Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques

Abstract

Objectives: To explore the effects of tofacitinib-an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)-with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand.

Methods: In this exploratory, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score (RAMRIS), quantitative RAMRIS (RAMRIQ) and dynamic contrast-enhanced (DCE) MRI) were assessed using a mixed-effect model for repeated measures. Treatment differences with p<0.05 (vs MTX monotherapy) were considered significant.

Results: In total, 109 patients were randomised and treated. Treatment differences in RAMRIS bone marrow oedema (BME) at month 6 were -1.55 (90% CI -2.52 to -0.58) for tofacitinib + MTX and -1.74 (-2.72 to -0.76) for tofacitinib monotherapy (both p<0.01 vs MTX monotherapy). Numerical improvements in RAMRIS synovitis at month 3 were -0.63 (-1.58 to 0.31) for tofacitinib + MTX and -0.52 (-1.46 to 0.41) for tofacitinib monotherapy (both p>0.05 vs MTX monotherapy). Treatment differences in RAMRIQ synovitis were statistically significant at month 3, consistent with DCE MRI findings. Less deterioration of RAMRIS and RAMRIQ erosive damage was seen at months 6 and 12 in both tofacitinib groups versus MTX monotherapy.

Conclusions: These results provide consistent evidence using three different MRI technologies that tofacitinib treatment leads to early reduction of inflammation and inhibits progression of structural damage.

Trial registration number: NCT01164579.

Keywords: DMARDs (synthetic); Inflammation; Magnetic Resonance Imaging; Methotrexate; Rheumatoid Arthritis.

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Figures

Figure 1

Patient disposition. aMean dose of methotrexate (MTX) at month 3 was 18.3 mg weekly; bmean dose of MTX at month 3 was 19.0 mg weekly; ccould not attend scheduled visits due to work. AE, adverse event; BID, twice daily; N, number of patients in population or analysis set; n, number of patients with an event.

Figure 2

Least squares (LS) mean change from baseline in wrist and metacarpophalangeal (MCP): (A) rheumatoid arthritis MRI score (RAMRIS) bone marrow oedema (BME), (B) RAMRIS synovitis, (C) RAMRIS bone erosions, (D) quantitative rheumatoid arthritis MRI score (RAMRIQ) BME, (E) RAMRIQ synovitis, (F) RAMRIQ bone erosions and wrist (G) dynamic contrast-enhanced MRI (DCE MRI) number of enhancing voxels (NVox) (evaluable set). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs methotrexate (MTX) monotherapy, using a mixed-effect model for repeated measures. MRI measurements were based on one hand (most symptomatic at baseline). RAMRIS and RAMRIQ scores relate to MRIs of the index hand (MCP joints 1–5 and 2–5, respectively) and wrist. DCE MRI measurements relate to MRIs of the index wrist using regions of interest (ROIs) defined within the area encompassing the distal radioulnar joint, the radiocarpal joint and the intercarpal–carpometacarpophalangeal joints. BID, twice daily.

Figure 3

Cumulative probability plots for rheumatoid arthritis MRI score (RAMRIS) endpoints and van der Heijde modification of the total Sharp score (mTSS). The distribution of changes by percentile is shown. BID, twice daily; BME, bone marrow oedema; MCP, metacarpophalangeal; MTX, methotrexate; SDC, smallest detectable change.