Evaluation of the Short-, Mid-, and Long-Term Effects of Tofacitinib on Lymphocytes in Patients With Rheumatoid Arthritis

Abstract

Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Altered lymphocyte cell counts and a potential association with increased infection rates have been reported in RA patients treated with JAK inhibitors. This analysis was undertaken to evaluate the short-, mid-, and long-term effects of tofacitinib on lymphocytes and infection rates in patients with RA.

Methods: In this post hoc analysis, absolute lymphocyte counts (ALCs) were obtained from phase III studies (12-24 months; n = 717-958) and phase I/II/III/long-term extension studies of tofacitinib (≤117 months) (All RA population; n = 7,061); lymphocyte subset counts (LSCs) were from phase II studies (1.5-6 months' exposure; n = 236-486), an ORAL Sequel vaccine substudy (~22 months; n = 198), and an ORAL Sequel lymphocyte substudy (~50 months; n = 55-1,035) of tofacitinib. The reversibility of ALC/LSC changes was evaluated. The relationship of ALC and LSC to infections was analyzed in the All RA population. The value of monitoring ALC alone was assessed by examining correlations between ALCs and LSCs.

Results: Tofacitinib treatment resulted in an initial increase in ALC versus pretreatment baseline, which gradually declined to steady state by ~48 months. CD4+ and CD8+ T cell counts decreased over long-term treatment, and ALC and LSC changes were reversible upon treatment cessation. Patients with ALCs of <500 cells/mm³ had an increased risk of serious infections. There was no strong association between CD4+ T cell, CD8+ T cell, B cell, or natural killer cell counts and serious infection incidence rates. ALC and CD4+ or CD8+ T cell counts correlated well (R = 0.65-0.86).

Conclusion: Our findings indicate that monitoring of ALC alone appears to be adequate to assess infection risk in tofacitinib-treated patients with RA.

Figure 1

Overview of the study and analysis populations. * = Prior tofacitinib exposure. † = ORAL Strategy is a phase IIIb/IV study. ‡ = Power calculations indicated that these sample sizes (patients with available pretreatment baseline data) were adequate to detect long‐term changes of ≥20% in each of the lymphocyte subset counts (LSCs) with at least 80% probability. § = Nearly all patients were originally participants in phase III studies and thus did not have pretreatment baseline LSC data. P = phase; LTE = long‐term extension; ALC = absolute lymphocyte count; RA = rheumatoid arthritis; BID = twice daily; Q2W = every 2 weeks; MTX = methotrexate; NK = natural killer; LSS = lymphocyte substudy.

Figure 2

Median change from baseline in absolute lymphocyte counts (ALCs) in rheumatoid arthritis (RA) patients from the phase III ORAL Standard study (0–12 months) (A), the phase III ORAL Start study (0–24 months) (B), and the phase I/phase II/phase III/long‐term extension All RA population (0–114 months) (C). Data reported here for the All RA population include patients experiencing up to 114 months of exposure to tofacitinib; however, due to limited numbers of patients with data after month 102, interpretations should be made with caution. Only 1 patient had data at month 117, and that data point was therefore removed. Q1, Q3 = first through third quartiles; BID = twice daily; MTX = methotrexate.

Figure 3

Median percentage change from baseline in lymphocyte subset counts (LSCs) in rheumatoid arthritis patients from phase II studies of tofacitinib 5 mg twice daily (short‐term), from the ORAL Sequel vaccine substudy of tofacitinib 10 mg twice daily (mid‐term), and at entry into the ORAL Sequel lymphocyte substudy (tofacitinib 5 mg or 10 mg twice daily) (long‐term). * = Includes only the subgroup of patients with pretreatment baseline LSC data (for CD3+ T cells, B cells, and natural killer [NK] cells, n = 14; for CD4+ and CD8+ T cells, n = 10). † = Cohort 1 type 1, i.e., the subgroup of patients in cohort 1 who originally participated in the phase II program and had pretreatment baseline data (for CD3+ T cells and B cells, n = 124; for CD4+ and CD8+ T cells, n = 51; for NK cells, n = 121). LV = last visit; M = month; NM = not measured.