, Fan H, Connell CA, Bananis E, Takiya L, Fleischmann R.
Semin Arthritis Rheum. 2018 Dec;48(3):406-415. doi: 10.1016/j.semarthrit.2018.07.006.

In this pooled analysis of Phase 3 Tofacitinib (TOF) trials, safety profiles were generally similar between patients receiving monotherapy and combination therapy. Although selected adverse events of interest showed lower incidence rates (IRs) for TOF monotherapy patients. TOF has been studied as monotherapy and in combination with csDMARDs. In this post-hoc analysis, data were pooled from six Phase 3 TOF studies in RA patients to further examine the safety profile when used as monotherapy or i...

Comparative Risk of Venous Thromboembolism with Tofacitinib versus Tumour Necrosis Factor Inhibitor: A Cohort study of Rheumatoid Arthritis Patients

Desai RJ, Pawar A, Weinblatt ME, Kim SC.
Desai RJ, et al. Arthritis Rheumatol. 2019 June;71(6):892-900.

Occurrences of venous thromboembolism (VTE) in 50, 865 RA patients initiating Tofacitinib (TOF) or a TNF inhibitor (TNFi) was infrequent. No significant risk of VTE for TOF versus TNFi was observed. Safety concerns of JAK inhibitor BARI include potentially increased risk of VTE at the higher 4 mg dose. It’s unclear if this is attributable to JAK-inhibition and extends to TOF. This study compared the risk of VTE with TOF, versus TNFi in real-world settings with RA patients. RA patients in...

Evaluation of the Short-, Mid-, and Long-term Effects of Tofacitinib on Lymphocytes in Patients with Rheumatoid Arthritis

van Vollenhoven R, Lee EB, Strengholt S, Mojcik C, Valdez H, Krishnaswami S, Biswas P, Lazariciu I, Hazra A, Clark JD, Hodge J, Wang L, Choy E.
Arthritis Rheumatol 2018 DOI: 10. 1002/art.40780

Tofacitinib (TOF) treatment is associated with short-term transient increases in absolute lymphocyte counts (ALC), followed by a gradual decline to reach steady state by ~48 months. Changes in both ALC and lymphocyte subset counts (LSC) were reversible upon TOF discontinuation. Low ALC but not LSC were associated with an increased risk of serious infective episodes (SIEs) and herpes zoster (HZ). This data supported the treatment recommendations on ALC counts for starting and continuing therapy w...

Herpes zoster in Tofacitinib: Risk is Further Increased with Glucocorticoids but not Methotrexate

Curtis JR, Xie F, Yang S, Bernatsky S, Chen L, Yun H, Winthrop K.
Arthritis Care Res 2018 DOI 10.1002/acr.23769

The rate of Herpes Zoster (HZ) in tofacitinib (TOF) users with concomitant glucocorticoids (GC) was approximately double that of other TOF combination therapies. TOF is an effective treatment for RA. Increased HZ risk has been observed with the use of JAK inhibitors, whereas the HZ risk with biologics and targeted RA therapies are comparable. This study evaluated the HZ risk in TOF users according to concomitant GC, MTX, both, or neither. MarketScan and Medicare data were used to identify 8030 ...

A Network Meta-Analysis Comparing Efficacy and Safety of Tofacitinib and Baricitinib

Bae SC and Lee YH.
Z Rheumatol. 2018 Sep 6. DOI 10.1007/s00393-018-0531-5

Tofacitinib (TOF) 10mg and baricitinib (BARI) 4mg, in combination with methotrexate (MTX), were the most efficacious treatments in RA patients with an inadequate response to DMARDs or biologics. Both combination treatments presented acceptable safety profiles and were not associated with a significant risk of serious adverse events. This study employed a Bayesian approach to Meta-Analysis; combining the available evidence across a network of Randomised Controlled trials (RCTs). Twelve RCTs cont...

Efficacy of Monotherapy with Biologics and JAK inhibitors for the Treatment of Rheumatoid Arthritis: A Systematic Review

Emery P, Pope JE, Kruger K, Lippe R, DeMasi R, Lula S, Kola B.
ADV Ther 2018; 35(10):1525–63 DOI: 10.1007/s12325-018-0757-2

The b/tsDMARDs evaluated in this systematic literature review (SLR) were shown to be efficacious as monotherapies, although combination therapies usually achieved better treatment outcomes. Current treatment guidelines recommend combining b/tsDMARDs with MTX in the treatment of RA; however, up to a third of patients are treated with monotherapy. While previous SLRs1–3 have compared the efficacy of b/tsDMARD mono- versus MTX combination therapy they covered a limited number of randomised co...

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

Atzeni F, Talotta R, Nucera V, Marino F, Gerratana E, Sangari D, Masala IF, Sarzi-Puttini P.
Exp Rev Clin Immunol 2018 Nov;14(11):945-956. DOI: 10.1080/1744666X.2018.1504678

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 usin...

Thromboembolism with Janus Kinase (JAK) Inhibitor for Rheumatoid Arthritis: How Real is the Risk?

Scott IC, Hider SL, Scott DL.
Drug Safety 2018 Jul;41(7):645–53

Current data suggests that JAK inhibitors may increase the risk of thromboembolism and pulmonary thrombosis (PT) in RA. Two JAK inhibitors – baricitinib (BARI) and tofacitinib (TOF) – are considered effective treatments for RA, however, there are concerns about the thromboembolic risks associated with them. In August 2017, the summary of product characteristics for BARI was revised to include a warning of developing DVT and pulmonary embolism (PE), with recommendations that BARI sho...

Long-term Radiographic and Patient-reported Outcomes in Patients with Rheumatoid Arthritis Treated with Tofacitinib: ORAL Start and ORAL Scan Post-hoc Analyses

Strand V, Kavanaugh A, Kivitz AJ, van der Heijde D, Kwok K, Akylbekova E, Soonasra A, Snyder M, Connell C, Bananis E, Smolen JS.
Rheumatol Ther. 2018 Dec;5(2):341-353. doi: 10.1007/s40744-018-0113-7

Tofacitinib (TOF) therapy reduced the progression of structural joint damage at 2 years, in patients of all disease states, compared with patients given methotrexate (MTX). Early intervention with DMARDs aim to prevent the development of future RA symptoms and inhibit the progression of structural damage to the joints. This post-hoc analysis uses data from two Phase 3 TOF studies, to examine the efficacy of early intervention with TOF on long-term radiographic outcomes and disease activity sta...

Analysis of Spontaneous Postmarket Case Reports Submitted to the FDA Regarding Thromboembolic Adverse Events and JAK Inhibitors

Verden A, Dimbil M, Kyle R, Overstreet B, Hoffman KB.
Drug Saf 2018 Apr; 41(4):357–61 DOI: 10.1007/s40264-017-0622-2

Thromboembolic-related adverse events (AEs) were, in general, not considered a class-wide safety concern after analysis of tofacitinib (TOF) and ruxolitinib (RUX) clinical data, though pulmonary thrombosis is considered a potential class-wide safety issue and portal vein thrombosis was considered a potential safety issue for RUX. During analysis of baricitinib (BARI) clinical trial data, the FDA expressed concerns regarding thromboembolic events. Following this, the CHMP have recently added a ...

Tofacitinib in Rheumatoid Arthritis: Lack of Early Change in Disease Activity Predicts a Low Probability of Achieving Low Disease Activity at Month 6

Van Vollenhoven RF, Lee EB, Fallon L, Zwillich SH, Wilkinson B, Chapman D, Demasi R, Keystone E.
Arthritis Care Res (Hoboken) 2019 Jan;71(1):71-79. DOI: 10.1002/acr.23585

This post-hoc analysis of two, Phase 3 studies, ORAL Start and ORAL Standard shows that early treatment response can predict long-term disease activity outcomes. EULAR recommendations suggest that treat-to-target strategies require regular target assessments with treatment approaches changed if targets are not reached at 6 months. To optimize this strategy, therapy outcomes should be known, and the relationship between short and long-term outcomes defined. The current analysis focused on the d...

Evaluation of Disease Activity in Patients with Rheumatoid Arthritis Treated with Tofacitinib by RAPID3: Post Hoc Analyses from Two Phase 3 Trials

Strand V, Lee EB, Yazici Y, Dikranian A, Wilkinson B, Takiya L, Zang C, Bananis E, Bergman MJ.
Clin Rheumatol 2018 Aug; 37(8):2043–53

Patients given tofacitinib (TOF) who achieved Routine Assessment of Patient Index Data 3 (RAPID3) remission or low disease activity (LDA) at 6 months, had improved long-term outcomes at 2 years, compared to patients with moderate or high disease activity (MDA/HDA) at 6 months. RAPID3¹ is a patient-reported evaluation of disease activity, based on pooled PROs; patient global assessment, patient assessment of arthritic pain and HAQ-DI scores. Previous studies with tocilizumab have suggested ...

Tofacitinib for Treating Rheumatoid Arthritis After the Failure of Disease-Modifying Anti-Rheumatic Drugs: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

Uttley L, Bermejo I, Shijie R, Martyn-St James M, Wong R, Scott DL, Young A, Stevenson M.
Pharmacoeconomics 2018 Sep; 36(9): 1063–72

In this National Institute for Health and Care (NICE) single technology appraisal of tofacitinib (TOF) plus methotrexate (MTX), TOF had similar efficacy and comparable costs to recommended bDMARDs plus MTX in patients with RA. NICE is an independent organisation responsible for providing national guidance on health technologies in England. To be recommended by NICE, the company must provide evidence to prove TOF’s effectiveness, both clinically and costly. This evidence based review, rep...

Effectiveness and Safety of Tofacitinib in Rheumatoid Arthritis: a Cohort Study

Machado MAÁ, Moura CS, Guerra SF, Curtis JR, Abrahamowicz M, Bernatsky S.
Arthritis Res Ther 2018; 20(1):60 doi: 10.1186/s13075-018-1539-6

A retrospective cohort study of tofacitinib (TOF) revealed that patients previously treated with methotrexate who initiated TOF, presented no differences in hospitalised infections or effectiveness, compared with non-TNF biologics. Currently, TOF is recommended in ACR and EULAR guidelines as an alternative to biologics after first-line cDMARD therapy. Previous indirect comparisons have shown that patients with RA who experience cDMARD failure show similar efficacy when given TNFis, abatacept, ...

Worldwide, 3-year, Post-Marketing Surveillance Experience with Tofacitinib in Rheumatoid Arthritis

Cohen S, Curtis JE, DeMasi R, Chen Y, Fan H, Soonasra A, Fleischmann R.
Rheumatol Ther 2018 Jun; 5(1):283–91

This real-world analysis of tofacitinib (TOF) revealed that AEs reported by patients with RA from 2012 to 2015 were consistent with the known safety profile of TOF – no new safety risks were identified. As of August 2017, it is estimated that more than 102 000 patients worldwide have received TOF, but TOF safety has not been evaluated in patients with real-world experience. This analysis addressed this – by evaluating the safety of TOF from post-marketing surveillance (PMS) reports ...

Effect of Discontinuation or Initiation of Methotrexate or Glucocorticoids on Tofacitinib Efficacy in Patients with Rheumatoid Arthritis: A Post Hoc Analysis

Fleischmann R, Wollenhaupt J, Cohen S, Wang L, Fan H, Bandi V, Andrews J, Takiya L, Bananis E, Weinblatt ME.
Rheumatol Ther 2018 Jun; 5(1):203–14. DOI: 10.1007/s40744-018-0093-7

Methotrexate (MTX) or Glucocorticoid (GC) discontinuation has little effect on CDAI response in patients given tofacitinib (TOF) for up to 3 years. Patients receiving TOF who showed initial improvements benefitted from initiation of MTX or GCs. Concomitant treatments such as MTX or GC are commonly used in combination with RA therapies to improve or accelerate clinical responses. However, their use is associated with many adverse events so clinicians aim to use them for a minimal duration. This ...

Tofacitinib with Conventional Synthetic Disease-modifying Antirheumatic Drugs in Chinese Patients with Rheumatoid Arthritis: Patient-reported Outcomes from a Phase 3 Randomised Controlled Trial

Li Z, An Y, Su H, Li H, Xu J, Zheng Y, Li G, Kwok K, Wang L, Wu Q.
Int J Rheum Dis 2018; 21(2):402–14

This Chinese sub-population of patients with RA from ORAL Sync reported significant improvements in patient-reported outcomes (PROs), which were maintained up to 12 months from tofacitinib (TOF) treatment initiation. ORAL Sync was a randomised, Phase 3 study investigating TOF therapy in combination with csDMARDs in patients with active RA who had previously had an inadequate response to csDMARDs. To date, this is the only Phase 3 study of TOF in patients from China with RA. This analysis inclu...

Effect of Glucocorticoids on the Clinical and Radiographic Efficacy of Tofacitinib in Patients with Rheumatoid Arthritis: A Posthoc Analysis of Data from 6 Phase III studies

Charles-Schoeman C, van der Heijde D, Bumester GR, Nash P, Zerbini CAF, Connell CA, Fan H, Kwok K, Bananis E, Fleischmann R.
J Rheumatol 2018 Feb; 45(2):177-87

In this post hoc analysis, six Phase 3 studies were used to analyse the effect of glucocorticoids (GC) on the efficacy of tofacitinib (TOF) in patients with RA. Concomitant use of GC did not affect the clinical or radiographic outcomes of patients treated with TOF. Data from all six clinical trials were evaluated, with four studies (ORAL Scan, ORAL Standard, ORAL Sync and ORAL Step) being pooled for analysis. In these studies, MTX was used as a comparison and patients were required to maintain ...

JAK Inhibition as a Therapeutic Strategy for Immune and Inflammatory Diseases

Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ.
Nat Rev Drug Discov 2017;16:843–62 DOI: 10.1038/nrd.2017.201

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. ...

Tofacitinib Therapy for Rheumatoid Arthritis: A Direct Comparison Study between Biologic-naive and Experienced Patients

Mori S, Yoshitama T, Ueki Y.
Intern Med. 2018 Mar 1;57(5):663-670. doi: 10.2169/internalmedicine.9341-17

This 6-month prospective direct comparison study analysed the effectiveness of tofacitinib (TOF) therapy on bDMARD-naïve and bDMARD-experienced patients. bDMARD-naïve patients were more responsive to TOF therapy than bDMARD-experienced patients. The study analysed the data of 113 patients diagnosed with high or moderate disease activity, defined using CDAI scores. All patients had failed to achieve CDAI low disease activity or remission with MTX therapy for ≥3 months. Patients were...

Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy

Winthrop KL, Curtis JR, Lindsey S, Tanaka Y, Yamaoka K, Valdez H, Hirose T, Nduaka CI, Wang L, Mendelsohn AM, Fan H, Chen C, Bananis E.
Arthritis Rheumatol 2017;69(10):1960–68

The results of this analysis of patients with herpes zoster (HZ) within the global tofacitinib (TOF) RA programme suggest that there is likely to be a greater HZ risk in patients receiving TOF and glucocorticoids compared with patients receiving TOF monotherapy. The global TOF RA development programme comprised 2 Phase 1, 9 Phase 2, 6 Phase 3 and 2 long-term extension studies. These studies included 6192 patients; data were reviewed to identify cases of HZ. Crude incidence rates of number of pa...

Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis

Mease P, Hall S, FitzGerald O, van der Heijde D, Merola J F, Avila-Zapata F, Cieslak D, Graham D, Wang C, Menon S, Hendrikx T, Kanik K S.
N Engl J Med 2017; 377:1537-50. DOI: 10.1056/NEJMoa1615975

In the Phase 3 OPAL Broaden trial of patients with active psoriatic arthritis (PsA) with inadequate response to ≥1 csDMARD, superior efficacy was observed in patients treated with tofacitinib (TOF) compared with those given placebo. Patients were randomised to: 5 mg TOF BID, 10 mg TOF BID, 40 mg adalimumab administered subcutaneously q2W, or placebo with a switch to 5 mg TOF at Month 3. Adalimumab was used as an active control in the study. A variety of primary and secondary endpoints wer...

Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors

Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba A, Kudlacz E, Wang C, Menon S, Hendrikx T, Kanik KS.
N Engl J Med 2017;377:1525–36.

The study data presented that tofacitinib (TOF) improves efficacy response rates in patients with severe psoriatic arthritis (PsA) who have an inadequate response to TNF inhibitors. The Phase 3 Oral Psoriatic Arthritis Trial (OPAL) Beyond study evaluated patients with active PsA who had inadequate responses to more than one TNFi. Patients were randomised 2:2:1:1 to 5 mg TOF BID or 10 mg TOF BID for 6 months; or PBO, with a switch to 5 mg TOF BID or to 10 mg BID at 3 months. Primary endpoints w...

Treatment Persistence and Healthcare Costs Among Patients with Rheumatoid Arthritis Changing Biologics in the USA

Chastek B, Chieh-I Chen, Proudfoot C, Shinde S, Kuznik A, Wei W.
Adv Ther. 2017 Nov;34(11):2422-2435. doi: 10.1007/s12325-017-0617-5

Updated treatment guidelines recommend the use of different mechanism of action (MOA) therapies earlier in the treatment course. Clinical studies have revealed that this approach may be better than TNFi cycling, and may be more cost effective. This study of Commercial and Medicare Advantage claims data showed that patients who switched MOA had higher treatment persistence and lower healthcare costs than TNFi cyclers. After the first TNFi claim, patients either cycled to another TNFi (n=935) or...

Lymphoma in the Tofacitinib Rheumatoid Arthritis Clinical Development Program

Mariette X, Chen C, Biswas P, Kwok K, Boy MG.
Arthritis Care Res (Hoboken). 2018 May;70(5):685-694. doi: 10.1002/acr.23421

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...

The Safety and Immunogenicity of Live Zoster Vaccination in Rheumatoid Arthritis Patients Before Starting Tofacitinib: A Randomized Phase II Trial

Winthrop KL, Wouters A, Choy E, Soma K, Hodge J, Nduaka C, Biswas P, Needle E, Passador MS, Mojcik C, Rigby W.
Arthritis Rheumatol. 2017 Oct;69(10):1969-1977. doi: 10.1002/art.40187

Patients with RA who started treatment with tofacitinib 2–3 weeks after being vaccinated against herpes zoster had similar varicella zoster virus (VZV)-specific humoral and cell-mediated responses to the live vaccine compared to patients who received placebo. In this Phase 2 study, humoral and cell-mediated immune responses were evaluated before receipt of live zoster vaccine (LZV) and at 2, 6 and 14 weeks after vaccination, having been randomised to tofacitinib 5 mg BID or placebo, 2&nda...

Herpes Zoster and Tofacitinib Therapy in Patients with Rheumatoid Arthritis

Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, Kawabata T, Riese R.
Arthritis Rheumatol 2014;66:2675–84

Patients who were treated with tofacitinib in the RA clinical development programme were more likely to develop herpes zoster than were those who received placebo. Cases of herpes zoster reported by investigators in the Phase 2, Phase 3 and long-term extension studies of tofacitinib were evaluated. Herpes zoster was noted in 5% of tofacitinib-treated patients; only 7% of these cases were serious, no patients with herpes zoster died and only 10% permanently discontinued tofacitinib treatment. T...

A Comparison of Discontinuation Rates of Tofacitinib and Biologic Disease-modifying Anti-rheumatic Drugs in Rheumatoid Arthritis: a Systematic Review and Bayseian Network Meta-analysis Regression

Park JS-K, Lee MY, Jang E-J, Kim H-L, Ha D-M, Lee E-K.
Clin Exp Rheumatol 2017;35:689–99

Based on a Bayesian network meta-analysis (NMA) in patients with RA who previously showed failure with csDMARDs or biologics, discontinuation rates between tofacitinib (TOF) and biologics (TNFis, abatacept [ABT], rituximab [RTX] and tocilizumab [TCZ]) differed based on previous treatments and reasons for discontinuation. Data were collected from randomised controlled trials (RCT) found from literature searches from the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE. Discon...

Analysis of Non-melanoma Skin Cancer across the Tofacitinib Rheumatoid Arthritis Clinical Programme

Curtis JR, Lee EB, Martin G, Mariette X, Terry TT, Chen Y, Geier J, Andrews J, Kaur M, Fan H, Nduaka CI.
Clin Exp Rheumatol 2017;35:614–22

Because non-melanoma skin cancer (NMSC) is one of the most common malignancies associated with RA immunomodulatory therapies, this analysis looked to determine the rate of NMSC incidence per 100 patient-years in patients with RA receiving TOF in the clinical trial programme. The Phase 1, 2, and 3 IRs (combined) for both TOF 5- and 10 mg were low and comparable to those of adalimumab, MTX and placebo, IRs remained stable over time. TOF doses used in the 2 Phase 1; 8 Phase 2; and 6 Phase 3 studi...

Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials

Cohen BS, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, Winthrop KL, Charles-Shoeman C, Thirunavukkarasu K, DeMasi R, Geier J, Kwok K, Wang L, Riese R, Wollenhaupt J.
Ann Rheum Dis 2017;76:1253-1262. DOI 10.1136/annrheumdis-2016-210457

This analysis of exposure to tofacitinib, an oral JAKi for the treatment of RA, for up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. Adverse events were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports. Data were collated into an integrated safety summary of tofacitinib in adult patients with active RA, and included data spanning the tofacitinib clinical programme: from 2 P...

Efficacy and Safety of Tofacitinib Monotherapy, Tofacitinib with Methotrexate, and Adalimumab with Methotrexate in Patients with Rheumatoid Arthritis (ORAL Strategy): A Phase 3b/4, Double-Blind, Head-To-Head, Randomised Controlled Trial

Fleischmann R, Mysler E, Hall S, Kivitz A, Moots R, Luo Z, DeMasi R, Soma K, Zhang R, Takiya L, Tatulych S, Mojcik C, Krishnaswami S, Menon S, Smolen J, on behalf of the ORAL Strategy investigators.
Lancet. 2017 Jul 29;390(10093):457-468. doi: 10.1016/S0140-6736(17)31618-5

In this first head-to-head non-inferiority trial assessing a JAKi ± MTX directly compared with a TNFi + MTX in patients with RA, tofacitinib (TOF) + MTX showed non-inferiority to adalimumab (ADA) + MTX. Non-inferiority was not shown for TOF monotherapy versus TOF + MTX, or versus ADA + MTX. In this 52-week study, MTX-inadequate responder (IR) patients were randomised 1:1:1 to receive TOF 5 mg BID monotherapy, TOF 5 mg BID + MTX or ADA 40 mg every other week + MTX. The primary endpoint, A...

Biologics or Tofacitinib for People with Rheumatoid Arthritis Naïve to Methotrexate: a Systematic Review and Network Meta-analysis

Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Tanjong Ghogomu E, Suarez-Almazor ME, Buchbinder R, Maxwell LJ, Tugwell P, Wells GA.
Cochrane Database Syst Rev. 2017 May 8;5:CD012657. doi: 10.1002/14651858.CD012657

This Cochrane systemic review and network meta-analysis looked at the benefits and harms of biologics or tofacitinib in patients with RA not previously treated with MTX. Using data from 19 RCTs including 6,485 participants, the review found that biologics (abatacept, adalimumab, etanercept, golimumab, infliximab, rituximab) in combination with MTX improved signs and symptoms of RA (ACR50) and increased the chances of remission (DAS <1.6 or DAS28 <2.6). There was also some evidence of an ...

Estimated Medical Expenditure and Risk of Job Loss among Rheumatoid Arthritis Patients undergoing Tofacitinib Treatment: Post Hoc Analyses of Two Randomized Clinical Trials

Rendas-Baum R, Kosinski M, Singh A, Mebus CA, Wilkinson BE and Wallenstein GV.
Rheumatology doi: 10.1093/rheumatology/kex087

The results of this post hoc analysis of two Phase 3 studies of tofacitinib (TOF) show that improvements in health-related quality of life related to TOF treatment are likely to translate into significant reductions in estimated medical expenditure and likelihood of current and future job loss. Data from 399 MTX inadequate responder (IR) patients from ORAL Step, and 716 TNF inhibitor (TNFi)-IR patients from ORAL Standard were included in this analysis. Patients were receiving 5 mg or 10 mg TOF...

Discontinuation of Tofacitinib after achieving Low Disease Activity in Patients with Rheumatoid Arthritis: a Multicentere, Observational Study

Kubo S, Yamaoka K, Amano K, Nagano S, Tohma S, Suematsu E, Nagasawa H, Iwata K and Tanaka Y.
Rheumatology. Doi 10.1093/rheumatology/kex068

This study showed that in patients who achieved low disease activity (LDA), it is possible to discontinue tofacitinib without flare in approximately one-third of patients. Patients from the tofacitinib Phase 3 programme and long-term extension study were enroled. Discontinuation was based on physician-patient decision making with informed consent. The primary endpoint was the proportion of patients who remained tofacitinib free at post-treatment Week 52. Of 64 patients treated with tofacitin...

EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-modifying Antirheumatic Drugs: 2016 Update

EULAR RA Management Task Force Smolen J, Landewé R, Bijlsma J, et al.
Ann Rheum Dis Published Online First: 06March2017. doi:10.1136/annrheumdis-2016-210715

The EULAR 2016 recommendations update, based on three systematic literature reviews (SLRs) and expert opinion, comprises four overarching principles and 12 recommendations compared with 14, respectively, in 2013. These recommendations intend to inform regarding EULAR’s most recent consensus on the management of RA, with the aim of attaining the best outcomes with current therapies. All DMARD types: csDMARDs, bDMARDs, tsDMARD and bsDMARD are addressed, and cost aspects are taken into consi...

Cardiovascular Safety of Tocilizumab versus Tumor Necrosis Factor Inhibitors in Patients with Rheumatoid Arthritis – a Multi-database Cohort Study

Kim SC, Solomon DH, Rogers JR, Gale S, Klearman M, Sarsour K and Schneeweiss S.
Arthritis Rheumatol 2017 Feb 28. doi: 10.1002/art.40084

This multi-database population-based US cohort study found no evidence of an increased cardiovascular (CV) risk among RA patients who switched from a different biologic drug or tofacitinib to tocilizumab (TCZ) versus to a TNF inhibitor (TNFi). The study used claims data in patients with RA newly starting treatment with TCZ or a TNFi from three large databases: Medicare (n=7397), PharMetrics (n=8119) and MarketScan (n=12512). Included within the analysis were 9218 TCZ initiators propensity-score...

Efficacy and Safety of Tofacitinib in Older and Younger Patients with Rheumatoid Arthritis

Curtis JR, Schulze-Koops H, Takiya L, Mebus CA, Terry KK, Biswas P and Jones TV.
Clin Exp Rheumatol 2017 Jan 4

In this analysis of patients with moderate to severe RA treated with tofacitinib (TOF) in Phase 3 and long-term extension (LTE) studies, patients aged 65 years had similar efficacy and a numerically higher risk of SAEs and discontinuations due to AEs compared with younger patients. The Phase 3 population included patients from five trials (n=3111) of TOF 5 mg or 10 mg BID or placebo. The LTE population (n=4102) included patients from two studies who had participated in Phase 1, 2 or 3 TOF stud...

Analysis of Haematological Changes in Tofacitinib-treated Patients with Rheumatoid Arthritis across Phase 3 and Long-term Extension Studies

Schulze-Koops H, Strand V, Nduaka C, DeMasi R, Wallenstein G, Kwok K and Wang L.
Rheumatology 2017;56:46–57.

In this analysis examining haematological changes after tofacitinib (TOF) treatment in patients with RA from pooled Phase 3 and LTE studies, TOF decreased mean lymphocyte counts and slightly increased mean haemoglobin (Hb) levels. The Phase 3 population included patients from six trials (n=4271) of TOF 5- or 10 mg BID, placebo or active comparator up to 24 months. The LTE population (n=4858) included patients from two studies (of up to 84 months), who had participated in Phase 1, 2 or 3 TOF st...

Evaluation of Real-World Experience with Tofacitinib Compared with Adalimumab, Etanercept, and Abatacept in RA Patients with 1 Previous Biologic DMARD: Data from a U.S. Administrative Claims Database

Harnett J, Gerber R, Gruben D, Koenig AS and Chen C.
J Manag Care Spec Pharm. 2016 Dec;22(12):1457-1471.

Data were examined to compare patient characteristics, treatment patterns and costs in patients with RA receiving tofacitinib (TOF) or common bDMARDs (adalimumab [ADA], etanercept (ETN) or abatacept [ABA]) who had previously received a single bDMARD. This study analyses real-world data from two US claims databases between November 2012 and October 2014. Data were collected from a total of 1252 patients in the Truven Marketscan Commercial and Medicare Supplemental databases. Pre-index (12-month...

Tofacitinib in Combination with Conventional DMARDs in Patients with Active Rheumatoid Arthritis: PROs from a Phase 3 Randomised Controlled Trial

Strand V, Kremer JM, Gruben D, Krishnaswami S, Zwillich SH, Wallenstein GV.
Arthritis Care Res 2016; Accepted article. DOI 10.1002/acr.23004

Further evidence is presented that treatment with tofacitinib improves patient-reported outcomes (PROs), in addition to improving underlying disease activity. Data were analysed from the Phase 3 ORAL Sync 12-month randomised controlled trial in adult patients with active RA and previous inadequate response to ≥1 conventional or biologic DMARD(s). Patients received (4:4:1:1) TOF 5mg or 10mg BID or Placebo advanced to 5 mg or 10 mg BID plus conventional DMARD(s). PROs assessed at Month 3 were...

Switching from Adalimumab to Tofacitinib in the Treatment of Patients with Rheumatoid Arthritis

Genovese, et al.
Arthritis Research & Therapy. 2016. DOI 10.1186/s13075-016-1049-3 [Epub ahead of print]

Results are reported from an analysis exploring the safety and efficacy of open-label tofacitinib (TOF) following blinded treatment with TOF or adalimumab (ADA) in patients with moderate to severe RA. The analysis included patients from ORAL Sequel, an open-label long-term extension study, which all patients entered following ORAL Standard (one of the studies in the TOF phase 3 program). Only those patients who had been randomized to ADA 40 mg Q2W + MTX or 10 mg TOF + MTX in ORAL Standard were...

Initial Experience with Tofacitinib in Clinical Practice: Treatment Patterns and Costs of Tofacitinib Administered as Monotherapy or in Combination with Conventional Synthetic DMARDs in 2 US Health Care Claims Databases

Harnett et al.
Clin Ther. 2016 Mar 28. doi: 10.1116/j.clinthera. 2016.03.038 [Epub ahead of print]

This study analyzes data from two US claims databases between November 2012 and June 2014. It was designed to build upon knowledge from tofacitinib Phase 3 clinical trials providing clinical insights from independent sources on treatment patterns and costs for tofacitinib. Data were collected from 337 patients in the Truven Marketscan (TM) and 118 patients in the Optum Clinformatics (OC) databases. In this early experience cohort for tofacitinib, approximately 75% of patients had previously re...

Real-world Comparative Risks of Herpes Virus Infections in Tofacitinib and Biologic-treated Patients with Rheumatoid Arthritis

Curtis et al.
Ann Rheum Dis. 2016 Apr 25;0:1–5 doi: 10.1136/annrheumdis-2016-209131

Herpes Zoster (HZ) complications can cause considerable morbidity including debilitating pain syndromes. Clinical trials of tofacitinib have suggested it may increase the risk of HZ. Although unclear, the mechanism may involve reduced CD4 T-cell function and interference of interferon signalling. Following approval of tofacitinib in the US in 2012, real-world data from Medicare (2006–2013) and from the US longitudinal database, Marketscan, (2010–2014) were analysed. A total of 252...

Extended-release once-daily formulation of tofacitinib: evaluation of pharmacokinetics compared with immediate-release tofacitinib and impact of food

Lamba et al.
J Clin Pharmacol. 2016 Mar 11. doi: 10.1002/jcph.734. [Epub ahead of print]

PK profile of TOF is rapid absorption and elimination with time to max concentration 0.5-1 hour and terminal half-life at 3 hours. It is currently approved for immediate release (IR) 5 mg BID, 10 mg total; however, decreasing the dosage to QD dosing may help increase compliance. This study performed in 24 healthy males compared the PK of XR and IR TOF under both single and multiple dose conditions and evaluated the effect of a high-fat meal on the PK of XR TOF. There were no clinically importa...

Tofacitinib or adalimumab versus placebo: patient-reported outcomes from a phase 3 study of active rheumatoid arthritis

Strand V, van Vollenhoven R, Bong Lee E et al.
Strand et al. Rheumatology (Oxford). 2016 Feb 29. doi:pii: kev442. [Epub ahead of print]

RA not only affects the physical aspects of a patient’s health but also has an impact on the psychological well-being causing a significant disease burden. This paper reports on the patient-reported outcomes (PROs) from the ORAL Standard study. This study investigated tofacitinib 5mg BID, 10mg BID, adalimumab vs. placebo over 12 months with a primary endpoint at month 3. All treatment groups showed significant improvements over placebo in HAQ-DI, PtGA and Pain with LSM changes in baselin...

Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials

Strand V, Ahadieh S, French J, Geier J, Krishnaswami S, Menon S, Checchio T, Tensfeldt TG, Hoffman E, Riese R, Boy M, Gomez-Reino JJ.
Arthritis Res Ther. 2015 Dec 15;17(1):362

Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. By modulating the signalling of cytokines that are integral to lymphocyte activation, proliferation, and function, tofacitinib may suppress multiple elements of immune response. A systematic literature search including all biologics and tofacitinib procured 66 RCTs and 22 LTEs that were included in a meta-analysis to provide estimated incidence rates, risk ratios, and risk differences of serious infection for each therapy. ...

Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs

Strand V, Kremer J, Wallenstein G, Kanik KS, Connell C, Gruben D, Zwillich SH, Fleischmann R.
Arthritis Research & Therapy (2015) 17:307 DOI: 10.1186/s13075-015-0825-9 [Epub ahead of print]

RA presents a significant health and socioeconomic burden particularly in physical functioning, fatigue, and emotional roles. A phase III 6-month study of tofacitinib in patients with active RA, who had prior inadequate responses to cDMARDs or bDMARDs, uses patient-reported outcomes (PROs) to assess the impact on quality of life. Patients were randomized 4:4:1:1 to receive tofacitinib 5 or 10 mg BID, or placebo for 3 months followed by tofacitinib 5 or 10 mg BID. At month 3, tofacitinib 5 and ...

Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibition

W Gao, T McGarry, C Orr, J McCormick, D J Veale, U Fearon.
Annals of the Rheumatic Diseases. 2015 Sep 9. doi:10.1136/annrheumdis-2014-207201

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis (Ps) and characterised by synovitis and progressive destruction of articular cartilage and bone. Recently developed agents for PsA target IL12p40, IL-6 and IL-17, several of which signal through the JAK family of receptor-associated tyrosine kinases. Tofacitinib is a drug of the JAK inhibitor class and is currently approved for the treatment of RA in 27 countries. This study evaluated the effect of tofacitini...

Cost-effectiveness of Tofacitinib in the Treatment of Moderate to Severe Rheumatoid Arthritis in South Korea

Min-Young Lee, Sun-Kyeong Park, Sun-Young Park, Ji-Hye Byun, Sang-Min Lee, Su-Kyoung Ko, and Eui-Kyung Lee.
Clinical Therapeutics. 2015:37(8). [Epub ahead of print]

This study evaluated the cost-effectiveness of introducing tofacitinib, an oral Janus kinase inhibitor, to the treatment of Korean patients with RA and an inadequate response to conventional DMARDs. The model showed that the inclusion of tofacitinib as a treatment strategy for moderate to severe RA is cost-effective; this conclusion was considered robust based on multiple sensitivity analyses. First-line tofacitinib used before the standard of care (base-case analysis) increased both treatment...

Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs

Charles-Schoeman C, Burmester G, Nash P, Zerbini CA, Soma K, Kwok K, Hendrikx T, Bananis E, Fleischmann R.
Annals of the Rheumatic Diseases. 2015 Aug 14. doi:pii: annrheumdis-2014-207178.

This study evaluated the efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in patients with inadequate response to sDMARDs or bDMARDs. Findings from this study show both doses of tofacitinib were associated with improvements in efficacy parameters at month 3 versus placebo, and clinical response was numerically greater with bDMARD-naïve versus bDMARD-IR patients (95% CI overlapping). Safety parameters were generally similar; however, patients receiving glucocorticoids had ...

Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study

Tanaka Y, Takeuchi T, Yamanaka H, Nakamura H, Toyoizumi S, Zwillich S.
Modern Rheumatology. 2015 Jul;25(4):514-21. doi: 10.3109/14397595.2014.995875.

The oral Janus kinase (JAK) inhibitor, Tofacitinib, preferentially inhibits signalling by heterodimeric receptors associated with JAK3 and/or JAK1, blocking signalling for several cytokines. The purpose of this study was to evaluate the efficacy of tofacitinib monotherapy versus placebo in Japanese patients with inadequate response to disease-modifying anti-rheumatic drugs (DMARDs). Data on response rates – ACR20/50/70, DAS28-4(ESR), and HAQ-DI – laboratory parameters and adverse eve...

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two, randomised, placebo-controlled, Phase 3 trials

Papp KA, Menter MA, Abe M, Elewski B, Feldman SR, Gottlieb AB, Langley R, Luger T, Thaci D, Buonanno M, Gupta P, Proulx J, Lan S, Wolk R, OPT Pivotal 1 and OPT Pivotal 2 Investigators.
British Journal of Dermatology. 7 July 2015 DOI: 10.1111/bjd.14018. [Epub ahead of print]

The management of moderate to severe chronic plaque psoriasis has benefited from the introduction of biological therapies, but unmet needs still remain, especially for oral therapies. Tofacitinib is an orally active agent that blocks signalling of key cytokines implicated in the immune response and inflammatory pathways of psoriasis. The Phase III studies presented in this paper analysed efficacy and safety endpoints. Both studies demonstrated that tofacitinib in both 5 mg and 10 mg twice daily...

Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial

Kremer JM, Kivitz AJ, Simon-Campos JA, Nasonov EL, Tony HP, Lee SK, Vlahos B, Hammond C, Bukowski J, Li H, Schulman SL, Raber S, Zuckerman A, Isaacs JD.
Arthritis Res Ther. 2015 Apr 6;17(1):95.

Mean increases from baseline in patient serum creatinine (SCr) levels have been observed in the clinical development programme for the JAK inhibitor tofacitinib. These increases predominantly occurred within the first three months, and reversed with tofacitinib withdrawal. This phase 1, randomised, placebo-controlled, parallel-group, 2-period study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib, relative to placebo, in 148 patients with active RA. Results sh...

Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme

Curtis JR, Lee EB, Kaplan IV, Kwok K, Geier J, Benda B, Soma K, Wang L, Riese R.
Ann Rheum Dis. 2015 Apr 22. pii: annrheumdis-2014-205847. doi: 10.1136/annrheumdis-2014-205847. [Epub ahead of print]

The developments of certain malignancies associated with chronic inflammatory diseases such as RA is known to occur to a greater extent than that of the general population. It is also know that certain RA treatments can affect malignancy rates. As such, newer immunomodulatory agents, such as the JAK inhibitor tofacitinib, are closely monitored for safety events of special interest, including malignancies. This paper analyses pooled malignancy data from the tofacitinib RA clinical development...

Super-enhancers delineate disease-associated regulatory nodes in T cells

Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O'Shea JJ.
Nature. 2015 Feb 16. doi: 10.1038/nature14154. [Epub ahead of print]

Transcription machinery (proteins responsible for activating or ‘switching off’ genes) is not distributed in the genome in a symmetrical (or even) manner. Some parts of the genome, so called super-enhancers (SEs), accumulate an exceptionally high level of proteins relevant to the regulation of transcription (i.e. the machinery is concentrated in particular parts of the genome). In this paper, the investigators asked about the locale of these regions in the genome of T cells. Then th...

The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis

Winthrop KL, Silverfield J, Racewicz A, Neal J, Lee EB, Hrycaj P, Gomez-Reino J, Soma K, Mebus C, Wilkinson B, Hodge J, Fan H, Wang T, Bingham CO 3rd.
Ann Rheum Dis. 2015 Mar 20. pii: annrheumdis-2014-207191. doi: 10.1136/annrheumdis-2014-207191. [Epub ahead of print]

The increased risk of serious infection among RA patients means vaccinations against pneumococcus and influenza are recommended in this group of patients. Studies evaluating immune response to these vaccines in conjunction with DMARD therapy can provide clinicians with important information relating to things such as timing of vaccination. This study aimed to assess the effect of tofacitinib on vaccine responses to PPSV-23 and the trivalent seasonal influenza vaccine in those whom tofacitinib...

Potential Mechanisms Leading to the Abnormal Lipid Profile in Patients With Rheumatoid Arthritis Versus Healthy Volunteers and Reversal by Tofacitinib

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...

Efficacy and Safety of Tofacitinib as Monotherapy in Japanese Patients With Active Rheumatoid Arthritis: A 12-Week, Randomized, Phase 2 Study

Tanaka Y, Takeuchi T, Yamanaka H, Nakamura H, Toyoizumi S, Zwillich S.
Mod Rheumatol. 2014 Dec 11:1–25. [Epub ahead of print]

In Japan, the biologic DMARDs infliximab, etanercept, adalimumab, golimumab and certolizumab pegol, as well as tocilizumab and abatacept are approved for use in patients with active RA and an inadequate response to existing therapies. However, not all patients respond to these therapies adequately, creating an unmet need for therapeutic options with alternative mechanisms of action. The oral JAK inhibitor tofacitinib has demonstrated efficacy as monotherapy or in combination with DMARDs for th...

The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis

Boyle DL, Soma K, Hodge J, Kavanaugh A, Mandel D, Mease P, Shurmur R, Singhal AK, Wei N, Rosengren S, Kaplan I, Krishnaswami S, Luo Z, Bradley J, Firestein GS.
Ann Rheum Dis. 2014 Nov 14. pii: annrheumdis-2014-206028. doi: 10.1136/annrheumdis-2014-206028. [Epub ahead of print]

Targeting intracellular pathways such as JAK/STAT represents a novel approach to the treatment of RA. Tofacitinib is an oral JAK inhibitor, proven to be effective in the treatment of RA, yet the pathways affected by tofacitinib and the effects on gene expression in situ are unknown. In this study, Boyle et al. tested the hypothesis that tofacitinib targets cytokine signalling critical to the pathogenesis of rheumatoid synovitis by investigating tofacitinib effects on synovial pathobiology. A...

Lipid profile changes in patients with chronic inflammatory arthritis treated with biologics and tofacitinib in randomized clinical trials: A systematic review and meta-analysis

Souto A, Salgado E, Maneiro JR, Mera A, Carmona L, Gómez-Reino JJ.
Arthritis Rheumatol. 2015;67(1):117–127

Systemic inflammation, reflected by high levels of C-reactive protein and the erythrocyte sedimentation rate, has been identified as an independent risk factor for cardiovascular disease, the most important cause of death in RA and SpA. Studies with TNF antagonists have given contradictory results on cardiovascular risk. As such, this systemic literature search aimed to analyse lipid changes in RA and SpA subjects treated with biologics or tofacitinib in randomized clinical trials. The search ...

Tofacitinib with methotrexate in third-line treatment of patients with active rheumatoid arthritis: Patient-reported outcomes from a Phase 3 trial

Strand V, Burmester GR, Zerbini CA, Mebus CA, Zwillich SH, Gruben D, Wallenstein GV.
Arthritis Care Res (Hoboken). 2014 Sep 3. doi: 10.1002/acr.22453. [Epub ahead of print]

For many patients with rheumatoid arthritis, improvements in pain, physical function, fatigue, and health-related quality of life (HRQoL) are more important and meaningful than improvements in joint swelling, tenderness, or inhibition of structural damage. These patient-perceived benefits of RA therapy contribute importantly to overall clinical efficacy. This paper presents patient-reported outcomes (PROs) form the ORAL Step trail, which assessed tofacitinib 5 mg or 10 mg twice daily, or pla...

Changes in serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib: results from clinical trials

Isaacs JD, Zuckerman A, Krishnaswami S, et al.
Arthritis Res Ther. 2014;16(4):R158

Despite preclinical and healthy volunteer studies of tofacitinib showing no evidence of nephrotoxicity, increases in mean serum creatinine levels have been observed in patients treated with the drug during the RA clinical development programme. This report explores the clinical significance of this change. Serum creatinine values and renal adverse event data were pooled from patients who received =1 dose of tofacitinib either with background DMARDs or as monotherapy in five Phase 3 studies a...

Analysis of Infections and All-Cause Mortality in Phase II, III and Long-Term Extension Studies of Tofacitinib in Patients with Rheumatoid Arthritis

Cohen S, Radominski SC, Gomez-Reino JJ, et al.
Arthritis Rheumatol. 2014;66(11):2924–2937

This study pools data from the global tofacitinib RA development programme (phase II, phase III and long-term extension studies) to determine the rate of infections and all-cause mortality with tofacitinib treatment. In total, 4,789 patients within these studies received tofacitinib, at varying doses and with varying duration. The overall incidence rate of serious infections was 3.09 events/100 patient-years (95% CI 2.73–3.49), which was stable over time, with pneumonia and skin and s...

Herpes Zoster and Tofacitinib Therapy in Patients with Rheumatoid Arthritis

Winthrop KL, Yamanaka H, Valdez H, et al.
Arthritis Rheumatol. 2014 Jun 18. [Epub ahead of print]

It is well established that patients with RA are at an increased risk of herpes zoster (HZ). What is less well known is whether some of the newer therapies available for treatment of RA increase this risk. Tofacitinib has been reported to be associated with an increased risk of HZ and this study quantifies that risk and reviews potential factors that represent an increased risk. Using data from the tofacitinib RA development programme; phase 2, 3, and long-term extension clinical trials, over 20...

Tofacitinib Versus Methotrexate In Rheumatoid Arthritis

Lee EB, Fleischmann R, Hall S, et al.
N Engl J Med. 2014;370(25):2377–2386.

ORAL Start is the latest trial to be reported in the tofacitinib clinical development programme. It compares the use of tofacitinib monotherapy to MTX monotherapy, in RA patients who have had either no or a sub-therapeutic dose of MTX in the past. Nine hundred and fifty eight patients received either tofacitinib (5 mg or 10 mg) twice daily, or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks. The co primary efficacy endpoints were ACR 70 response, and mean c...

Safety and Efficacy of Tofacitinib, an Oral Janus Kinse Inhibitor, for the Treatment of Rheumatoid Arthritis, in Open-Label Longterm Extension Studies

Wollenhaupt J, SIlverfield J, Lee Eb et al.
J Rheumatol 2014;41;837-852

This study pooled data from two LTE studies involving patients who had previously participated in qualifying phase I, II and III studies. Data up to 60 months was included for safety aspects and efficacy data up to 48 months. However data for 10 mg BID and tofacitinib monotherapy was limited after 24 and 36 months respectively. Over the two studies, 4102 patients were treated for a total of 5963 patient years. Herpes zoster, both serious and non-serious, had a higher incidence rate in tofacitini...

Effects of Janus Kinase Inhibitor tofacitinib on circulating serum amyloid A and interlukin-6 during treatment for rheumatoid arthritis

Migita K, Izumi Y, Jiuchi Y et al.
Clinical and Experimental Immunology doi.10.1111/cei.12234

Tofacitinib is a JAK inhibitor currently approved for the treatment of RA in some parts of the world. In this paper, Migita et al tested the effects of tofacitinib on circulating serum amyloid A (SAA). SAA is a major acute-phase reactant in RA and studies have shown it may be a better marker for the assessment of inflammatory joint disease compared with C-reactive protein. SAA is induced by the binding of IL-6 and the activation of the JAK/STAT pathway, which is inhibited by tofacitinib. Results...

Inhibition of TAK1 and/or JAK can rescue impaired chondrogenic differentiation of human mesenchymal stem cells in osteoarthritis-like conditions

Van Beuningen HM, de Vries-van Melle ML, Vitters El et al.
Tissue Engineering Part A doi:10/1089/ten.TEA.2013.0553

As it is nonvascularized and noninnervated, articular cartilage has a limited capacity to repair which presents a major clinical problem. In order to circumvent this inability to repair, stem cells can be placed into the joint or stimulated within the bone marrow. However, as the cartilage requiring repair is often in diseased joints, the factors involved in the disease state are potentially non-beneficial to the chondrogenesis of mesenchymal stem cells. In this study van Beuningen et al. invest...

The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Tofacitinib, a Janus Kinase Inhibitor, in Humans

Dowty ME, Lin J, Ryder TF et al.
DMD doi:10.1124/dmd.113.054940

The PK of tofacitinib has previously been described in several papers covering a range of diseases. This current study was used to better understand the PK, metabolism and clearance mechanisms of tofacitinib in healthy human subjects. Six subjects took a single 50mg dose of 14C-tofacitinib orally and consequently had urine, faeces and plasma collected. These were assayed for radioactivity and profiled for metabolites. Tofacitinib was found to be rapidly absorbed, with peak plasma concentration...

Effects of tofacitinib on lymphocytes in rheumatoid arthritis: relation to efficacy and infectious adverse events

Sonomoto K, Yamaoka K, Kubo S et al.
Rheumatology doi:10.1093/rheumatology/ket466

Due to its function as a JAK1/3 inhibitor, tofacitinib has effects on a wide ranging variety of cells. The authors of this paper have previously reported a suppression in cytokine production by CD4+ T lymphocytes caused by tofacitinib, while others have reported reduced chemokine production from fibroblast-like synoviocytes. The effects of tofacitinib on other cells however remain largely unknown. This study focused on tofacitinib’s effects on CD4+ T lymphocyte proliferation and on subsets...

Preclinical to Clinical Translation of Tofacitinib, a Janus Kinase Inhibitor, in Rheumatoid Arthritis

Dowty M, Jesson MI, Ghosh S, et al.
J Pharmacol Exp Ther. 2013. DOI:10.1124/jpet.113.209304

Preclinical studies can provide insight into mechanisms of efficacy and optimal dosing regimens. In this study, Dowty et al. compare the pharmacokinetic / pharmacodynamic profiles of tofacitinib in a murine arthritis model and in patients with rheumatoid arthritis from tofacitinib clinical trials. The main driver of efficacy in both preclinical murine arthritis models and clinical RA was found to be inhibition of JAK1 heterodimer signalling, where total drug exposure (Cave) was a predictor of pr...

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update

Smolen JS, Landewé R, Breedveld FC, Buch M, Burmester G, Dougados M, Emery P, Gaujoux-Viala C, Gossec L, Nam J, Ramiro S, Winthrop K, de Wit M, Aletaha D, Betteridge N, Bijlsma JWJ, Boers M, Butterger.
Ann Rheum Dis. 2013 doi: 10.1136/annrheumdis-2013-204573

The 2010 EULAR recommendations represented a significant step forward in the management of rheumatoid arthritis, and they have been widely adopted across the world. However, in the rapidly evolving world of rheumatology, it was recognised that a substantial amount of new evidence has accumulated, both on agents approved at that time as well as data on new compounds that have become available over the last 3–4 years. This motivated EULAR to form an international task force to update their r...

The JAK inhibitor, tofacitinib, reduces the t cell stimulatory capacity of human monocyte-derived dendritic cells

Kubo S, Yamaoka K, Kondo M, et al.
Ann Rheum Dis 2013. doi: 10.1136/annrheumdis-2013-203756

The role of JAKs is highly important in lymphocyte differentiation, but their function in dendritic cells in unknown. In this study, the authors used tofacitinib, a JAK inhibitor, to assess the function of these kinases in dendritic cell activity. The results show that tofacitinib reduced the expression of CD80/CD86 by suppressing the activation of interferon regulatory factor (IRF)-7 and production of type 1 interferon (IFN), and also decreased T cell stimulatory capability. This suggests a nov...

Proposal for a new nomenclature of disease-modifying antirheumatic drugs

Smolen JS et al.
Ann Rheum Dis 2013. doi: 10.1136/annrhuemdis-2013-204317

With the recent emergence of new therapeutics for rheumatoid arthritis, new nomenclature for disease-modifying antirheumatic drugs (DMARDs) may be needed to more accurately describe the new agents. Currently, DMARDs are divided into two broad groups: synthetic DMARDs (sDMARDs) and biological DMARDs (bDMARDs). The authors propose dividing synthetic DMARDs into conventional synthetic DMARDs (csDMARDs) which would encompass traditional DMARDs (e.g. methotrexate, leflunomide), and targeted synthetic...

Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis

Kremer J, Li ZG, Hall S et al.
Ann Intern Med. 2013;159;253-261

Many patients with active RA have an inadequate response to biologic and nonbiologic DMARDs. Kremer et al carried out a one year, randomized trial studying the efficacy of tofacitinib in conjunction with background nonbiologic DMARDs (primarily methotrexate) in these patients. The results showed that using tofacitinib in combination with nonbiologic DMARDs rapidly improved physical function and reduced signs and symptoms of RA versus placebo, measured by ACR20 rates, DAS28 and HAQ-DI. The data f...

The JAK inhibitor tofacitinib for active rheumatoid arthritis: results from phase III trials

Salgado E & Gomez-Reino JJ.
International Journal of Clinical Rheumatology June 2013; 8(3):311–13

The tofacitinib ORAL research program involves six phase 3 trials (Standard, Solo, Step, Scan, Sync and Start) to assess the safety and efficacy of tofacitinib 5 and 10 mg twice daily as monotherapy, or with either background MTX or traditional DMARD therapy. This report by Salgado et al. provides an overall analysis of the each of the study designs and the clinical results to date. The results show that tofacitinib effectively controlled the signs and symptoms of RA across a range of patient po...

Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050

Fridman JS, Scherle PA, Collins R, et al.
Journal of Immunology 2010; 184(9):5298-307

This preclinical characterisation study examined the efficacy and tolerability of the small molecule INCB028050 (now known as baricitinib), an orally bioavailable, selective Janus kinase (JAK) 1/JAK2 inhibitor, in rodent models of arthritis. The decision to investigate its effects of INCB028050 followed positive evidence for the related compound ruxolitinib, the JAK inhibitor tofacitinib and the IL-6 inhibitor tocilizumab in rheumatoid arthritis (RA). In this preclinical study, INCB028050 was sh...

Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550)

Ghoreschi K, Jesson MI, Li X, et al.
Journal of Immunology 2011; 186(7):4234-43

This study investigated the effects of the novel Janus kinase (JAK) inhibitor CP-690,550 (now known as tofacitinib) on adaptive and innate immune responses, in order to establish the mode of action of JAK inhibitors in the setting of inflammatory diseases. The inhibition of specific JAK/STAT-dependent pathways by CP-690,550 was determined through analysis of cytokine stimulation of mouse and human T cells in vitro.The effects of CP-690,550 on Th-cell differentiation of naive...

The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type 1 interferon

Rosengren S, Corr M, Firestein GS, et al.
Annals of Rheumatic Diseases 2012; 71:440-47

This study investigated the effect of the novel Janus kinase (JAK) inhibitor CP-690,550 [tofacitinib] in fibroblast-like synoviocytes (FLSs) collected from patients with rheumatoid arthritis (RA). Human FLSs were cultured from the synovial tissue of patients with RA who were undergoing arthroplastic surgery, cultured and then serum-starved 48 hours prior to stimulation. Quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) or multiplex bead assay were used to...

A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone

Kremer JM, Cohen S, Wilkinson BE, et al.
Arthritis & Rheumatism 2012; 64(4):970-81

This study was one of two 24-week, phase 2b studies undertaken to characterise the efficacy and safety dose-response profile of the oral Janus kinase (JAK) inhibitor tofacitinib. Six doses of tofacitinib (20 mg daily and 1, 3, 5, 10 and 15 mg twice daily) and placebo were compared as add-on therapy in adults with active RA despite methotrexate (MTX) therapy. At week 12, ACR 20 response rates were significantly higher with all tofacitinib doses than with placebo (tofacitinib 45.7–58.1%...

Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis

Fleischmann R, Kremer J, Cush J, et al.
The New England Journal of Medicine 2012; 367(6):495-507

This is the first phase 3 study to be published for the oral Janus kinase (JAK) inhibitor tofacitinib. This study investigated tofacitinib as a monotherapy in adults with active rheumatoid arthritis who previously failed to respond to disease modifying anti-rheumatic drugs (DMARDs). The study demonstrated that tofacitinib, compared to placebo, was more likely to be associated with reductions in the signs and symptoms of rheumatoid arthritis and improvement in physical function. 59.8% of patients...

Tofacitinib or adalimumab versus placebo in rheumatoid arthritis

van Vollenhoven RF, Fleischmann R, Cohen S, et al.
The New England Journal of Medicine 2012; 367(6):508-19

The ORAL Standard trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This 12-month, phase 3 study compared the efficacy of tofacitinib with the TNF inhibitor adalimumab or placebo. Patients with active RA despite background methotrexate (MTX) were randomised to 5 or 10 mg tofacitinib twice daily, 40 mg adalimumab fortnightly, or placebo, which was switched to tofacitinib at month 3 in non-responders and month 6 f...

Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial

Burmester GR, Blanco R, Charles-Schoeman C, et al.
The Lancet 2013; 381(9865):451-60

The ORAL Step trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This 6-month, double-blind, parallel-group phase 3 study investigated the efficacy and safety of tofacitinib in adults with moderate to severe rheumatoid arthritis (RA) with an inadequate response to tumour necrosis factor (TNF) inhibitors. Patients were randomised to 5 or 10 mg tofacitinib twice daily or placebo, which was switched to tofaciti...

Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a randomised study

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...

Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: Twelve-month data from a twenty-four–month phase III randomized radiographic study

van der Heijde D, Tanaka Y, Fleischmann R, et al.
Arthritis & Rheumatism 2013; 65(3):559-70

The ORAL Scan trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This is the 12-month interim results published for the ORAL Scan study, a 24-month, phase 3 study that compared the effects of tofacitinib and placebo on structural preservation in patients with active RA despite methotrexate therapy. Patients were randomised to 5 or 10 mg tofacitinib twice daily or placebo, which was switched to 5 or 10 mg tofaciti...