Jennifer Hodge

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

Objective Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. Methods A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). Results Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. Conclusions Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. Trial registration number NCT00976599.

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

Objective To evaluate tofacitinibs effect upon pneumococcal and influenza vaccine immunogenicity. Methods We conducted two studies in patients with rheumatoid arthritis using the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and the 2011–2012 trivalent influenza vaccine. In study A, tofacitinib-naive patients were randomised to tofacitinib 10 mg twice daily or placebo, stratified by background methotrexate and vaccinated 4 weeks later. In study B, patients already receiving tofacitinib 10 mg twice daily (with or without methotrexate) were randomised into two groups: those continuing (‘continuous’) or interrupting (‘withdrawn’) tofacitinib for 2 weeks, and then vaccinated 1 week after randomisation. In both studies, titres were measured 35 days after vaccination. Primary endpoints were the proportion of patients achieving a satisfactory response to pneumococcus (twofold or more titre increase against six or more of 12 pneumococcal serotypes) and influenza (fourfold or more titre increase against two or more of three influenza antigens). Results In study A (N=200), fewer tofacitinib patients (45.1%) developed satisfactory pneumococcal responses versus placebo (68.4%), and pneumococcal titres were lower with tofacitinib (particularly with methotrexate). Similar proportions of tofacitinib-treated and placebo-treated patients developed satisfactory influenza responses (56.9% and 62.2%, respectively), although fewer tofacitinib patients (76.5%) developed protective influenza titres (≥1:40 in two or more of three antigens) versus placebo (91.8%). In study B (N=183), similar proportions of continuous and withdrawn patients had satisfactory responses to PPSV-23 (75.0% and 84.6%, respectively) and influenza (66.3% and 63.7%, respectively). Conclusions Among patients starting tofacitinib, diminished responsiveness to PPSV-23, but not influenza, was observed, particularly in those taking concomitant methotrexate. Among existing tofacitinib users, temporary drug discontinuation had limited effect upon influenza or PPSV-23 vaccine responses. Trial registration numbers NCT01359150, NCT00413699.

JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

The inflammatory diseases ulcerative colitis and Crohns disease constitute the two main forms of inflammatory bowel disease (IBD). They are characterized by chronic, relapsing inflammation of the gastrointestinal tract, significantly impacting on patient quality of life and often requiring prolonged treatment. Existing therapies for IBD are not effective for all patients, and an unmet need exists for additional therapies to induce and maintain remission. Here we describe the mechanism of action of the Janus kinase (JAK) inhibitor, tofacitinib, for the treatment of IBD and the effect of JAK inhibition on the chronic cycle of inflammation that is characteristic of the disease. The pathogenesis of IBD involves a dysfunctional response from the innate and adaptive immune system, resulting in overexpression of multiple inflammatory cytokines, many of which signal through JAKs. Thus JAK inhibition allows multiple cytokine signaling pathways to be targeted and is expected to modulate the innate and adaptive immune response in IBD, thereby interrupting the cycle of inflammation. Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated as a targeted immunomodulator for IBD. Clinical development of tofacitinib and other JAK inhibitors is ongoing, with the aspiration of providing new treatment options for IBD that have the potential to deliver prolonged efficacy and clinically meaningful patient benefits.

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

Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV).

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

Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV).

The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis

Abstract 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. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS.

Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers

This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naïve CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4 weeks after withdrawal.

FRI0110 Assessment of Immunogenicity of Live Zoster Vaccination in Rheumatoid Arthritis Patients on Background Methotrexate before and after Initiating Tofacitinib or Placebo

Background Tofacitinib is an oral JAK inhibitor for the treatment of RA. Clinical guidelines recommend live zoster vaccine (LZV) to prevent shingles in RA, but this has not been studied in RA patients (pts) and the effect of tofacitinib on humoral or cell-mediated responses to LZV is unknown. Objectives To evaluate the effect of tofacitinib upon the immune response (IR) and safety of LZV. Methods Pts were aged ≥50 years with active RA (≥4 tender/painful joints and ≥4 swollen joints) despite methotrexate (MTX) ≥4 months (15–25 mg/wk before screening) (study NCT02147587). Pts with prior history of zoster vaccination were excluded, as were those receiving any vaccine in the 6 wks prior to randomisation. After screening, eligible pts on background MTX received LZV and then either tofacitinib 5 mg BID or placebo (PBO) starting 2–3 wks post-vaccination. Both humoral (varicella-zoster virus [VZV]-specific IgG via gpELISA) and cell-mediated responses (VZV-specific T cell enumeration via ELISPOT) before vaccination (baseline [BL], day of vaccination), and then at 2, 6 and 14 wks post-vaccination were measured. Primary endpoint: geometric mean fold rise (GMFR) in VZV-specific IgG titre at 6 wks post-vaccination. Secondary endpoint: proportion of pts achieving a ≥1.5 fold rise in VZV-specific IgG titre 6 wks post-vaccination. Exploratory endpoint: GMFR in VZV-specific T cells (spot-forming cells/106 peripheral blood mononuclear cells) by ELISPOT between BL and 6 wks post-vaccination. Pts were followed for 12 wks after randomisation for safety. Results 112 pts were randomised to PBO (n=57) and tofacitinib (n=55). Most PBO (93%) and tofacitinib (98%) pts were evaluable for IR endpoints. Pts were similar with regard to sex, age, baseline disease activity and baseline VZV immune measures (i.e. IgG, ELISPOT). The GMFR in VZV-specific IgG titre at 6 wks was 2.11 for tofacitinib and 1.74 for PBO. GMFRs in tofacitinib and PBO pts were comparable with GMFRs in healthy people ≥50 years as indicated in the LZV labels. The proportion of pts with a 1.5 fold rise in IgG titre at 6 wks post-vaccination rise trended higher for tofacitinib (57.4%) vs PBO (43.4%). The VZV-specific T cell GMFR at 6 wks increased similarly for tofacitinib (1.50) and PBO (1.29). SAEs occurred in 0 and 3 (5.5%) of PBO and tofacitinib arms respectively. One pt had cutaneous dissemination with vaccine-strain VZV (Oka strain virus) 2 days after starting tofacitinib (16 days post-vaccination). This pt was found to lack pre-existing immunity to VZV, consistent with vaccine-induced disease. The event resolved after tofacitinib discontinuation and antiviral therapy. Conclusions Pts starting tofacitinib had similar VZV-specific humoral and cell-mediated IRs to LZV as compared to PBO-treated pts. Vaccination appeared safe in pts subsequently treated with tofacitinib; however, one patient who lacked pre-existing VZV immunity developed vaccine-induced disease. Acknowledgement Previously presented (Winthrop K et al. Arthritis Rheumatol 2015; 67 (S10): Abstr 12L) and reproduced with permission. This study was funded by Pfizer Inc. Editorial support was provided by S. Johnson of Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest K. Winthrop Grant/research support from: BMS, Pfizer Inc, Consultant for: Pfizer Inc, UCB, AbbVie, Lilly, BMS, Galapagos, and Amgen, A. Wouters Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Choy Grant/research support from: Amgen, Boehringer Ingelheim, Chugai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer Inc, Roche, and UCB, Speakers bureau: Amgen, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Hospira, MSD, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi-Aventis, and UCB, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Hodge Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Nduaka Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, P. Biswas Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. McNeil Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Passador Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Mojcik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, W. Rigby Grant/research support from: Amgen, Pfizer Inc and Roche., Consultant for: for Bristol-Myers Squibb, Eli Lilly, Pfizer Inc and Roche

OP0163 Evaluation of Influenza and Pneumococcal Vaccine Responses in Rheumatoid Arthritis Patients Using Tofacitinib

Background Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To evaluate effects of tofacitinib alone, and in combination with methotrexate (MTX), on immunogenicity of influenza and pneumococcal polysaccharide vaccines (NCT01359150). Methods Patients (pts) with RA were randomised 1:1 to receive tofacitinib 10 mg BID or placebo (PBO), stratified by background MTX. All pts were vaccinated with the 2011-2012 trivalent influenza vaccine (constituents: A/California/7/2009 (H1N1); A/Perth/16/2009 [H3N2]; B/Brisbane/60/2008) and PNEUMOVAX-23® (PPV23, Merck & Co., Inc) pneumococcal vaccine 28 days post-drug initiation. Pneumococcal antibody (Ab) concentrations and influenza Ab titres were measured at vaccination and 35 days post-vaccination. Primary endpoint: proportion of pts achieving a satisfactory humoral response at 35 days post-vaccination to (a) pneumococcal vaccine (≥2-fold increase in Ab concentrations against ≥6 of 12 pneumococcal antigens [Ag]) and (b) influenza vaccine (≥4-fold increase in Ab titres against ≥2 of 3 influenza Ag). Secondary endpoints included proportion of pts achieving protective influenza hemagglutination (HI) titres (≥1:40 influenza Ab titre in ≥2 of 3 Ag), and fold increase of serotype-specific anti-influenza and anti-pneumococcal Ab levels. Results 214 of 223 randomised pts were vaccinated. Immunogenicity evaluations and analyses were performed in 200 pts (tofacitinib, N=102; PBO, N=98, approximately half of each group received MTX). At 35 days post-vaccination, similar proportions of pts developed satisfactory humoral responses to influenza vaccine in the two groups; fewer tofacitinib-treated pts achieved a satisfactory humoral response to PPV23 vaccine, particularly in pts with background MTX (Table 1). The proportion of pts achieving protective influenza HI titre was lower with tofacitinib (76.5%) vs PBO (91.8%). Post-vaccination pneumococcal Ag and influenza serotype-specific geometric mean fold rise (GMFRs) were lower in pts receiving tofacitinib vs PBO. Conclusions Similar proportions of RA pts receiving tofacitinib 10 mg BID vs PBO achieved adequate influenza vaccine humoral responses with or without MTX. PPV23 immunogenicity was decreased in pts receiving tofacitinib vs PBO, particularly in those also receiving MTX. To maximise vaccine response, PPV23 should be given prior to MTX or tofacitinib initiation, as per general recommendations for patients with RA. Disclosure of Interest K. Winthrop Grant/research support from: Oxford Immunotech; Pfizer Inc., Consulting fees or other remuneration: Abbott; Pfizer Inc; UCB; Amgen; Cellestis, J. Neal Grant/research support from: Pfizer Inc., Consultant for: Pfizer Inc., P. Hrycaj Grant/research support from: Pfizer Inc., Consultant for: Pfizer Inc., K. Soma Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., B. Wilkinson Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Hodge Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Zwillich Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., T. Wang Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Rottinghaus Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., T. Kawabata Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Riese Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., C. Mebus Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., C. Bingham III Grant/research support from: BMS, Janssen/J&J, Genentech/Roche, UCB, Consultant for: Pfizer Inc., Abbott, Amgen, BMS, Celgene, Genentech/Roche, Janssen/J&J, UCB