Cytokine Signalling Forum

Publications





November 21

Upadacitinib in patients with psoriatic arthritis and an inadequate response to non-biological therapy: 56-week data from the phase 3 SELECT-PsA 1 study

McInnes IB, Kato K, Magrey M, Merola JF, Kishimoto M, Pacheco-Tena C, Haaland D, Chen L, Duan Y, Zueger P, Liu J, Lippe R, Pangan AL, Behrens F.
RMD Open. 2021;7(3):e001838

Analysis of data over 56 weeks shows that efficacy responses are maintained with upadacitinib 15 mg and 30 mg. Following the publication of 12-week data from the Phase III, randomised double-blind, SELECT-PsA 1 study, earlier this year, McInnes, et al. now report the 56-week efficacy and safety data of upadacitinib 15 mg and 30 mg in patients with PsA and an inadequate response to non-biological therapy Efficacy responses and inhibition of radiographic progression were maintained with upadacitin...

October 21

Radiographic progression of structural joint damage over 5 years of baricitinib treatment in patients with rheumatoid arthritis: Results from RA-BEYOND

van der Heijde D, Kartman CE, Xie L, Beattie S, Schlichting D, Mo D, Durez P, Tanaka Y, Fleischmann R.
J Rheumatol. 2021 Sep 15:jrheum.210346.

Oral baricitinib maintained lower levels of radiographic progression than initial csDMARD or placebo through 5 years in patients with active RA.It is well known that persistent joint inflammation in RA can lead to irreversible structural damage that impacts on patient physical function and quality-of-life. To this end, van der Heijde, et al. evaluated the effect of baricitinib on inhibiting radiographic progression of structural joint damage over 5 years in patients with active RA. Results from ...

Keywords: JAK, Baricitinib, Clinical, Radiographic

May 21

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...

Keywords: JAK, Tofacitinib, Clinical, Radiographic

February 21

Upadacitinib Monotherapy Versus Methotrexate Monotherapy in Methotrexate-naïve Japanese Patients with Rheumatoid Arthritis: A Sub-analysis of The Phase 3 SELECT-EARLY study

Takeuchi T, Rischmueller M, Blanco R, Xavier RM, Ueki Y, Atsumi T, Chen S, Friedman A, Pangan AL, Strand V, van Vollenhoven RF.
Mod Rheumatol 2021;26:1–16.

In this sub-analysis of the Phase 3 SELECT-EARLY study, UPA demonstrated clinical efficacy superior to placebo in the Japanese subpopulation. Along with a favourable efficacy observed with the Japan-specific 7.5 mg dose of UPA for all secondary endpoints. SELECT-EARLY was designed to study the safety and efficacy of UPA 15 and 30mg as monotherapy, but it also included a subset of 138 Japanese patients, 40% of whom were randomised to receive UPA 7.5mg. This was designed to meet the requirements...

Keywords: JAK, Upadacitinib, Clinical, Phase 3

Filgotinib Versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and Inadequate Response to Methotrexate: A Phase III Randomised Clinical Trial

Combe B, Kivitz A, Tanaka Y, van der Heijde D, Simon JA, Baraf HSB, Kumar U, Matzkies F, Bartok B, Ye L, Guo Y, Tasset C, Sundy JS, Jahreis A, Genovese MC, Mozaffarian M, Landewé RBM, Bae S-C, Keystone EC, Nash P.
Ann Rheum Dis. 2021 Jan 27:annrheumdis-2020-219214

Filgotinib improved RA signs and symptoms, physical function, and inhibited radiographic progression. FIL 200mg plus MTX, but not FIL 100mg plus MTX showed non-inferiority to ADA plus MTX, based on DAS28(CRP) low disease activity. FIL was also well tolerated in RA patients with inadequate response to MTX. This 52-week, phase 3 randomised clinical trial (FINCH 1) evaluated the efficacy and safety of FIL in patients with RA randomised to FIL 200 or 100mg, ADA 40mg, or placebo, all with background...

Keywords: JAK, Filgotinib, Clinical, Efficacy

September 20

Assessment of the association of baseline anti-CarbV and anti-MCV antibodies with response to treatment and radiographic progression in an RA population treated with either methotrexate or baricitinib: post-hoc analyses from RA-BEGIN

López-Romero P, Martinez-Gamboa L, Bang H, de la Torre I, Holzkämper T, Feist E.
Arthritis Res Ther. 2020;22(1):193

Autoantibodies associated with the onset of RA have gained attention in recent years as prognostic biomarkers. Though not used diagnostically, anti-CarbV (carbamylated vimentin) and anti-MCV (vimentin modified by citrullination) baseline titers are being investigated as predictors of treatment response. In this post-hoc analysis of data from the RA-BEGIN cohort of active RA patients, López-Romero and colleagues consider the potential predictive values of baseline anti-CarbV and anti-MCV t...

Keywords: JAK, Baricitinib, Clinical, Radiographic

August 20

Efficacy and Safety of Upadacitinib Monotherapy in Methotrexate-naïve Patients with Moderately to Severely Active Rheumatoid Arthritis (SELECT-EARLY): A Randomized, Double-blind, Active-comparator, Multi-center, Multi-country Trial

van Vollenhoven R, Takeuchi T, Pangan AL, Friedman A, Mohamed MEF, Chen S, Rischmueller M, Blanco R, Xavier RM, Strand V.
Arthritis Rheumatol 2020

Upadacitinib monotherapy demonstrated superior clinical, radiographic, and patient-reported outcomes versus methotrexate in methotrexate-naïve RA patients. This 48-week double-blind active comparator study investigated upadacitinib monotherapy in patients with early RA, who were either methotrexate-naïve, or who had very limited exposure. 947 patients were randomised to once-daily upadacitinib 15 or 30 mg, or weekly methotrexate. Unusually, there were two separate primary endpoints, s...

Keywords: JAK, Upadacitinib, Efficacy

July 20

Pharmacological Treatment of Psoriatic Arthritis: A Systematic Literature Research for the 2019 Update of the EULAR Recommendations for the Management of Psoriatic Arthritis

Kerschbaumer A, Smolen JS, Dougados M, De Wit M, Primdahl J, McInnes I, Van Der Heijde D, Baraliakos X, Falzon L, Gossec L.
Annals of the Rheumatic Diseases 2020;79:778-786

This SLR reviewed data on pharmacological treatment of PsA. Findings informed the 2019 EULAR taskforce when updating recommendations for PsA management. Overall, no new safety signals were reported. Encouragingly, LTEs of JAKi did not report any venous thromboembolic events or PEs. Efficacy was demonstrated for a range of bDMARD and tsDMARD therapies in various disease domains. Efficacy varied between PsA manifestations and between therapies. Observational data demonstrated efficacy when switchi...

Keywords: Cytokine Signalling, Safety

August 19

Upadacitinib versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase 3, Double-Blind, Randomized Controlled Trial

Fleischmann R, Pangan AL, Song IH, Mysler E, Bessette L, Peterfy C, Durez P, Ostor AJ, Li Y, Zhou Y, Othman AA, Genovese MC.
Arthritis Rheumatol 2019 DOI: 10.1002/art.41032

UPA demonstrated superiority to ADA in terms of clinical, functional and patient-reported outcomes with comparable radiographic inhibition. As many RA patients fail to achieve LDA and remission with TNF inhibitors and MTX there is a requirement for additional treatment options. In this SELECT-COMPARE study the clinical and functional outcomes of UPA were compared to ADA in MTX-IR patients. 1629 MTX-IR were randomly assigned 2:2:1 to; UPA 15mg QD, ADA 40mg Q2W or PBO, with background MTX. Key e...

Keywords: JAK, Upadacitinib, Clinical, Efficacy

February 19

Tofacitinib in Combination with Methotrexate in Patients with Rheumatoid Arthritis: Clinical Efficacy, Radiographic and Safety Outcomes from the 24-Month Phase 3 ORAL Scan Study

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

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

Keywords: JAK, Tofacitinib, Clinical, Safety

September 18

Structural Damage Progression in Patients with Early Rheumatoid Arthritis Treated with Methotrexate, Baricitinib, or Baricitinib plus Methotrexate Based on Clinical Response in the Phase 3 RA-BEGIN Study

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

August 18

Two Years of Sarilumab in Patients with Rheumatoid Arthritis and an Inadequate Response to MTX: Safety, Efficacy and Radiographic Outcomes

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

June 18

Effects of Baricitinib on Radiographic Progression of Structural Joint Damage at 1 year in Patients with Rheumatoid Arthritis and an Inadequate Response to Conventional Synthetic Disease-modifying Antirheumatic Drugs

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

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

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

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

Keywords: JAK, Tofacitinib, Clinical, Radiographic

May 18

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 ...

Keywords: JAK, Tofacitinib, Clinical, PRO

February 18

Radiographic Joint Damage in Early Rheumatoid Arthritis Patients: Comparing Tocilizumab- and Methotrexate-based Treat-to-target Strategies

Teitsma X, Jacobs JWG, Welsing PMJ, Pethӧ-Schramm A, Borm MEA, van Laar JM, Lafeber FPJG, Bijlsma JWJ.
Rheumatology (Oxford) 2018; 57(2):309–17

Tocilizumab (TCZ) therapy in DMARD-naïve patients with RA, is more effective at reducing erosion progression, particularly in the feet, compared with treat-to-target methotrexate (MTX) therapy. This analysis looked at radiographic joint damage, including separate examination of erosion progression and joint space narrowing (JSN) in the hands and feet of patients enrolled in the U-Act-Early trial. Radiographic damage is a common symptom of RA, with treat-to-target strategies aimed at pre...

Keywords: IL-6, Tocilizumab, Clinical, Radiographic

December 17

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

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

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

Keywords: JAK, Tofacitinib, Clinical, Phase 3

June 17

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

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

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

Keywords: JAK, Tofacitinib, Clinical, Safety

May 17

Tocilizumab Combination Therapy or Monotherapy or Methotrexate Monotherapy in Methotrexate-naïve Patients with Early Rheumatoid Arthritis: 2-year Clinical and Radiographic Results from the Randomized, Placebo-controlled FUNCTION Trial

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

February 17

Baricitinib in Patients with Inadequate Response or Intolerance to Conventional Synthetic DMARDs: Results from the RA-BUILD Study

Dougados M, van der Heijde D, Chen Y-C, Greenwald M, Drescher E, Liu J, Beattie S, Witt S, de la Torre I, Gaich C, Rooney T, Schlichting D, de Bono S, Emery P.
Ann Rheum Dis 2017;76:88–95.

Baricitinib improved symptoms of RA in the RA-BUILD trial, a Phase 3 study of baricitinib in patients with moderately to severely active RA, refractory to or intolerant to csDMARDs. As well as providing a short-term (24 weeks) benefit, there appeared to be joint damage benefit, considered a marker of long-term disability. RA-BUILD was a 24-week randomised, double-blind, placebo-controlled parallel-group study. Patients were randomised 1:1:1 to receive once-daily doses of placebo (n=228) or bari...

Keywords: JAK, Baricitinib, Clinical, Phase 3

October 16

RAPID3 and ACR/EULAR Provisional Definitions as Predictors of Radiographic Outcome in a Rheumatoid Arthritis Clinical Trial with Tocilizumab

Khawaja MN, Bergman MJ, Yourish J, Pei J, Reiss W, Keystone E.
Arthritis Care Res 2016; Accepted article. DOI 10.1002/acr.23008.

The findings reported represent the first validation of RAPID3 (Routine Assessment of Patient Index Data 3) remission ± SJC ≤1 as an alternative to the established SDAI or Boolean remission definitions, which can be time consuming and costly to measure. RAPID3 is a pooled index of the patient-reported measures: function, pain and Patient Global estimate of status. Data were analysed from the TociLIzumab Safety and THE Prevention of Structural Joint Damage (LITHE) study, a 2-year doubl...

Keywords: IL-6, Tocilizumab, Clinical, Radiographic

March 16

Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study)

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

April 15

Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: Results of a phase III study

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

May 14

14-3-3eta is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage

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

August 13

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...

Keywords: JAK, Tofacitinib, Clinical, Phase 3

June 13

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...

Keywords: JAK, Baricitinib, Preclinical, Selectivity

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...

Keywords: JAK, Tofacitinib, Clinical, Phase 3