Cytokine Signalling Forum

Publications





September 21

Efficacy and safety of filgotinib in methotrexate-naive patients with rheumatoid arthritis with poor prognostic factors: post hoc analysis of FINCH 3

Aletaha D, Westhovens R, Gaujoux-Viala C, Adami G, Matsumoto A, Bird P, Messina OD, Buch MH, Bartok B, Yin Z, Guo Y, Hendrikx T, Burmester GR.
RMD Open. 2021;7(2):e001621.

Post hoc analysis of the phase III FINCH study shows that filgotinib may be an alternative treatment option for patients with RA who have poor prognostic factors (PPFs), especially those not responding to standard treatment such as methotrexate (MTX). PPFs are associated with severe disease and risk for disease progression in patients with RA. Consequently, the 2019 EULAR management guidelines for RA recommend early treatment escalation for patients with PPFs who have inadequate response to fir...

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...

August 21

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 ...

Baricitinib and the Risk of Incident Interstitial Lung Disease: A Descriptive Clinical Case Report from Clinical Trials

Salvarani C, Sebastiani M, Dieude P, Garcia M, Deberdt W, Rogai V, de la Torre I, Inciarte-Mundo J, Balsa A.
Rheumatol Ther. 2021 Jun 28. DOI: 10.1007/s40744-021-00332-w

Findings from a descriptive clinical case report from clinical trials show that patients with RA, treated with baricitinib, are at low risk to developing non-infectious interstitial lung disease (ILD) during treatment. Salvarani, et al. used a descriptive, multicentric, retrospective cohort study of eight randomised trials and one long-term extension study to estimate the number of incident ILD cases reported. Their findings showed that the risk of developing non-infectious ILD during baricit...

Upadacitinib Monotherapy Improves Patient-Reported Outcomes in Rheumatoid Arthritis: Results From SELECT-EARLY and SELECT-MONOTHERAPY

Strand V, Tundia N, Wells A, Buch MH, Radominski SC, Camp HS, Friedman A, Suboticki JL, Dunlap K, Goldschmidt D, Bergman M.
Rheumatology (Oxford). 2021;60(7):3209–21

Upadacitinib treatment results in statistically significant and clinically meaningful improvements in health-related quality of life. Strand, et al. evaluated the effect of upadacitinib monotherapy versus methotrexate (MTX) on patient-reported outcomes (PRO) in MTX-naïve and MTX-inadequate responder patients with moderately-to-severely active RA. Their research from the SELECT-EARLY and SELECT-MONOTHERAPY randomised controlled trials found that upadacitinib monotherapy resulted in clinical...

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...

July 21

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

Solipuram V, Mohan A, Patel R, Ni R.
Auto Immun Highlights. 2021;12(1):8.

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

Upadacitinib in Patients with Psoriatic Arthritis and Inadequate Response to Biologics: 56-Week Data from the Randomized Controlled Phase 3 SELECT-PsA 2 Study

Mease PJ, Lertratanakul A, Papp KA, van den Bosch FE, Tsuji S, Dokoupilova E, Keiserman MW, Bu X, Chen L, McCaskill RM, Zueger P, McDearmon-Blondell EL, Pangan AL, Tillett W.
Rheumatol Ther. 2021;8(2):903–919

Fifty-six-week data suggest that upadacitinib could be a favourable long-term treatment option in patients with PsA who are refractory to biologic therapy. As the need for additional therapeutic agents that can effectively control disease activity continues, new data from a 56-week analysis of the oral reversible JAK1 inhibitor, upadacitinib, currently under investigation for the treatment of PsA, shows that efficacy of the drug is maintained over the duration of this study. Mease, et al. expl...

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry

Sparks JA, Wallace ZS, Seet AM, Gianfrancesco MA, Izadi Z, Hyrich KL, et al.
Ann Rheum Dis. 2021 May 28. DOI: 10.1136/annrheumdis-2021-220418

Results from the COVID-19 Global Rheumatology Alliance physician registry show that people with RA using rituximab or JAKi, at COVID-19 onset, are more likely to experience poor COVID-19 outcomes, ranging from hospitalisation to death, compared with use of TNFi. The ongoing COVID-19 pandemic has had a significant impact on people with RA, many of whom are treated with b/tsDMARDs. To help address some of the knowledge gaps around the influence of b/tsDMARDs on COVID-19 outcomes, Sparks, et al. a...

Comparison of the effects of baricitinib and tocilizumab on disease activity in patients with rheumatoid arthritis: a propensity score matching analysis

Asai S, Takahashi N, Kobayakawa T, Kaneko A, Watanabe T, Kato T, Nishiume T, Ishikawa H, Yoshioka Y, Kanayama Y, Watanabe T, Hirano Y, Hanabayashi M, Yabe Y, Yokota Y, Suzuki M, Terabe K, Ishiguro N, Imagama S, Kojima T.
Clin Rheumatol. 2021 Jun 16. DOI: 10.1007/s10067-021-05815-3

The influence of inflammation on patient global assessment (PGA) improvements differs between baricitinib and tocilizumab differs. Adequate PGA improvement remains one of the unmet needs in current RA treatment. Asai, et al. compared the effects of baricitinib and tocilizumab on disease activity in patients with RA while investigating the influence of inflammation on PGA improvement. Using data from a multicentre registry, 48 propensity-matched pairs of patients, who had been observed for long...

June 21

JAK/STAT pathway and nociceptive cytokine signalling in rheumatoid arthritis and psoriatic arthritis

Crispino N, Ciccia F.
Clin Exp Rheumatol. 2021;39(3):668-675.

The JAK/STAT pathway is receiving increasing attention in modulation of nociceptive responses, given its clear role in cytokine signalling. The authors of this review speculate that JAKinibs may have an effect on the modulation of nociception and reduction of pain. Crispino N, et al. review the impact of pain in patients with rheumatic disease and the physiological basis of modulating nociceptive pain. They examine the role of cytokines in the modulation of pain and analyse current clinical JAK...

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...

Efficacy of baricitinib in patients with moderate-to-severe rheumatoid arthritis with 3 years of treatment: results from a long-term study

Smolen JS, Xie L, Jia B, Taylor PC, Burmester G, Tanaka Y, Elias A, Cardoso A, Ortmann R, Walls C, Dougados M.
Rheumatology (Oxford). 2021;60(5):2256-2266.

Baricitinib 4mg may be considered for long-term treatment of early and refractory rheumatoid arthritis following results demonstrating efficacy and tolerability for up to 3 years. Smolen JS, et al. analysed data from two completed 52-week, phase III studies, RA-BEGIN (DMARD-naïve) and RA-BEAM (MTX-IR), and one ongoing long-term extension study (RA-BEYOND) – providing data for 148 weeks in total. Results demonstrated that the long-term maintenance of clinically relevant treatment g...

Efficacy of Long-Term Treatment with Once-Daily Baricitinib 2 mg in Patients with Active Rheumatoid Arthritis: Post Hoc Analysis of Two 24-Week, Phase III, Randomized, Controlled Studies and One Long-Term Extension Study

Wells AF, Jia B, Xie L, Valenzuela GJ, Keystone EC, Li Z, Quebe AK, Griffing K, Otawa S, Haraoui B.
Wells AF, et al. Rheumatol Ther. 2021. Epub ahead of print. DOI: 10.1007/s40744-021-00317-9.

Analysis by Wells, et al. demonstrates long-term efficacy and tolerability of baricitinib 2 mg daily for up to 120 weeks in patients with rheumatoid arthritis. Using data from two completed phase III studies, RA-BEAM (csDMARD-IR patients) and RA-BEACON (TNFi-IR patients), and one ongoing long-term extension study (RA-BEYOND), results demonstrated that the long-term maintenance of clinically relevant treatment goals, including LDA, remission and normative physical function, is achievable with b...

May 21

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...

Conversion of Functional Assessment of Chronic Illness Therapy-Fatigue to Patient-Reported Outcomes Measurement Information System Fatigue Scores in Two Phase III Baricitinib Rheumatoid Arthritis Trials

Bingham CO 3rd, Bartlett SJ, Kannowski C, Sun L, DeLozier AM, Cella D.
Arthritis Care Res (Hoboken). 2021;73(4):481-488.

Study shows that conversions from FACIT-F to PROMIS Fatigue are feasible and applicable for RA clinical trials. The Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), developed for use in cancer patients, has been validated for measuring fatigue in RA, and is often the tool used in European clinical trials; with 10 out of its 13 items being relevant for patients with RA. The Patient-Reported Outcomes Measurement Information System (PROMIS), developed and calibrated in th...

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...

Trial of Upadacitinib and Adalimumab for Psoriatic Arthritis

McInnes IB, Anderson JK, Magrey M, Merola JF, Liu Y, Kishimoto M, Jeka S, Pacheco- Tena C, Wang X, Chen L, Zueger P, Liu J, Pangan AL, Behrens F.
N Engl J Med. 2021;384(13):1227-1239.

Upadacitinib efficacy proves to be greater than placebo, and non-inferior to adalimumab, in treating patients with psoriatic arthritis (PsA). Already approved for the treatment of rheumatoid arthritis, McInnes, et al. studied oral upadacitinib at a dose of 15 mg or 30 mg, alongside placebo or adalimumab, in this 24-week, Phase III trial, in over 1700 patients with PsA. At the primary endpoint (Week 12), ACR20 response was greater with upadacitinib than placebo, and non-inferior to adalimumab; ...

April 21

Filgotinib, a Novel JAK1-Preferential Inhibitor for the Treatment of Rheumatoid Arthritis: An Overview from Clinical Trials

Tanaka Y, Kavanaugh A, Wicklund J, McInnes IB.
Mod Rheumatol. 2021 Mar 19:1-26. Epub ahead of print. DOI 10.1080/14397595.2021.1902617

Filgotinib is the latest JAKinib to enter the international market for the treatment of RA, receiving regulatory approval in Japan and Europe late last year. In this review paper, Tanaka Y et al. examine the clinical evidence supporting its use as a later-line treatment, in accordance with international RA management guidelines, and provide their expert opinions on JAKinibs from a clinical perspective. The core clinical programme evaluating filgotinib in patients with moderately-to-severely acti...

March 21

Upadacitinib in Rheumatoid Arthritis: A Benefit–Risk Assessment Across a Phase III Program

Conaghan PG, Mysler E, Tanaka Y, Da Silva-Tillmann B, Shaw T, Liu J, Ferguson R, Enejosa JV, Cohen S, Nash P, Rigby W, Burmester G.
Drug Saf. 2021 Feb 2. DOI: 10.1007/s40264-020-01036-w

Upadacitinib 15 mg has a favourable benefit–risk profile according to an assessment of data from the phase III SELECT clinical trial programme. In this review of data for the once-daily, oral JAK inhibitor, Conaghan PG, et al. provided insights into the benefit–risk profile of upadacitinib in approximately 4400 patients with RA. Based on pooled data from five pivotal studies, benefits and risks were assessed up to the time of regulatory submission, and additional long-term integra...

Effects of One-Year Tofacitinib Therapy on Bone Metabolism in Rheumatoid Arthritis

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...

Safety and Efficacy of Filgotinib: Up to 4-Year Results From an Open-Label Extension Study of Phase 2 Rheumatoid Arthritis Programs

Kavanaugh A, Westhovens RR, Winthrop KL, Lee SJ, Tan Y, An D, Ye L, Sundy JS, Besuyen R, Meuleners L, Stanislavchuk M, Spindler AJ, Greenwald M, Alten R, Genovese MC.
J Rheumatol. 2021 Feb 1:jrheum.201183. DOI: 10.3899/jrheum.201183.

A long-term extension study of filgotinib showed consistent safety profile and sustained efficacy with the drug for up to four years. The DARWIN 3 study, for patients who previously completed either the 24-week DARWIN 1 study (filgotinib + MTX) or the DARWIN 2 study (filgotinib monotherapy), enrolled 739 patients with RA. At the time of analysis, 440 patients had received four years or more of filgotinib. Exposure-adjusted incidence rate per 100 patient-years-of-exposure for TEAEs was 24.6 i...

Post-Approval Comparative Safety Study of Tofacitinib and Biological Disease-Modifying Antirheumatic Drugs: 5-Year Results from a United States–Based Rheumatoid Arthritis Registry

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...

Which Patient-reported Outcomes do Rheumatology Patients Find Important to Track Digitally? A Real-world Longitudinal Study in Arthritis Power

Nowell WB, Gavigan K, Kannowski CL, Cai Z, Hunter T, Venkatachalam S, Birt J, Workman J, Curtis JR.
Arthritis Res Ther. 2021;23(1):53.

Fatigue, physical function, pain, and morning joint stiffness are the most important PROs to track, according to the rheumatology patients who experience these symptoms. Increasingly used, alongside clinical measures, to track symptoms and assess disease activity over time, patient-reported outcomes (PROs) are also important indicators of quality of life and treatment effectiveness. To enable us to better understand which PROs patients with rheumatic and musculoskeletal disease consider most im...

February 21

Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity

Ptacek J, Hawtin RE, Sun D, Louie B, Evensen E, Mittleman BB, Cesano A, Cavet G, Bingham CO III, Cofield SS, Curtis JR, Danila MI, Raman C, Furie RA, Genovese MC, et al.
PLoS ONE 2021;16(1):e0244187

This analysis provides evidence that immune cell signalling pathways are important in RA. There were consistent differences between RA patients and healthy controls in IFNα, IL-6, IL-10 and GM-CSF+ IL-2 induced JAK/STAT signalling in multiple immune cell subsets. We know that RA is characterised by dysregulation of immune responses, but the exact cause is unknown. Recently, single-cell transcriptomics and mass cytometry confirmed the critical role of activated immune cells and fibroblasts...

January 21

Poster: JAKi Recommendations for Use

Nash P, et al.
Ann Rheum Dis 2021;80:71–87.

Points to Consider for the Treatment of Immune-Mediated Inflammatory Diseases With Janus Kinase Inhibitors: A Consensus Statement. The poster highlights all the key considerations from the consensus statement. Download by Clicking on the Links Above

EULAR Definition of Difficult-to-Treat Rheumatoid Arthritis

Nagy G, Roodenrijs NMT, Welsing PMJ, Kedves M, Hamar A, van der Goes MC, Kent A, Bakkers M, et al.
Ann Rheum Dis 2021;80:31–35.

A significant proportion of people with RA remain symptomatic despite treatment according to current management recommendations. Different terms have traditionally been used to describe this subpopulation, including severe, refractory, resistant to multiple drugs or treatments, established and difficult-to-treat. A recent survey indicated that – in addition to new drugs – new management approaches are needed for optimal treatment in these patients. A EULAR Task Force agreed the unifo...

Points to Consider for the Treatment of Immune-Mediated Inflammatory Diseases With Janus Kinase Inhibitors: A Consensus Statement

Nash P, Kerschbaumer A, Dorner T, Dougados M, Fleischmann RM, Geissler K, McInnes I, Pope JE, van der Heijde D, Stoffer-Marx M, Takeuchi T, Trauner M, Winthrop KL, de Wit M, Aletaha D, Baraliakos X, Boehncke W-H, Emery P, Isaacs JD, Kremer J, Lee EB, et al.
2021 Jan;80(1):71-87. doi: 10.1136/annrheumdis-2020-218398. Epub 2020 Nov 6.

JAKi are approved in various immune-mediated inflammatory diseases. With five JAKi now licensed, this paper reviews key points to consider in their use to assist clinicians, patients, and other stakeholders once the decision is made to commence JAKi. The consensus was developed by a Steering Committee and an expanded Task Force using EULAR standard operating procedures. The committee included patients as well as experts in rheumatology, gastroenterology, haematology, dermatology, and infectious ...

October 20

Preclinical characterisation of itacitinib, a Novel Selective Inhibitor of JAK1, for the Treatment of Inflammatory Diseases

Covington M, He X, Scuron M, Li J, Collins R, Juvekar A, Shin N, Favata M, Gallagher K, Sarah S, Xue CB, Peel M, Burke K, Oliver J, Fay B, Yao W, Huang T, Scherle P, Diamond S, Newton R, Zhang Y, Smith.
European Journal of Pharmacology. 2020 Oct 15;885:173505. doi: 10.1016/j.ejphar.2020.173505

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

Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19

Zhang X, Zhang Y, Qiao W, Zhang J, Qi Z.
Journal of International Immunopharmacology. 2020 Sep;86:106749. doi: 10.1016/j.intimp.2020.106749.

BARI may potentially interrupt the passage of SARS-CoV-2 into the target cells by binding to AAK1 and GAK, which are regulators of the ACE2 receptor regulator identified for its uptake, and could also treat cytokine storm through suppression JAK1/JAK2. Professor Zhang and et al reviewed BARI, as a potential drug to prevent SARS-COV-2 from entering target cells. They also evaluated BARI’s ability to control COVID-19 induced cytokine storm. As a cell surface protein, ACE2 is involved in re...

Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA

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 ...

July 20

COVID-19 revisiting inflammatory pathways of arthritis

Schett G, Manger B, Simon D, Caporali R.
Nat Rev Rheumatol 2020 doi.org/10.1038/s41584-020-0451-z

This review investigates the potential implications of COVID-19 on the field of rheumatology. Common pathways in COVID-19 and RA have provided rationale for the trial of DMARD therapies in treatment of severe COVID-19 infections. Safety considerations of RA patients undergoing immunomodulatory treatments are reviewed. Recommendations suggest that RA patients should continue DMARD treatment, whereas glucocorticoid use could be deleterious in COVID-19 infection and should be considered carefully, ...

April 20

Long-term Effectiveness of Live Herpes Zoster Vaccine in Patients with Rheumatoid Arthritis Subsequently Treated with 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...

February 20

EULAR Recommendations for the Management of Rheumatoid Arthritis – 2019 Update and Consensus Statement on JAKinibs

Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, McInnes IB, Sepriano A, et al.
Ann Rheum Dis. 2020 Jan 22. pii: annrheumdis-2019-216655.

The EULAR recommendations for the management of RA have become increasingly useful in providing rheumatologists, patients, payers and other stakeholders with the evidence-based guidance and views of experts on the optimal use and sequence of pharmaceutical therapies in patients with RA. Over the course of the last decade, the evolution of the treatment landscape has already required two updates. The release of the new addition updates the 2016 recommendations. An international task force consid...

January 19

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...

September 18

RA-BEGİN Faz 3 Çalışmasında Metotreksat, Baricitinib veya Baricitinib ve Metotreksat ile Tedavi Edilen Erken Romatoid Artritli Klinik Yanıt Alınan Hastalarda Yapısal Hasar Progresyonu

van der Heijde D, Durez P, Schett G, Naredo E, Østergaard M, Meszros G, De Leonardis F, De La Torre I, López-Romero P, Schlichting D, Nantz E, Fleichmann R.
Clinical Rheumatology 2018;37:2381–90 DOI 10.1007/s10067-018-4221-0

Patients with active RA and little or no prior DMARD treatment, who achieved sustained clinical responses, were less likely to show structural damage progression, irrespective of treatment. RA-BEGIN was a 52-week double-blind, multicentre Phase 3 trial, which assessed the safety and efficacy of BARI as monotherapy or in combination with MTX versus MTX monotherapy, in RA patients with no or limited prior DMARDs use.1-4 This post-hoc analysis evaluated the structural damage progression in patients...

Keywords: JAK, Baricitinib, Clinical, Efficacy

Translated by: Toz

Barisitinib’in Havuzlanmış Faz II ve Faz III Çalışmalarında Lipit Profili ve Statin Tedavisinin Etkisi

Taylor PC, Kremer JM, Emery P, Zuckerman SH, Ruotolo G, Zhong J, Chen L, Witt S, Saifan C, Kurzawa M, Otvos JD, Connelly MA, Macias WL, Schlichting DE, Rooney TP, de Bono S, McInnes IB.
Ann Rheum Dis. 2018 Jul;77(7):988-995. DOI 10.1136/annrheumdis-2017-212461

Baricitinib (BARI) was associated with increased lipid levels; baseline statins did not alter these profiles. The introduction of statins during treatment reduced total cholesterol and LDL-C. The use of anti-inflammatory drugs in RA patients has been shown to alter lipid levels and is associated with reduced atherogenic risk. Increases in lipid levels, specifically HDL-C and LDL-C, have been observed in Phase 2 BARI studies1. This study analysed data from seven randomised RA Phase 2/3 studies o...

Keywords: JAK, Baricitinib, Real World, Cardiovascular

Translated by: Toz

Subkutan Tocilizumab ile Tedavi Edilen Romatoid Artrit Hastalarında Metotreksat Tedavisinin Kesilmesi Sonrası Devam Eden Yanıt

Kremer JM, Rigby W, Singer NG, Birchwood C, Gill D, Reiss W, Pei J, Michalska M.
Arthritis Rheumatol 2018;70:1200–08 DOI 10.1002/art.40493

The COMP-ACT study showed patients achieving low disease activity (LDA) with tocilizumab (TCZ) plus methotrexate (MTX) can discontinue MTX, while maintaining disease control for up to 16 weeks. Previous studies have shown TCZ to be efficacious as a monotherapy or in combination with MTX in patients with RA1,2. Patients frequently discontinue taking DMARDs, such as MTX, due to intolerance or adverse events. COMP-ACT is a randomised, double-blind, 52-week study evaluating the sustained efficacy of...

Keywords: IL-6, Tocilizumab, Clinical, Efficacy

Translated by: Toz

Romatoid Artrit Tedavisinde Biyolojikler ve JAK İnhibitörleri ile Monoterapinin Etkinliği: Sistematik Bir Derleme

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...

Keywords: JAK, Baricitinib, Clinical, Efficacy

Translated by: Toz

August 18

Yalnız Tocilizumab veya Tocilizumab ve Metotreksat Kombinasyonu ile Tedavi Edilen Romatoid Artritli Hastalarda Remisyona Ulaştıktan Sonra Tocilizumabın Kesilmesi: Prospektif Randomize Kontrollü Çalışmadan Sonuçlar (SURPRISE çalışmasının ikinci yılından)

Kaneko Y, Kato M, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, Miyata M, Murakawa Y, Yasuoka H, Hirata S, Tanaka E, Miyasaka N, Yamanaka H, Yamamoto K, Takeuchi T, the SURPRISE study group.
Ann Rheum Dis 2018; 77:1268–1275 DOI: 10.1093/rheumatology/key121

The second-year results from the SURPRISE study show that low disease activity (LDA) can be maintained after discontinuation of tocilizumab with continued methotrexate after remission is achieved. Discontinuation of biologic agents in patients who have achieved remission or low disease activity (LDA) is desirable from a risk–benefit point of view. Compared with TNF inhibitors, little is known regarding TCZ-free remission or LDA, but studies indicate that only a small proportion of patien...

Keywords: IL-6, Tocilizumab, Clinical, Efficacy

Translated by: Toz

MTX'e Yetersiz Yanıtlı Romatoid Artrit Hastalarında İki Yıllık Sarilumab Tedavisinin Etkinlik, Güvenlilik ve Radyografik Sonuçları

Genovese MC, van Adelsberg J, Fan C, Graham NMH, van Hoogstraten H, Parrino J, Mangan EK, Spindler A, Huizinga TWJ, van der Heijde D, for the EXTEND study investigators.
Rheumatology 2018;57:1423–1431 DOI: 10.1093/rheumatology/key121

Two-year treatment of active, moderate-to-severe RA with sarilumab, along with dose reduction in the event of laboratory abnormalities, resulted in durable efficacy outcomes and a safety profile consistent with previous reports involving IL-6R inhibition. Durable long-term safety and efficacy, reduced joint damage progression, and conserving health-related quality of life and work productivity are important goals of therapy in RA.1 Sarilumab significantly reduced disease activity, improved phy...

Keywords: IL-6, Sarilumab, Clinical, Safety

Translated by: Toz

JAK İnhibitörleri ile Tedavi Edilen Romatoid Artrit Hastalarında Advers Olaylar, Klinik Düşünceler ve Yönetim Önerileri

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...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Toz

July 18

Romatoid Artrit'de Janus Kinaz (JAK) İnhibitörü Alanlarda Tromboembolizm: Gerçek Risk Nedir?

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...

Keywords: JAK, Baricitinib, Clinical, Safety

Translated by: Toz

Hastalık Modifiye Edici Biyolojik Anti-Romatizmal İlaçlara Dirençli Aktif Romatoid Artritli Hastalarında Upadacitinib'ın Etkinliği ve Güvenliği (SELECT-BEYOND): Çift Kör, Randomize Kontrollü, Faz 3 Çalışma

Genovese MC, Fleischmann R, Combe B, Hall S, Rubbert-Roth A, Zhang Y, Zhou Y, Mohamed M-EF, Meerwein S, Pangan AL.
Lancet 2018;391:2513–24

Upadacitinib (UPA) extended release formulation was effective in treating patients with moderate-to-severe RA with an inadequate response to bDMARDs. Phase 2 study data has shown that UPA is an efficacious and safe treatment for active RA.1,2 SELECT-BEYOND was a double-blind, long-term extension, Phase 3 study to assess the efficacy of UPA in patients with RA who were bDMARD-IR. The first 12-weeks of SELECT-BEYOND were placebo-controlled, with a double-blind period followed by an ongoing double...

Keywords: JAK, Upadacitinib, Clinical, Phase 3

Translated by: Toz

Hastalığı Modifiye Edici Konvansiyonel Sentetik Anti-Romatizmal İlaçlara Yetersiz Yanıtlı Romatoid Artritli Hastalarında Upadacitinib Etkinliği ve Güvenliği (SELECT-NEXT): Randomize, Çift Kör, Plasebo Kontrollü Faz 3 Çalışma

Burmester GR, Kremer JM, Van den Bosch F, Kivitz A, Bessette L, Li Y, Zhou Y, Othman AA, Pangan AL, Camp HS.
Lancet 2018;391:2503–12

Patients with moderate-to-severe active RA had significant improvements in clinical signs and symptoms with upadacitinib (UPA) compared with placebo. In Phase 2 studies, UPA showed favourable efficacy when administered twice daily as an immediate-release formulation at doses of 6–12 mg in patients with active RA who had TNFi-IR.1,2 An extended-release formulation allowing once-daily (QD) administration was developed for Phase 3 studies. SELECT-NEXT was a double-blind, multicentre, Phase 3...

Keywords: JAK, Upadacitinib, Clinical, Phase 3

Translated by: Toz

June 18

Konvansiyonel Sentetik Hastalık Modifiye Edici Antiromatizmal İlaçlara Yetersiz Yanıtlı Romatoid Artritli Hastalarda Baricitinibin 1.yılında Yapısal Eklem Hasarının Radyografik Progresyonu Üzerine Olan Etkileri

van der Heijde D, Dougados M, Chen YC, Greenwald M, Drescher E, Klar R, Xie L, de la Torre I, Rooney TP, Witt SL, Schlichting DE, de Bono S, Emery P.
RMD Open. 2018 May 8;4(1):e000662. DOI: 10.1136/rmdopen-2018-000662

Once daily baricitinib (BARI) inhibited radiographic progression of structural joint damage in patients with an inadequate response or intolerance to csDMARDs over 48 weeks. Current treatment goals aim to use DMARDs to inhibit structural joint damage and prevent long-term functional disability. In RA-BUILD¹, BARI was shown to significantly reduce radiographic joint damage progression in patients with active RA, with an intolerance or inadequate response to csDMARDs. Here, the authors repor...

Keywords: JAK, Baricitinib, Clinical, Radiographic

Translated by: Toz

Tofacitinib ile Tedavi Edilen Romatoid Artritli Hastalarda Uzun Dönem Radyografik ve Hasta Bildirimli Sonuçlar: ORAL Start ve ORAL Scan Post-hoc Analizler

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...

Keywords: JAK, Tofacitinib, Clinical, Radiographic

Translated by: Toz

May 18

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 ...

April 18

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, ...

Effect of Filgotinib, a Selective JAK1 Inhibitor, with or without Methotrexate in Patients with Rheumatoid Arthritis: Patient-Reported Outcomes

Genovese MC, Westhovens R, Meuleners L, van der Aa A, Harrison P, Tasset C, Kavanaugh A.
Arthritis Res Ther 2018; 20(1):57 doi: 10.1186/s13075-018-1541-z

Patient-reported outcomes (PROs) from two, Phase 2b, filgotinib (FIL) studies, DARWIN 1 and 2, revealed that patients receiving FIL had improved and sustained PRO responses compared with placebo. With suboptimal RA treatment, patients lose joint functional ability, which heavily influences patient quality of life. The previously reported data from the DARWIN studies, concluded that patients given FIL achieved clinically relevant dose-dependent improvements compared with patients given placebo&s...

January 18

Romatoid Artritte Subkutanöz Tocilizumab: 22 Ülkede Yürütülen Ortak-Çerçeve, Faz 4 Çalışma Programı TOZURA’dan Bulgular

Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Bernasconi C, Pethö-Schramm A.
Rheumatology (Oxford). 2018 Mar 1;57(3):499-507. DOI: 10.1093/rheumatology/kex443

This multi-national TOZURA study programme confirmed the efficacy and safety profile of subcutaneous tocilizumab (TC-SC) when administered as either monotherapy or in combination with csDMARDs. TOZURA was a Phase 4 study programme that evaluated open-label, TCZ-SC in patients with moderate-to-severe RA. A total of 1804 patients with active RA were enrolled in the study programme. Patients had inadequate responses to csDMARDs, anti-TNF therapies, or they were MTX-naïve. TCZ-SC was administe...

Keywords: IL-6, Tocilizumab, Clinical, Phase 4

Translated by: Bahtiyar Toz

Yeni Tanı Erken Romatoid Artrit Hastalarında Tocilizumab veya Metotreksat- Temelli Bir Tedavi Stratejisinin Hasta Bildirimli Sonuçları

Teitsma XM, Jacobs JWG, Welsing PMJ, Pethö-Schramm A, Borm MEA, Hendriks L, Denissen NHAM, van Laar JM, Lafeber FPJG, Bijlsma JWJ.
Rheumatology (Oxford) 2017 Dec 1;56(12):2179-2189 doi: 10.1093/rheumatology/kex319

Patient-reported outcomes (PROs) vastly improved in the first 24 weeks post-initiation of tocilizumab (TCZ) therapies compared to methotrexate (MTX) monotherapy in the U-Act-Early trial. U-Act-Early was a two-year, treat-to-target study that compared the safety and efficacy of TCZ and MTX treatment strategies in DMARD-naïve patients with early RA. Sustained remission was classed as more effective in patients given TCZ monotherapy or combination therapy with MTX compared to MTX alone. TCZ th...

Keywords: IL-6, Tocilizumab, Clinical, PRO

Translated by: Bahtiyar Toz

November 17

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...

May 17

Metotreksat-Naif Erken Romatoid Artritli Hastalarda Metotreksat Monoterapisi veya Tocilizumab Kombinasyonu veya Monoterapisi: Randomize, Plasebo Kontrollü FUNCTION Çalışmasından 2 Yıllık Klinik ve Radyografik Sonuçlar

Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Blanco R, Kadva A and Dimonaco S.
Ann Rheum Dis Published Online First: 7 April 2017. Doi 10.1136/annrheumdis-20160210561

Burmester et al. present data showing that 52-week efficacy and safety of intravenous tocilizumab plus methotrexate, or tocilizumab monotherapy are maintained through to Week 104 in patients with early rheumatoid arthritis. Patients were assigned to four treatment groups: 4 mg/kg TCZ + MTX, 8 mg/kg TCZ + MTX, 8 mg/kg TCZ + placebo or placebo + MTX. Patients not achieving DAS28 ≤3.2 at Week 52 and who were not receiving 8 mg/kg TCZ were rescued to 8 mg/kg TCZ + MTX. Of the 1162 randomly assi...

Keywords: IL-6, Tocilizumab, Clinical, Phase 3

Translated by: Bahtiyar Toz

April 17

Romatoid Artrit Tedavisinde Sentetik ve Biyolojik Modifiye Antiromatizmal İlaçlar EULAR Önerileri: 2016 Güncellemesi

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...

Translated by: Bahtiyar Toz

TNF İnhibitörlerine İntolerans/ Yetersiz Yanıtlı Romatoid Artrit Hastalarında Sarilumumab Kullanımı Hasta- Bildirimli Sonuçları İyileştirmektedir

Strand V, Reaney M, Chen C-I, Proudfoot CWJ, Guillonneau S, Bauer D, Mangan E, Graham NMH, van Hoogstraten H, Lin Y, Pacheco-Tena C, Fleischmann R.
RMD Open 2017;3:e000416. DOI:10.1136/rmdopen-2016-000416

Evidence is presented that treatment with sarilumab demonstrates patient-reported benefits in TNF-IR patients with moderate to severe RA. These improvements complement the clinical efficacy previously reported for sarilumab, and are consistent with those seen in the MOBILITY trial (MTX-IR patients)1, yet in a more difficult-to-treat population. Data were analysed from the 24-week Phase 3 TARGET randomised controlled trial in adult patients with active RA and previous inadequate response or into...

Keywords: IL-6, Sarilumab, Clinical, Phase 3

Translated by: Bahtiyar Toz

March 17

Romatoid Artrit Hastalarında Selektif JAK-1 inhibitörü olan ABT-494 Faz 2b Çalışması

Kremer JM, Emery P, Camp HS, Friedman A, Wang L, Othman AA, Khan N, Pangan AL, Jungerwirth S and Keystone EC.
Arthritis Rheumatol 2016;68:2867–77

The summary and accompanying slide deck have been developed in conjunction with the Genovese et al. study (Study 1) which examined ABT-494 in MTX-IR patients in order to compare and contrast the data. In these two Phase 2b studies, ABT-494 (a novel selective JAK-1 inhibitor) was shown to be effective in patients with active RA who were non-responders to MTX or at least one TNF inhibitor. Patients with active RA who had an inadequate response to MTX (study 1) or were refractory to or intoleran...

Keywords: JAK, Upadacitinib, Clinical, Phase 2

Translated by: Bahtiyar Toz

Romatoid Artrit Hastalarında Selektif JAK-1 inhibitörü olan ABT-494 Faz 2b Çalışması

Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, Wang L, Othman AA, Khan N, Pangan AL and Jungerwirth S.
Arthritis Rheumatol 2016;68:2857–66

The summary and accompanying slide deck have been developed in conjunction with the Kremer et al. study (Study 2) which examined ABT-494 in TNF-IR patients in order to compare and contrast the data. In these two Phase 2b studies, ABT-494 (a novel selective JAK-1 inhibitor) was shown to be effective in patients with active RA who were non-responders to MTX or at least one TNF inhibitor. Patients with active RA who had an inadequate response to MTX (study 1) or were refractory to or intolerant ...

Keywords: JAK, Upadacitinib, Clinical, Phase 2

Translated by: Bahtiyar Toz

January 17

Aktif Romatoid Artrit Olguları Faz 2b Çalışmasında Baricitinibin Lipid, Apolipoprotein ve Lipoprotein Partikülleri Üzerine Etkileri

Kremer J, Genovese MC, Keystone E, Taylor PC, Zuckerman SH, Ruotolo G, Schlichting DE, Crotzer VL, Nantz E, Beattie SD and Macias WL.
Arthritis Rheumatol 2017. DOI 10.1002/art.40036.

In this analysis of the effect of baricitinib on changes in lipid profile, lipoprotein particle size and apolipoprotein content, increases in serum lipids were observed with HDL-C increases correlating with improved clinical outcomes. Eligible patients (N=301) met the inclusion criteria for the Phase 2b randomised, double-blind, placebo-controlled study.1 Patients were assigned in a 2:1:1:1:1 ratio to once-daily doses of placebo or baricitinib 1, 2, 4, or 8 mg, respectively. Those receiving 2 m...

Keywords: JAK, Baricitinib, Clinical, Phase 2

Translated by: Bahtiyar Toz

July 16

Romatoid Artrit Hastalarında�Adalimumab Tedavisinden Tofacitinib’e Geçiş

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...

Keywords: JAK, Tofacitinib, Real World

Translated by: Bahtiyar Toz

Orta ve ciddi Romatoid Artritte oral Janus Kinaz inhibitörü peficitinib'in (ASP015K) monoterapi olarak ekinlik ve güvenliği, Japonya verisi: 12 haftalık, randomize, çift-kör, plasebo-kontrollü faz llb çalışma

Takeuchi et al.
Ann Rheum Dis. 2016 Jun;75:1057-64. doi: 10.1136/annrheumdis-2015-208279. Epub 2015 Dec 15

Peficitinib (ASP015K) is a novel orally bioavailable JAK inhibitor in development for the treatment of RA. It inhibits JAK1, JAK2, JAK3 and Tyk2 enzyme activities and has moderate selectivity or JAK3 inhibition. Here the authors report the findings of a 12-week, randomized, double-blind, placebo-controlled phase IIb study evaluating efficacy, safety and dose response of peficitinib (25, 50, 100, or 150 mg) as once-daily oral monotherapy in Japanese patients with moderate to severe RA. The prim...

Keywords: JAK, Peficitinib, Clinical, Phase 2

Translated by: Bahtiyar Toz

Aktif Romatoid Artrit Hastalarında Klinik Pratikte Tocilizumab'ın İki Yıllık Etkinliği

Notario Ferreira, Ferrer González MA, Morales Garrido P, et al.
Reumatol Clin. 2016; May 10 doi: 10.1016/j.reuma.2016.03.014 [Epub ahead of print]

The efficacy and safety of tocilizumab has been studied in several randomized clinical trials (RCTs) but due to the strict inclusion and exclusion criteria of RCTs, real-life observational studies are needed to supplement the findings from these trials. This small longitudinal, open-label study from an outpatient clinic in Spain evaluated the effectiveness, survival rate and reasons for treatment discontinuations in 85 patients treated with tocilizumab over a 24-month period. The study also as...

Keywords: IL-6, Tocilizumab, Real World

Translated by: Bahtiyar Toz

Metotreksat Tedavisi Almakta Olan Aktif Romatoid Artritli Japon Hastalarda Baricitinibin Etkinliği ve Güvenliği: 12 Haftalık, Çift Kör, Randomize Plasebo Kontrollü Bir Çalışma

Tanaka Y, Emoto K, Cai Z, et al.
J Rheumatol. 2016;43(3):504–511.

Clinical trials have shown baricitinib once daily to be effective in patients with RA. However, this Janus kinase (JAK) 1/JAK2 inhibitor has not been evaluated in a Japanese population. In this 12-week, placebo-controlled study, 145 Japanese patients were enrolled and received placebo, 1 mg, 2 mg, 4 mg or 8 mg oral baricitinib daily. Efficacy results were encouraging and consistent with earlier trials. Significantly more baricitinib patients achieved ACR20 response at Week 12 of treatment compa...

Keywords: JAK, Baricitinib, Clinical, Phase 3

Translated by: Bahtiyar Toz

May 16

Aktif Psoriatik Artritli Erişkin Hastaların Faz 2b Çalışmasında Anti-İnterlökin-6 Monoklonal Antikoru Clazakizumab'ın Etkinliği ve Güvenliği

Mease et al.
Arthritis Rheumatol. 2016 Mar 24. DOI 10.1002/art.39700 [Epub ahead of print]

Encouraging results have been seen with clazakizumab in RA, but the results of anti-IL6 therapy in patients with psoriatic arthritis (PsA) have so far been unclear. This Phase 2b dose-ranging study examined the efficacy and safety of clazakizumab given subcutaneously q4w, with or without MTX, in 165 patients with PsA who had inadequate response to NSAIDs. ACR20 response at Week 16, the primary endpoint, was significantly higher in patients receiving clazakizumab 100 mg compared with placebo (52...

Keywords: IL-6, Clazakizumab, Clinical, Phase 2

Translated by: Bahtiyar Toz

Klinik Uygulamada Tofasitinib’in İlk Deneyimi: �ABD'de İki Sağlık Veritabanında Monoterapi veya Konvansiyonel Sentetik DMARD'larla Kombine Olarak Uygulanan Tofasitinibin Tedavi Şekilleri ve Maliyetleri

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...

Keywords: JAK, Tofacitinib, Real World, Value

Translated by: Bahtiyar Toz

Tofasitinib ve Biyolojik Tedavi Alan Romatoid Artrit Hastalarında Herpes Virüs Enfeksiyonlarının �Gerçek-Dünya Karşılaştırmalı Riskleri

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...

Keywords: JAK, Tofacitinib, Real World, Infections

Translated by: Bahtiyar Toz

Tofasitinibin günde bir kez kullanılan uzatılmış salınımlı formulasyonu: çabuk salınımlı tofasitinib ile farmakokinetik karşılaştırılması ve yemek etkisinin değerlendirilmesi

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...

Keywords: JAK, Tofacitinib, Preclinical, PK-PD

Translated by: Bahtiyar Toz

Refrakter Romatoid Artrit Hastalarında Barisitinib Tedavisi

Genovese et al.
N Engl J Med. 2016 Mar 31;374(13):1243-52. doi: 10.1056/NEJMoa1507247

For patients who have an inadequate response or unacceptable side effects associated with biologic DMARDs, the options for treatment beyond conventional DMARDs are limited. This phase 3 trial of the JAK 1/2 inhibitor, baricitinib, studied its efficacy in bDMARD-IR patients. 527 patients were randomized to either baricitinib 2mg, 4mg or placebo for up to 24 weeks. At week 12 the primary endpoints were tested hierarchically to control type 1 error; these endpoints were ACR20, HAQ-DI score, DAS28...

Keywords: JAK, Baricitinib, Clinical, Phase 3

Translated by: Bahtiyar Toz

March 16

Tofasitinib veya adalimumab tedavilerinin plasebo ile kaşılaştırılması: aktif romatoid artrit hastalarının faz 3 çalışmasından hasta bildirimli sonlanım (PRO)

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...

Keywords: JAK, Tofacitinib, Clinical, Phase 3

Translated by: Bahtiyar Toz

Erken Artrit de VPAC1 Reseptör Ekspresyonunun Klinik İlişkisi: IL-6 ve Hastalık Aktivitesi ile İlişkisi

Seoane I, Ortiz A, Piris L et al.
 PLoS ONE 11(2): e0149141. doi:10.1371/journal. pone.0149141

VPAC1 and VPAC2 both mediate anti-inflammatory and immunoregulatory responses in RA. Both these are receptors of vasoactive intestinal peptide (VIP), a broadly distributed peptide found in neural, endocrine and immune cells, which triggers biological response when interacting with the aforementioned receptors. It has recently been described in Martinez et al. that those patients with low levels of VIP have worse disease outcome.1 This study analyzed 250 blood samples from the Princesa early Art...

Keywords: IL-6, Preclinical

Romatoid Artrit tanılı yaşlı hastalarda biyolojik tedavilerin kardiyovasküler risk üzerindeki etkileri

Zhang et al.
Ann Rheum Dis 2016;0:1–6 doi:10.1136/ annrheumdis-2015-207870 [Epub ahead of print]

Since RA patients are at an increased risk of a CV event, there have been several studies to determine if RA treatments alter this risk. In a retrospective study, Zhang and colleagues assess the risk of CV events in patients initiating bDMARDs. Using Medicare medical and pharmacy claims data, the incidence rate (IR) of acute myocardial infarction (AMI) and of a composite CHD* was calculated across RA patients initiating 8 different biologics: ABA, ADA, CER, ETA, GOL, INF, RIT, and TOC. There we...

Keywords: IL-6, Tocilizumab, Real World, Cardiovascular

Erken gebelikte uygulanan tosilizumab �tedavisinin gebelik sonuçları: �Alman Embriyotox Farmakovijilans Merkezindan vaka serisi

Weber-Schoendorfer et al.
Reproductive Toxicology doi:10.1016/j.reprotox.2016.01.002

MTX users have an increased incidence of spontaneous abortions (SABs) compared to baseline risk (42.5%1 vs. 13-17%2). Tocilizumab (TCZ) has been shown to have similar efficacy with or without MTX. There is currently limited data on the effect of TCZ on pregnancy, but with more safety data, TCZ could be an alternative for RA patients of reproductive age. The patients were enrolled at Embryotox Berlin, a pharmacovigilance center providing risk assessment during pregnancy, between 2011 and 2014 d...

Keywords: IL-6, Tocilizumab, Real World, Safety

Metotreksata yetersiz yanıtlı romatoid artritli hastalarında metotreksata tosilizumab eklenmesi yada tosilizumab tedavisine geçiş tedavilerinin karşılaştırılması: �52 haftalık prospektif, randomize kontrollü çalışma (SURPRISE çalışması)

Kaneko et al.
Ann Rheum Dis 2016 Jan 5 DOI: 10.1136/annrheumdis-2015-208426 [Epub ahead of print

MTX is the primary drug in RA management because of its long-term effectiveness and safety profile; however, in patients who have insufficient response (IR) to MTX, treatment adjustments are needed – either to combine a bDMARD with MTX or to switch to a bDMARD from MTX. In the SURPRISE study, the efficacy and safety of adding TCZ to MTX (ADD-ON) or switching MTX to TCZ (SWITCH) was evaluated in 233 patients with moderate to highly active RA who were randomised 1:1. Both treatment groups we...

Keywords: IL-6, Tocilizumab, Clinical, Phase 3

Translated by: Bahtiyar Toz

LITHE çalışmasında tocilizumab tedavisine yanıtın erken göstergesi olarak eklem hasarı �biyogöstergelerinin kanda erken dönemde değişikliği

Bay-Jensen A, Platt A, Siebuhr A, Christiansen C, Byrjalsen I, Karsdal M.
Arthritis Research & Therapy (2016) 18:13 DOI: 10.1186/s13075-015-0913-x

One of the major challenges of RA treatment is choosing the correct treatment and dose for the individual patient, as treatment response can be heterogeneous. To help select the appropriate treatment, there is a need for effective and non-invasive ways to monitor disease activity and progression. In the LITHE study, Bay-Jensen et al. investigate whether early biomarker measurements could predict early joint protection response to TCZ. The biomarkers (CRPM, VICM, C1M, C2M, C3M, and CTX-I/OC [bone...

Keywords: IL-6, Tocilizumab, Clinical

Translated by: Bahtiyar Toz

April 15

Aktif Romatoid Artritli ve Metoktreksata Yetersiz Yanıtlı Hastalarda Sarilumab artı Metotreksat: Bir Faz III Çalışmanın Sonuçları

Genovese MC, Fleischmann R, Kivitz A et al.
Arthritis Rheumatol. Vol. 67, No. 6, June 2015, pp 1424–1437

Biologic DMARDs targeting TNF-alpha, IL-1, T-cell co-stimulatory blockade, B-cell depletion, and IL-6R, as well as the newer JAK inhibitors have greatly improved clinical outcomes in RA. However, not all patients respond to current biologic or small molecule DMARDs. Sarilumab is a fully human anti-IL-6Rα mAb that binds membrane-bound and soluble human IL-6R with high affinity, blocking cis and trans IL-6-mediated signalling. This study (MOBILITY) is the first randomised, double-blind,...

Keywords: IL-6, Sarilumab, Clinical, Phase 3

Translated by: Ege Sinan TORUN

March 15

Aktif Romatoid Artritli Hastalarda Monoterapi Olarak Oral Selektif Bir JAK-3 İnhibitörü Olan Decernotinib’in Randomize, Çift-Kör, Plasebo-Kontrollü, On İki-Haftalık Bir Doz-Aralığı Çalışması

Fleischmann RM, Damjanov NS, Kivitz AJ, et al.
Arthritis Rheumatol. 2015;67(2):334–343.

Decernotinib (VX-509; Vertex Pharmaceuticals Incorporated) is a JAK 3 inhibitor currently under investigation for its potential use in the treatment of RA. The potency and selectivity profiles of this oral compound have already been established in previous trials, so this study aimed to establish the efficacy and safety profiles of the drug, in RA patients who have had an inadequate response to at least one DMARD. Four doses; 25 mg, 50 mg, 100 mg and 150 mg, were evaluated in this placebo-contr...

Keywords: JAK, Decernotinib, Clinical, Phase 2

Translated by: Ege Sinan TORUN

İnflamatuar hastalıkların tedavisi için NLRP3 inflamazomunun küçük-moleküllü bir inhibitörü

Coll RC, Robertson AA, Chae JJ, et al.
Nat Med. 2015 Feb 16. doi: 10.1038/nm.3806. [Epub ahead of print]

A team of scientists at Trinity College Dublin and the University of Queensland Australia, led by Professor Luke O'Neill, have identified a key molecule that may result in the development of new anti-inflammatory therapies for diseases such as: cryopyrin-associated periodic syndrome (CAPS), multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis. Professor O'Neill and his team have identified MCC950 as a potent, selective, small-molecule inhibitor of the ...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Ege Sinan TORUN

December 14

JAK inhibitörü tofacitinib romatoid artritte sinovyal JAK1-STAT sinyalizasyonunu baskılar

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...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Ege Sinan TORUN

Romatoid artritte tedavi için terapötik fırsat olarak TNFα ve IL-17’nin kombine inhibisyonu: Yeni bir bispesifik antikorun geliştirilmesi ve nitelendirilmesi.

Fischer JA, Hueber AJ, Wilson S, Galm M, Baum W, Kitson C, Auer J, Lorenz S, Moelleken J, Bader M, Tissot AC, Tan SL, Seeber S, Schett G.
Arthritis Rheumatol. 2015;67(1):51–62

Single cytokine inhibition, e.g. TNFα or IL-6, has fundamentally improved the therapeutic armamentarium for the treatment of RA; yet clinically meaningful responses are achieved in only about half of RA patients treated. In addition, it is now well established that the pathogenesis of RA involves multiple mechanisms of cell activation and cell recruitment. These two factors have led to the emergence of the concept of dual specificity, sparking interest in the biologic arena, with a foc...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Ege Sinan TORUN

September 14

Dalak tirozin kinaz inhibitörü fostamatinib’in aktif metaboliti dendritik hücrelerin CD4+ T hücrelerini «çalıştırma» (priming) kapasitesini ortadan kaldırır

Platt AM, Benson RA, McQueenie R, et al.
Rheumatology (Oxford). 2015;54(1):169–177

SYK is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors. While the clinical development of the first SYK inhibitor, fostamatinib, was stopped due to poor results in the phase 3 RA programme, there remain important questions of mechanism which may aid future developments of this target. In these murine studies, investigators sought to gain an understanding of how the active metabolite of fostamatinib, ...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Ege Sinan TORUN

Plak Psoriasis’de Secukinumab — İki Faz 3 Çalışmanın Sonuçları

Langley RG, Elewski BE, Lebwohl M, et al.
N Engl J Med. 2014;371(4):326–338.

Secukinumab is a fully human monoclonal antibody that selectively binds to and neutralises interleukin-17A, a cytokine shown to play a crucial role in plaque psoriasis, as well as other immune-mediated diseases. These two pivotal phase 3 studies in plaque psoriasis, FIXTURE and ERAUSRE, were sponsored by Novartis Pharmaceuticals. Secukinumab met all primary endpoints, PASI 75 response and the response of 0 or 1 on the modified investigator’s global assessment, as well as key secondary ...

Keywords: Cytokine Signalling, Clinical, Phase 3

Translated by: Ege Sinan TORUN

August 14

Tofacitinib ile tedavi edilen aktif romatoid artritli hastalarda serum kreatinin düzeylerinde değişiklikler: klinik çalışmalardan elde edilen sonuçlar

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...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Ege Sinan TORUN

Romatoid Artritli Hastalarda Tofacitinib’in Faz II, III ve Uzun-Dönem Uzatma Çalışmalarında Enfeksiyonun ve Tüm-Nedenlere-Bağlı Mortalitenin Analizi

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...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Ege Sinan TORUN

July 14

Romatoid Artrit Hastalarında Tofacitinib ve Herpes Zoster

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...

Keywords: JAK, Tofacitinib, Infections

Translated by: Bahtiyar Toz

Nosiseptif duyu nöronları, interlökin-23 aracılı psöriasiform deri inflamasyonuna neden olur

Riol-Blanco L, Ordovas-Montanes J, Perro M, et al.
Nature. 2014;510(7503):157–161.

The abnormal activation of skin immune cells, such as dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, by IL-23 is known to provoke psoriasis-type inflammation. What is less well known is how peripheral nerves regulate cutaneous immune responses. In this study, IL-23-dependent psoriasis-like inflammation was induced in mice to help determine the precise molecular mechanism of neuroimmune communication in the skin. Finding...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Şafak Mirioğlu

Romatoid Artritte Metotreksata Karşı Tofacitinib

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...

Keywords: JAK, Tofacitinib, Clinical, Phase 3

Translated by: Şafak Mirioğlu

June 14

Anti-inflamatuar genlerin p38 MAP kinaz ve MAP kinaz kinaz 6 tarafından farklı regülasyonu

Hammaker D, Boyle DL, Topolewski K et al.
Journal of Inflammation 2014, 11:14

Several p38α inhibitors have been developed and evaluated in RA. However, despite pre-clinical data showing promise, the compounds have been shown to have little therapeutic efficacy. Previous studies have suggested this may be a result of inhibitors blocking the role of p38 in limiting inflammation. Previous studies by the same authors have shown that the targeting of MKK3 or MKK 6, which are the upstream activators of p38, may be superior to p38 blockade as the anti-inflammatory eff...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

Alternatif p38 MAPKlar Kollajen ile Uyarılmış Artrit için Gereklidir

Criado G, Risco A, Alsina-Beauchamp D et al.
Arthritis and Rheumatology Vol66, No. 5, May2014 pp 1208-1217

MAPK family proteins are regulatory proteins, affecting processes such as synthesis and release of proinflammatory molecules which contribute to the pathogenesis of RA. In particular, the p38 MAPK protein family is central to proinflammatory cytokine production. There are four member of the p38 group; p38α, p38β, p38γ and p38δ. This study sought to evaluate p38γ and p38δ deficiency in mice CIA model. In p38γ-/- or p38&delt...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Şafak Mirioğlu

Büyüme Hormonu Reseptörü Tarafından JAK2 Protein Kinaz Aktivasyonunun Mekanizması

Brooks AJ, Dai W, O’Mara ML et al.
Science 344, 2014; doi: 10.1126/science.1249783

Class I cytokine receptors are key regulators of many processes within the body. The receptors use the JAK-STAT signalling pathway, the deregulation of which causes it to become an important pathway in oncogenesis. Despite this, the processes responsible for JAK2 activation by class I receptors remains elusive. Previous studies using growth hormone and its receptor have led to a model of receptor activation where hormone induced receptor dimerization resulted in close proximity of the receptor ...

Keywords: JAK, Preclinical, MOA

Translated by: Bahtiyar Toz

Protein kinaz TYK2'nin psödokinaz–kinaz alanlarının yapısı Janus kinaz (JAK) otoinhibisyonu için bir mekanizma ortaya çıkarmaktadır

Lupardus PJ, Ultsch M, Wallweber H et al.
Proc Natl Acad Sci U S A. 2014 May 19. pii: 201401180. [Epub ahead of print]

The JAK family of kinases (JAK1, JAK2, JAK3 and TYK2) are receptor-associated tyrosine kinases that act downstream of many cytokines and interferons. Recent studies have provided structural information about the kinase and pseudokinase domains of JAKs however the molecular mechanism by which JAK activity is regulated by the pseudokinase domain is poorly understood. This study builds on a recent finding that the N terminus of the JAK1 pseudokinase group may act as a switch for kinase activation ...

Keywords: JAK, Preclinical, MOA

Translated by: Şafak Mirioğlu

Tirozin kinaz 2 tarafından tanınan interferon-α reseptörünün temel yapısı

Wallweber HJA, Tam C, Franke Y et al.
Nat Struct Mol Biol. 2014 May;21(5):443-8. doi: 10.1038/nsmb.2807. Epub 2014 Apr 6

Janus kinases, JAKs, are essential in the mediation of cytokine and interferon signalling whilst also being crucial to body processes such as immune function, hematopoeises, metabolism and cellular growth. However, it is not known is how the four members of the JAK family interact with and are activated by over 30 cytokine receptors with near perfect affinity and specificity. Currently, there are no crystal structures available for any JAK bound to a cytokine receptor. This study sought address...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

May 14

AG490, farelerde JAK2-STAT3 inhibisyonu yaparak T reg ve Th17 hücrelerinin resiprok regülasyonu aracılığıyla Otoimmün Artriti baskılar

Park JS, Lee J, Lim MA et al.
J Immunol 2014; 192:4417-4424

In this study, Park et al sought to investigate the effects of the JAK2 inhibitor, AG490 in RA. Using murine CIA models, both preventative and therapeutic models were investigated. In the preventative model, CIA mice treated with AG490 showed a significantly lower incidence rate of arthritis and arthritic scores when compared to mice injected with vehicle. In the therapeutic model, as in the preventative, AG490 treated mice exhibited less severe arthritis. Through further experiments, it was de...

Keywords: JAK, Preclinical, MOA

Translated by: Bahtiyar Toz

Oral Januz Kinaz İnhibitörü Tofacitinibin Romatoid Artrit tedavisinde Etkinliği ve Güvenliliği, Açık-Etiketli Uzun-dönem Çalışma

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...

Keywords: JAK, Tofacitinib, Clinical, Phase 3

Translated by: Bahtiyar Toz

Januz–aktive kinaz yolağının inhibisyonu,tümör nekroz faktör alfa ile indüklenen IL-18 biyoaktivitesini, kaspaz-1 inhibisyonu aracılığıyla, azaltır

Marotte H, Tsou PS, Fedorova T et al.
Arthritis Research and Therapy 2014,16:R102

IL-18, a member of the IL-1 family, has been shown to play an important role in immune response and is involved in the pathogenesis of RA. The study objective was to examine the role of the JAK pathway in modulating TNFa-induced-IL18 bioactivity by reducing caspase-1 function. Caspase-1 is the protease that cleaves pro-IL-18 to IL-18, thereby activating it. In testing it was noted that by blocking the JAK pathway significantly decreased caspase-1 transcription, expression and activity showing th...

Keywords: JAK, Preclinical, MOA

Translated by: Bahtiyar Toz

RA sinovyal doku eksplantlarında Btk inhibisyonu agonist ile indüklenen insan makrofaj aktivasyonunu ve inflamatuar gen ekspresyonunu baskılar

Hartkamp LM, Fine JS, van Es IE et al.
Ann Rheum Dis Published Online First 24 April 2014 doi:10.1136/annrheumdis-2013-204143

Bruton’s tyrosine kinase, a downstream target of PI3K signalling, has been shown to be crucial in the B lymphocyte and myeloid cell contribution to murine models of arthritis. Synovial tissue samples were taken from biologically naïve RA (n=16) and PsA (n=12) patients in order to assess the expression of BTK. Separate RA synovial explants (n=8) were used to assess the effects of the specific BTK inhibitor RN486. BTK was expressed at equivalent levels in both RA and PsA synovial tissu...

Keywords: BTK, Preclinical, MOA

Translated by: Bahtiyar Toz

Romatoid artrit ve eklem hasarı patogenezi ile ilişkili yeni bir medyatör: 14-3-3eta

Maksymowych WP, van der Heijde D, Allaart CF et al.
Arthritis Research and Therapy 2014, 16:R99

A major clinical imperative among rheumatologists is the ability to class patients into risk categories for radiographic progression. Indeed, identification of new independent biomarkers predictive of RA disease progression is a key target from OMERACT. This study by Maksymowych et al. sought to clarify the role of 14-3-3? in RA and whether it provided any clinically and/or serologically important prognostic information. First described as being elevated in RA in 2007, 14-3-3? has a strong corre...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

April 14

Romatoid Artrit Tedavisinde Kullanılan Janus Kinaz inhibitörü Tofasitinibin Serum Amiloid A ve IL-6 üzerine etkisi

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...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Bahtiyar Toz

Hipoksi ve STAT3 sinyalizasyonunun etkileşimleri romatoid artritte proinflamatuvar yolları düzenler

Gao W, McCormick J, Connolly M et al.
. ARD published online first 13 Feb 2014. Doi: 10.1136/annrheumdis-2013-204105

Hypoxia is a key driving force in joint inflammation, however little is known about the effect it can have on JAK/STAT signalling in rheumatoid arthritis. Due to the development of JAK inhibitors as therapeutics it is important to understand any links there may be. Previous studies have shown that HIF1a, a protein associated with hypoxia, facilitates the binding of STAT3 to haptoglobin promoter in HepG2 human hepatoma cells. HIF1a also requires interaction of Notch signalling pathways with STAT3...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Şafak Mirioğlu

March 14

Romatoid Artrit gelişme riski olan bireylerde sinovyumun özellikleri

de Hair MJH, van de Sande MGH, Ramwadhdoebe TH et al.
Arthritis and Rheumatology March 2014:66;513-522

This study expands on previous findings that synovial inflammation does not coincide with the appearance of rheumatoid arthritis. This was a markedly larger study compared to previous, with 55 individuals assessed. All 55 subjects were positive for IgM rheumatoid factor and/or anti-citrillinated protein antibody as well as possessing no physical evidence of arthritis. 15 of the individuals tested developed arthritis after a median time of 13 months. In these patients the presence of inflammatory...

Keywords: Preclinical, MOA

Translated by: Bahtiyar Toz

Romatoid Artrit Hastalarının Preklinik Dönemde Proinflamatuar Otoreaktif T Hücre Yanıtı

Aslam A, Nam J, Hunt L et al.
The Lancet, Volume 383, Page S22, 26 February 2014

Before the onset of clinically apparent disease, the pathogenesis of RA goes through a number of sequential phases. The presence of autoimmunity through RF and ACPAs can be detected up to 13 years before the onset of clinical synovitis. An important component of the immune system is Treg cells which limit damage caused by excessive immune activity. These cells have been found to be dysfunctional in RA. This study aimed to identify autoreactive T cells to a known RA-associated antigen and determi...

Keywords: Preclinical, MOA

Translated by: Bahtiyar Toz

Osteoartrit benzeri durumlarda TAK1 ve/veya JAK inhibisyonu insan mezenkimal kök hücrelerinin bozulmuş kıkırdak farklılaşmasını düzeltebilir

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...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

February 14

Januz kinaz inhibitörü Tofasitinibin insanlarda farmakokinetik, metabolizma ve klirens mekanizması

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...

Keywords: JAK, Tofacitinib, Preclinical, PK-PD

Translated by: Bahtiyar Toz

Romatoid artritte tofacitinibin lenfositler üzerindeki etkileri: Etkinlikle ve enfeksiyöz yan etkilerle olan ilişki

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...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Şafak Mirioğlu

January 14

IPI-145, PI3K-δ ve PI3K-γ inhibisyonu ile otoimmün ve inflamatuar hastalık modellerinde immün yanıt aktivitesini baskılar ve ortadan kaldırılmasını sağlar

Winkler DG, Faia KL, DiNitto JP et al.
Chemistry and Biology Nov 13 20, 1364-1374

Phosphoinositide-3 kinases (PI3K) are cell signalling proteins that act as a central node for relaying signals from cell surface receptors and downstream mediators. Specifically they phosphorylate phosphatidylinositol to phosphatidylinositol-3,4,5-trisphosphate (PIP3). This acts a docking site for signalling proteins, leading to the activation of downstream effectors such as BTK. Therefore, inhibition of the PI3K-d and PI3K-? isoforms (PI3K-a and PI3K-ß demonstrated embryonic lethality in ...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

Yeni Oral Küçük Molekül İnhibitörü RO9021 ın Dalak Tirozin Kinazı Selektif İnhibisyonuna Bağlı Doğuştan ve Adaptif İmmün Yanıt Üzerinde Ortaya Çıkan Etkiler: Otoimmün Hastalık Tedavisinde SYK Etkileri

Liao C, Hsu J, Kim Y et al.
Arthritis Research and Therapy 2013 15:R146

Spleen tyrosine kinase (SYK) has already been described as a potential therapeutic target for the treatment of autoimmune diseases. Previously the SYK inhibitor fostamatinib was in clinical development for the treatment of rheumatoid arthritis, but has since been suspended. However, investigation into SYK inhibition continues with RO2091, a novel ATP-competitive inhibitor of SYK with reasonable selectivity, potency and oral bioavailability which has been shown to suppress various innate and adap...

Keywords: Cytokine Signalling, Preclinical, Selectivity

Translated by: Bahtiyar Toz

STA-21, gelecek vadeden STAT3 inhibitörü olup Th17 ve Treg resiprok olarak düzenler, osteoklastogenezi inhibe eder ve otoimmün inflamasyonu iyileştirir

Park JS, Kwok SK, Lim MA et al.
Arthritis and Rheumatism doi: 10.1002/art.38305

STAT3 (signal transducer and activator of transcription 3) is the major transcription factor in the differentiation of Th17 cells, which along with IL-17 are significant in the development of RA. STA-21 is a new small molecule with significant inhibitory effects on STAT3, impeding DNA binding activity, dimerization and STAT3-dependent luciferase activity. While the effect of STA-21 in RA has not been fully determined, it has been hypothesised that STA-21 will suppress arthritis in animal models ...

Keywords: Cytokine Signalling, Preclinical, MOA

Translated by: Bahtiyar Toz

Oral Btk inhibitörü İbrutinib Osteoklast Aracılı Kemik Kaybına Karşı Koruyucudur

Shinohara M, Chang BY, Buggy JJ et al.
Bone 2014;60:8-15

Ibrutinib is a first-in-class, orally available Btk (Bruton’s tyrosine kinase) inhibitor which has been shown to be effective in the treatment against certain types of leukemia and autoimmune disorders. Btk regulates the expression of genes involved in the differentiation and function of osteoclasts, and therefore inhibiting Btk suppresses osteoclastic bone resorption. Results from in vitro testing showed the suppressive effects on osteoclasts and murine models of RA showed ibrutinib treat...

Keywords: BTK, Preclinical, MOA

Translated by: Bahtiyar Toz

Romatoid Artrit de Januz Kinaz İnhibitörü Tofasitinibin Preklinikten Kliniğe Geçişi

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...

Keywords: JAK, Tofacitinib, Preclinical, PK-PD

Translated by: Bahtiyar Toz

October 13

Selektif JAK1 inhibitörü GLPG0634 nin inflamatuar hastalıkların tedavisinde preklinik özellikleri

Van Rompaey L, Galien R, van der Aar EM, et al.
Journal of Immunology 2013;191:3568–77

JAK inhibitors have been identified as having a critical role as therapeutic targets for autoimmune, inflammatory and oncological diseases. GLPG0634 was shown to inhibit JAK1/JAK2 but with a much greater effect on JAK1, a critical pathway in the signal transduction of many inflammatory cytokines. In rodent testing, GLPG0634 showed significant dose-dependent reduction in disease progression in collagen-induced arthritis models, with comparable efficacy to etanercept. An orally bioavailable treatm...

Keywords: JAK, Filgotinib, Preclinical

Translated by: Bahtiyar Toz

JAK inhibitörü Tofasitinib İnsan Monosit Kökenli Dendritik Hücrelerinin T hücre stimülator kapasitesini azaltır

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...

Keywords: JAK, Tofacitinib, Preclinical, MOA

Translated by: Bahtiyar Toz, MD

Hastalık-modifiye edici antiromatizmal ilaçların terminolojisinde yeni öneri

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...

Keywords: Cytokine Signalling

Translated by: Bahtiyar Toz

Inhibition of JAK/STAT signalling pathway in rheumatoid synovial fibroblasts using small molecule compounds

Migita K, Izumi Y, Torigoshi T et al.
Clin Exp Immunol. 2013 Aug 23. doi: 10.1111/cei.12190

Current JAK inhibitors CP-690,550 and INCB020850 have inhibitory effects on multiple JAK pathways, therefore Migita et al. tested whether selective inhibition of JAK3, using PF-956980, would be enough to ameliorate the rheumatoid inflammatory process. The results indicated that the inhibition of JAK3 alone is does not achieve control of STAT3-dependent signalling, and while it is suggested that the targeting of singular JAK pathways should lead to fewer adverse events, it appears that this appro...

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...

August 13

Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial

Westhovens R, Keyser FD, Rekalov D, et al.
Ann Rheum Dis. 2013 May; 72(5):741–4

This phase2 trial assessed the efficacy of GLPG0259, a first-in-class ATP-competitive inhibitor of MAPKAPK5. The trail involved 31 patients with active RA and an inadequate response MTX. Patients received either 50 mg/day GLPG0259 with MTX or a placebo with MTX (patients randomised 2:1) for 12 weeks with the primary efficacy variable being ACR 20 response at week 12. Analysis showed that 5 patients (26.3%) in the GLPG0259 group and 3 patients (27.3%) in the placebo group achieved ACR 20 at 12 we...

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...

June 13

Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor

Pine PR, Chang B, Schoettler N, et al.
Clinical Immunology 2007; 124:244-57

This study investigated the capacity of the novel oral spleen tyrosine kinase (Syk) inhibitor R406, and its prodrug R788 (fostamatinib), to suppress the reversed passive Arthrus reaction (RPA) and collagen-induced arthritis (CIA) in rats. R406 (0.1, 1, 5 and 10 mg/kg) and R788 (10 and 30 mg/kg) reduced the cutaneous RPA reaction and inflammatory oedema in a dose-dependent manner, with statistically significant reductions in extravascular leakage and tissue swelling (72% reduction with R406 10 mg...

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...

An Oral Spleen Tyrosine Kinase (Syk) Inhibitor for Rheumatoid Arthritis

Weinblatt ME, Kavanaugh A, Genovese MC, et al.
The New England Journal of Medicine 2010; 363(14):1303-12

This is the first phase 2 study to be published for spleen tyrosine kinase (Syk) inhibitor R788 (fostamatinib). This phase 2 study ingestigated the efficacy and safety of fostamatinib in patients with active RA despite long-term treatment with methotrexate. In this 6-month, double-blind, placebo-controlled trial, patients were randomised to receive two doses of R788 (100 mg twice daily or 150 mg once daily) or placebo once or twice daily. Significantly more patients on R788 achieved ACR 20 respo...

An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents

Genovese MC, Kavanaugh A, Weinblatt ME, et al.
Arthritis & Rheumatism 2011; 63(2):337-45

This was the first phase 2 study to be published investigating the efficacy and safety of the spleen kinase (Syk) inhibitor R788 (fostamatinib) in patients with refractory rheumatoid arthritis (RA). In this multicentre, randomised, double-blind, placebo-controlled, 3-month trial, patients with active RA on stable background treatment (excluding biologics) were randomised to receive 100 mg R788 or placebo twice daily. Differences in ACR20 responses were significant at week 6 (p=0.003), but not th...

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...

Effects of fostamatinib (R788), an oral spleen tyrosine kinase inhibitor, on health-related quality of life in patients with active rheumatoid arthritis: analyses of patient-reported outcomes from a randomized, double-blind, placebo-controlled trial

Weinblatt ME, Kavanaugh A, Genovese MC, et al.
The Journal of Rheumatology 2013; 40(3):369-78

This phase 2 clinical trial assessed the influence of fostamatinib on patient reported outcomes (PROs) in 457 patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). Patients received either placebo or fostamatinib 100 mg twice daily or 150 mg once daily (1:1:1) for 24 weeks in addition to their baseline MTX. Patients taking fostamatinib 100 mg twice daily had statistically significant improvements in health-related quality of life scores for pain, p...