Background/Purpose: Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. Herpes zoster (HZ) is more common in patients (pts) with RA vs the general population.¹ HZ risk is increased with tofacitinib use,² and seems to further increase with concomitant use of conventional synthetic DMARDs (eg MTX) or glucocorticoids (GC).³ This increased risk may be linked to treatment-induced IFN suppression,³ as varicella-zoster virus replication may be limited by IFN activity.⁴ We evaluated whether tofacitinib + MTX and/or GC suppressed IFN pathway proteins to a greater extent than tofacitinib alone.

Methods: This post hoc analysis pooled data from 1 Phase (P) 2 (Japan study [NCT00687193]) and 2 P3 (ORAL Scan [NCT00847613]; ORAL Start [NCT01039688]) tofacitinib studies. Serum samples were collected at baseline (BL), Week (W) 12, and/or W24 from pts with RA treated with tofacitinib 5 or 10 mg twice daily alone (Japan study; ORAL Start) or with stable MTX (15–25 mg/week for ≥ 6 weeks; ORAL Scan), and/or GC (≤ 10 mg/day prednisone or equivalent; all studies). A total of 376 proteins associated with cellular/inflammatory processes, including 6 IFN pathway proteins (CXCL9, CXCL10, CXCL11, IL-12, IFNγ, and IL-20), were measured using a homogeneous, solution-based assay (Olink Proseek^® Multiplex Assay, Uppsala, Sweden). Protein-level changes at W12 (Japan study; ORAL Scan) and/or W24 (ORAL Scan; ORAL Start) were compared for both regimens using linear regression models. The dependent variable was change from BL in protein levels at W12 or W24. The independent variable was MTX or GC status. Age, gender, GC status (in MTX model), BL protein levels, and tofacitinib dose were covariates. Separate regressions were performed for each study; GC results were combined via meta-analysis using fixed-/random-effect models. Significance was considered at p < 0.1 after controlling for false discovery rate (FDR).

Results: In total, 659 samples were obtained from 321 pts. Of the 6 IFN pathway proteins, IFNγ and IL-20 were below the limit of detection. There were no statistical differences between tofacitinib alone vs tofacitinib + MTX and/or GC in changes in levels of the 4 detectable IFN pathway proteins (CXCL9, CXCL10, CXCL11, and IL-12) at W12/W24. Significant differences were observed for 2 of 370 other proteins: MMP-1 (FDR-adjusted p = 0.08) and IL1 decoy receptor (IL1Ra; FDR-adjusted p = 0.09); levels were decreased at W12 for tofacitinib + MTX to a greater extent vs tofacitinib alone (Figure 1).

Conclusion: Tofacitinib + MTX and/or GC may not suppress IFN pathway proteins to a greater extent than tofacitinib alone. There were differences at W12 for tofacitinib + MTX vs tofacitinib alone in MMP-1 and IL1Ra, but it is not clear whether these were due to ethnicity differences in the study populations receiving these treatments (global vs Japan). Analyses of biomarker changes with tofacitinib are ongoing.

1. McDonald JR et al. Clin Infect Dis 2009;48:1364-71.
2. Winthrop KL et al. Arthritis Rheumatol 2014;66:2675-84.
3. Winthrop KL et al. Arthritis Rheumatol 2017;69:1960-8.
4. Ku CC et al. Cell Biosci 2016;6:21.

Acknowledgments: Study sponsored by Pfizer Inc. Medical writing support was provided by Sarah Piggott of CMC Connect and funded by Pfizer Inc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/biomarker-changes-for-patients-with-rheumatoid-arthritis-receiving-tofacitinib-with-methotrexate-or-glucocorticoids-vs-tofacitinib-monotherapy/