Characterization and Changes of Lymphocyte Subsets in Baricitinib-Treated Patients With Rheumatoid Arthritis: An Integrated Analysis

Yoshiya Tanaka, Iain B McInnes, Peter C Taylor, Nicole L Byers, Lei Chen, Stephanie de Bono, Maher Issa, William L Macias, Veronica Rogai, Terence P Rooney, Douglas E Schlichting, Steven H Zuckerman, Paul Emery, Yoshiya Tanaka, Iain B McInnes, Peter C Taylor, Nicole L Byers, Lei Chen, Stephanie de Bono, Maher Issa, William L Macias, Veronica Rogai, Terence P Rooney, Douglas E Schlichting, Steven H Zuckerman, Paul Emery

Abstract

Objective: Baricitinib is an orally administered inhibitor of JAK1 and JAK2 that has been shown to be effective in treating rheumatoid arthritis (RA). This study was undertaken to analyze changes in lymphocyte cell subsets during baricitinib treatment and to correlate these changes with clinical outcomes.

Methods: An integrated analysis was conducted by pooling data from 3 completed phase III trials comparing placebo with baricitinib treatment (RA-BEAM, RA-BUILD, and RA-BEACON) and 1 ongoing long-term extension study (RA-BEYOND) in patients with active RA (n = 2,186).

Results: Baricitinib treatment was associated with an early transient increase in total lymphocyte count at week 4, which returned to baseline by week 12. Transient changes within normal reference ranges in T cells and subsets were observed with baricitinib treatment, up to week 104. B cells and relevant subpopulations increased after 4 weeks of baricitinib treatment, with no further increases noted through 104 weeks of treatment. Natural killer (NK) cells temporarily increased after 4 weeks of baricitinib treatment, before decreasing below baseline levels and then stabilizing over time. With baricitinib treatment, few correlations were observed between changes in lymphocyte subsets and clinical end points, and most correlations were also observed within the placebo group. A modest potential association between low NK cell numbers and treatment-emergent infections was observed in the baricitinib 4 mg/day treatment group, but not for serious infections or herpes zoster.

Conclusion: Overall, these findings demonstrate that changes in lymphocyte subsets were largely within normal reference ranges across the baricitinib phase III RA clinical program and were not associated with increased risk of serious infections.

Trial registration: ClinicalTrials.gov NCT01710358 NCT01721057 NCT01721044 NCT01885078.

© 2018 Eli Lilly and Company. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Figures

Figure 1
Figure 1
Top, Total lymphocyte counts during treatment. Values are the median and 25th–75th percentiles. Bottom, Patients with treatment‐emergent low lymphocyte count (TE low) and with treatment‐emergent high lymphocyte count (TE high). Values are the number (%) of the number at risk (NAR). *** = P ≤ 0.001 versus placebo, based on the least squares mean difference change from baseline. ULN = upper limit of normal; LLN = lower limit of normal.
Figure 2
Figure 2
T cell counts during treatment. Counts of CD3+ cells (A), CD4+ cells (B), CD8+ cells (C), Th1 cells (D), Th17 cells (E), and Treg cells (F) are shown. Values are the median and 25th–75th percentiles. A–C include patients with TE high T cell count and TE low T cell count. Values are the number (%) of the NAR. * = P ≤ 0.05; ** = P ≤ 0.01; *** = P ≤ 0.001 versus placebo, based on the least squares mean difference change from baseline. See Figure 1 for definitions.
Figure 3
Figure 3
B cell counts during treatment. Counts of CD19+ B cells (A), switched memory B cells (B), non‐switched memory B cells (C), mature naive B cells (D), and immature transitional B cells (E) are shown. Values are the median and 25th–75th percentiles. A includes patients with TE high B cell count and TE low B cell count. Values are the number (%) of the NAR. * = P ≤ 0.05; *** = P ≤ 0.001 versus placebo, based on the least squares mean difference change from baseline. See Figure 1 for definitions.
Figure 4
Figure 4
Top, Natural killer (NK) cell count during treatment. Values are the median and 25th–75th percentiles. Bottom, Patients with TE low NK cell count and with TE high NK cell count. Values are the number (%) of the NAR. *** = P ≤ 0.001 versus placebo, based on the least squares mean difference change from baseline. See Figure 1 for other definitions.

References

    1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011;365:2205–19.
    1. Tanaka Y. Current concepts in the management of rheumatoid arthritis. Korean J Intern Med 2016;31:210–8.
    1. Furst DE, Emery P. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine‐associated cell targets. Rheumatology (Oxford) 2014;53:1560–9.
    1. Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol 2016;12:25–36.
    1. Smolen JS, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease‐modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017;76:960–77.
    1. Shi JG, Chen X, Lee F, Emm T, Scherle PA, Lo Y, et al. The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. J Clin Pharmacol 2014;54:1354–61.
    1. Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 2016;374:1243–52.
    1. Dougados M, van der Heijde D, Chen YC, Greenwald M, Drescher E, Liu J, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA‐BUILD study. Ann Rheum Dis 2017;76:88–95.
    1. Fleischmann R, Schiff M, van der Heijde D, Ramos‐Remus C, Spindler A, Stanislav M, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease‐modifying antirheumatic drug treatment. Arthritis Rheumatol 2017;69:506–17.
    1. Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales L, Reyes Gonzaga J, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 2017;376:652–62.
    1. Emery P, McInnes I, Genovese M, Smolen J, Kremer J, Dougados M, et al. Characterization of changes in lymphocyte subsets in baricitinib‐treated patients with rheumatoid arthritis in two Phase 3 studies [abstract]. Arthritis Rheumatol 2015;67 Suppl 10 URL: .
    1. Tanaka Y, Fleischmann R, Schiff M, Takeuchi T, Keystone E, Weinblatt M, et al. Characterization of changes in lymphocyte subsets in baricitinib‐treated patients with rheumatoid arthritis in a phase 3 study (RA‐BEAM) [abstract]. Ann Rheum Dis 2016;75 Suppl 2:262–3.
    1. Takeuchi T, Fleischmann R, Schiff M, Issa M, Macias W, Rooney T, et al. Characterization of changes in lymphocyte subsets in baricitinib‐treated patients with early, DMARD naïve, rheumatoid arthritis in a phase 3 study [abstract]. Ann Rheum Dis 2017;76 Suppl 2:1147.
    1. Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol 2017;13:320.
    1. Mujtaba MA, Komocsar WJ, Nantz E, Samaniego MD, Henson SL, Hague JA, et al. Effect of treatment with tabalumab, a B cell–activating factor inhibitor, on highly sensitized patients with end‐stage renal disease awaiting transplantation. Am J Transplant 2016;16:1266–75.
    1. Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty‐eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8.
    1. Papp KA, Menter MA, Raman M, Disch D, Schlichting DE, Gaich C, et al. A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate‐to‐severe psoriasis. Br J Dermatol 2016;174:1266–76.
    1. Clark JD, Flanagan ME, Telliez JB. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem 2014;57:5023–38.
    1. Hodge JA, Kawabata TT, Krishnaswami S, Clark JD, Telliez JB, Dowty ME, et al. The mechanism of action of tofacitinib–an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol 2016;34:318–28.
    1. Van Vollenhoven R, Choy E, Lee EB, Hazra A, Anisfeld A, Lazariciu I, et al. Tofacitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: changes in lymphocytes and lymphocyte subset counts and reversibility after up to 8 years of tofacitinib treatment [abstract]. Ann Rheum Dis 2016;75 Suppl 2:258.
    1. Schulze‐Koops H, Strand V, Nduaka C, DeMasi R, Wallenstein G, Kwok K, et al. Analysis of haematological changes in tofacitinib‐treated patients with rheumatoid arthritis across phase 3 and long‐term extension studies. Rheumatology (Oxford) 2017;56:46–57.
    1. Westhovens R, Taylor PC, Alten R, Pavlova D, Enríquez‐Sosa F, Mazur M, et al. Filgotinib (GLPG0634/GS‐6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose‐finding study (DARWIN 1). Ann Rheum Dis 2017;76:998–1008.
    1. Kavanaugh A, Kremer J, Ponce L, Cseuz R, Reshetko OV, Stanislavchuk M, et al. Filgotinib (GLPG0634/GS‐6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose‐finding study (DARWIN 2). Ann Rheum Dis 2017;76:1009–19.
    1. Kremer JM, Emery P, Camp HS, Friedman A, Wang L, Othman AA, et al. A phase IIb study of ABT‐494, a selective JAK‐1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti‐tumor necrosis factor therapy. Arthritis Rheumatol 2016;68:2867–77.
    1. Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, et al. Efficacy and safety of ABT‐494, a selective JAK‐1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol 2016;68:2857–66.
    1. Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti–tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo‐controlled, 52‐week trial. Arthritis Rheum 2004;50:1400–11.
    1. Samson M, Audia S, Janikashvili N, Ciudad M, Trad M, Fraszczak J, et al. Inhibition of interleukin‐6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum 2012;64:2499–503.
    1. Daïen CI, Gailhac S, Audo R, Mura T, Hahne M, Combe B, et al. High levels of natural killer cells are associated with response to tocilizumab in patients with severe rheumatoid arthritis. Rheumatology (Oxford) 2015;54:601–8.
    1. Roll P, Muhammad K, Schumann M, Kleinert S, Einsele H, Dörner T, et al. In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment. Arthritis Rheum 2011;63:1255–64.

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