Filgotinib decreases both vertebral body and posterolateral spine inflammation in ankylosing spondylitis: results from the TORTUGA trial.

Objectives: To assess the effects of filgotinib on inflammatory and structural changes at various spinal locations, based on MRI measures in patients with active AS in the TORTUGA trial.

Methods: In the TORTUGA trial, patients with AS received filgotinib 200 mg (n = 58) or placebo (n = 58) once daily for 12 weeks. In this post hoc analysis, spine MRIs were evaluated using the Canada-Denmark (CANDEN) MRI scoring system to assess changes from baseline to week 12 in total spine and subscores for inflammation, fat, erosion and new bone formation (NBF) at various anatomical locations.

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

Objective: This analysis evaluated efficacy and safety of filgotinib, a Janus-associated kinase 1-preferential inhibitor, in methotrexate (MTX)-naive patients with rheumatoid arthritis (RA) with multiple poor prognostic factors (PPFs).

Methods: This was a post hoc analysis of the phase III, randomised, double-blind, active-controlled, FINCH 3 study (clinicaltrials.gov NCT02886728).

Impact of filgotinib on sacroiliac joint magnetic resonance imaging structural lesions at 12 weeks in patients with active ankylosing spondylitis (TORTUGA trial).

Objective: To assess the effect of filgotinib, which preferentially inhibits Janus kinase 1 (JAK1), on MRI measures of structural change in the SI joint in patients with active AS in the TORTUGA trial.

Methods: Adults with active AS and inadequate response/intolerance to two or more NSAIDs were randomized 1:1 to filgotinib 200 mg (n = 58) or placebo (n = 58) once daily for 12 weeks. In this post hoc analysis, T1-weighted MRI scans of the SI joint were evaluated by two independent readers using Spondyloarthritis Research Consortium of Canada (SPARCC) Sacroiliac Joint Structural Score (SSS) definitions for erosion, backfill, fat metaplasia and ankylosis.

An Integrated Analysis of the Safety of Tofacitinib in Psoriatic Arthritis across Phase III and Long-Term Extension Studies with Comparison to Real-World Observational Data.

Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA).

Objective: Our objective was to compare the incidence rates (IRs) of adverse events in tofacitinib clinical trials and real-world observational data for alternative treatments.

Methods: The tofacitinib "dose-comparison cohort" included months 0-12 of two phase III studies (tofacitinib 5 [n = 238] and 10 [n = 236] mg twice daily [BID]); the "all-tofacitinib comparison cohort" (n = 783) included two phase III and one ongoing long-term extension study (data cutoff May 2016).

Effect of filgotinib on health-related quality of life in active psoriatic arthritis: a randomized phase 2 trial (EQUATOR).

Objective: To examine the effects of filgotinib, an oral, selective Janus kinase 1 inhibitor, on health-related quality of life (HRQoL) using the Psoriatic Arthritis Impact of Disease (PsAID)9 questionnaire in active PsA.

Methods: Patients were randomized 1 : 1 to filgotinib 200 mg or placebo once daily for 16 weeks in EQUATOR, a multicentre, double-blind, phase 2 randomized controlled trial. HRQoL was assessed with PsAID9 at Weeks 4 and 16.

Effect of tofacitinib on patient-reported outcomes in patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors in the phase III, randomised controlled trial: OPAL Beyond.

Objectives: Tofacitinib is an oral Janus kinase inhibitor for treatment of psoriatic arthritis (PsA). Patient-reported outcomes (PROs) were evaluated in patients with PsA with inadequate responses to tumour necrosis factor inhibitors (TNFi-IR) in a 6-month, phase III randomised controlled trial (OPAL Beyond [NCT01882439]).

Methods: Patients (N=394) received tofacitinib 5 or 10 mg twice daily or placebo (advancing to tofacitinib 5 or 10 mg twice daily at month 3).

Tofacitinib or adalimumab versus placebo: patient-reported outcomes from OPAL Broaden-a phase III study of active psoriatic arthritis in patients with an inadequate response to conventional synthetic disease-modifying antirheumatic drugs.

Objectives: Tofacitinib is an oral Janus kinase inhibitor for treatment of psoriatic arthritis (PsA). We evaluated patient-reported outcomes (PROs) in patients with PsA refractory to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR) and tumour necrosis factor inhibitor-naïve in a 12-month, phase III randomised controlled trial (OPAL Broaden [NCT01877668]).

Methods: Patients (N=422) received tofacitinib 5 mg or 10 mg twice daily, adalimumab 40 mg subcutaneously every 2 weeks or placebo advancing to tofacitinib 5 mg or 10 mg twice daily at month 3.

Efficacy of Tofacitinib for the Treatment of Psoriatic Arthritis: Pooled Analysis of Two Phase 3 Studies.

Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post hoc analysis assessed the efficacy of tofacitinib using pooled data from two phase 3 studies of patients with active PsA.

Methods: Data were pooled from OPAL Broaden (NCT01877668) and OPAL Beyond (NCT01882439).

Disease-specific composite measures for psoriatic arthritis are highly responsive to a Janus kinase inhibitor treatment that targets multiple domains of disease.

Background: The multiple disease domains affected in psoriatic arthritis (PsA) may make composite endpoints appropriate for assessing changes in disease activity over time. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Data from two phase 3 studies of patients with PsA were used to evaluate the effect of tofacitinib on composite endpoints.

Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial.

Background: At present, biological disease-modifying anti-rheumatic drugs (DMARDs) are the only treatment recommended for patients with ankylosing spondylitis who have not responded to first-line treatment with non-steroidal anti-inflammatory drugs (NSAIDs). The TORTUGA trial investigated the efficacy and safety of filgotinib, an oral selective Janus kinase 1 (JAK1) inhibitor, for the treatment of patients with active ankylosing spondylitis.

Methods: In this completed, randomised, double-blind, placebo-controlled, phase 2 trial, we enrolled adult patients from 30 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine).

Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients.

Objectives: Minimally important changes (MICs) for SPondyloArthritis Research Consortium of Canada (SPARCC) MRI scores are ⩾2.5 for SI joint and ⩾5 for spine. This post hoc analysis assessed achievement of MIC in SPARCC scores in biologic-naïve patients with AS treated with tofacitinib or placebo, and correlation with clinical responses.

The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis.

The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations.

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

Background: Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who had previously had an inadequate response to tumor necrosis factor (TNF) inhibitors.

Methods: In this 6-month randomized, placebo-controlled, double-blind, phase 3 trial, we randomly assigned 395 patients, in a 2:2:1:1 ratio, to four regimens: 5 mg of tofacitinib administered orally twice daily (132 patients); 10 mg of tofacitinib twice daily (132 patients); placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (66 patients); or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (65 patients).

Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study.

Objectives: To compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis).

Methods: In this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10 mg twice daily. The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12.

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

Objectives: Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR).

Methods: Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA).

Monotherapy rapamycin allows an increase of CD4 CD25 FoxP3 T cells in renal recipients.

CD4(+) CD25(bright+) FoxP3(+) regulatory T cells (Tregs) may control donor-specific allogeneic responses in kidney transplant recipients. Recent evidence demonstrated that three phenotypical Treg-subsets, naive (CCR7(+)CD45RO(-)), central-memory (CCR7(+)CD45RO(+)) and effector-memory (CCR7(-)CD45RO(+)), are essential for the development and function of antigen-specific suppression in the lymphoid and peripheral tissues. Also, it has been appreciated that Tregs are affected by immunosuppressive agents.

Generation of donor-specific regulatory T-cell function in kidney transplant patients.

Background: In the search for mechanisms that can induce and maintain transplant tolerance, donor-specific CD4CD25FoxP3 regulatory T cells have been frequently mentioned. However, it remains to be demonstrated, whether these cells are generated after clinical transplantation.

Methods: We prospectively analyzed the phenotype and function of peripheral regulatory CD4CD25 T cells of 79 patients before, 3, 6, and 12 months after kidney transplantation.

End-stage renal failure and regulatory activities of CD4+CD25bright+FoxP3+ T-cells.

Background: The defensive immune system in patients with end-stage renal failure is impaired at multiple levels. This state of immune incompetence is associated with continuous activation of the immune system. An additional explanation for this state of activation may be the disturbed function of CD4(+)CD25(bright+)FoxP3(+) regulatory T-cells.

The effect of rabbit anti-thymocyte globulin induction therapy on regulatory T cells in kidney transplant patients.

Background: Prevention of alloreactivity by rabbit anti-thymocyte globulins (rATG) may not only result from immunodepletion but also from the induction of T cells that control allogeneic immune responses. In the present prospective and controlled study, we investigated the effect of rATG on the frequency, function and phenotype of peripheral immunoregulatory CD4+ T cells in kidney transplant (KTx) patients.

Methods: After transplantation, 16 patients received ATG-induction therapy and triple therapy consisting of tacrolimus, MMF and steroids.

Impact of immunosuppressive drugs on CD4+CD25+FOXP3+ regulatory T cells: does in vitro evidence translate to the clinical setting?

Success of solid-organ transplantation requires the continuous administration of immunosuppressive drugs to prevent graft rejection. The currently prescribed immunosuppressive medication targets the immune system in a nonspecific fashion, leading to debilitating side effects that diminish patient survival and quality of life. Therefore, it is important to minimize immunosuppression, but this requires the development of alternative therapeutic strategies to induce and maintain transplant tolerance.