Introduction

Treatment options for rheumatoid arthritis (RA) include multiple classes of agents, and patients often receive background or concomitant treatment [1, 2] such as methotrexate (MTX) or glucocorticoid (GC), to improve or expedite clinical response. However, many patients experience adverse events with MTX or GC [3,4,5], and GCs should be used at the lowest possible dose for a minimum duration to minimize unwanted reactions [1, 2]. Therefore, it is important to understand the potential impact of discontinuing concomitant MTX or GC on the clinical efficacy of RA treatments.

Tofacitinib is an oral Janus kinase inhibitor approved for the treatment of RA. The efficacy and safety of tofacitinib 5 and 10 mg twice daily (BID) administered as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), mainly MTX, in patients with active RA have been demonstrated in phase II [6,7,8,9,10], phase III [11,12,13,14,15,16], and phase IIIb/IV [17] studies of up to 24 months’ duration and in long-term extension (LTE) studies with up to 114 months of observation [18,19,20].

In this study, post hoc analyses evaluated: (1) the possible effect of discontinuing MTX or GC on clinical responses in patients with RA receiving tofacitinib in two LTE studies, and (2) the potential effect of initiating MTX or GC in patients originally receiving tofacitinib without MTX or without GC, respectively, at LTE baseline.

Methods

Study Design

These were post hoc, pooled analyses from two multicenter, open-label LTE studies (ORAL Sequel [A3921024; NCT00413699] and Study A3921041 [NCT00661661]). ORAL Sequel was a global study that was ongoing at the time of the analysis (March 2015 data cut-off; database not locked; some values may change for the final locked database). Study A3921041 was conducted in patients in Japan. Full details of the LTE studies were reported previously [18, 19]. Both LTE studies were conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines. The final protocols were reviewed and approved by the Institutional Review Boards and/or Independent Ethics Committee at each study center, and all patients provided written, informed consent.

Patients

Full inclusion and exclusion criteria for the two LTE studies have been previously reported [18, 19]. In summary, patients aged ≥ 18 years (ORAL Sequel) or ≥ 20 years (A3921041) with a diagnosis of RA based on the American College of Rheumatology (ACR) 1987 Revised Criteria [21] were eligible to enroll in the LTE studies if they had completed a prior qualifying tofacitinib phase I (ORAL Sequel only), phase II, or phase III index study [6,7,8,9,10,11,12,13,14,15,16, 22,23,24,25,26], and patients must have received tofacitinib for at least 3 years in the LTE studies to be included in this analysis.

Patients with any serious medical condition (e.g., severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, neurologic or cerebral disease, or history of lymphoproliferative disease) that would make treatment with tofacitinib potentially unsafe were excluded from the LTE studies.

Study Treatment

Patients received tofacitinib 5 or 10 mg BID in the LTE studies. Patients from phase II index studies initiated LTE study treatment with tofacitinib 5 mg BID, whereas patients from phase III index studies initiated LTE study treatment with tofacitinib 10 mg BID, except for patients from China and Japan who all initiated treatment with tofacitinib 5 mg BID per protocol. During the LTE studies, tofacitinib dose could be reduced from 10 to 5 mg BID for reasons of safety, and could be increased from 5 to 10 mg BID for reasons of inadequate response, at the discretion of the investigator.

The tofacitinib dose groups in the analysis were based on the total daily dose (TDD), defined as 5 mg BID for TDD < 15 mg and 10 mg BID for TDD ≥ 15 mg, and calculated by adding all doses received by each patient and dividing by the number of days a dose of tofacitinib was received in the study. Patients receiving tofacitinib 5 or 10 mg BID in the LTE studies were pooled to form a combined all-tofacitinib group.

Patients in the LTE studies were permitted to receive background RA therapy. Dose adjustments to permitted concomitant RA medications (including MTX, leflunomide, sulfasalazine, antimalarials, auranofin, injectable gold preparations, nonsteroidal anti-inflammatory drugs, and/or GCs at approved doses) were at the discretion of the investigator for inadequate efficacy or safety reasons, or could be tapered or discontinued in response to adequate RA disease control.

Analyses

Data from patients receiving tofacitinib 5 or 10 mg BID were pooled into a combined tofacitinib dose group for these analyses.

In patients who began LTE study treatment within 14 days of receiving the last tofacitinib dose in the qualifying index study, baseline values were taken from the index study, otherwise baseline values from the LTE studies were used. LTE baseline values were used for MTX and GC use/dose for all patients.

Discontinuation of MTX or GC was assessed separately in patients who received MTX or GC at baseline, and was defined as no MTX or GC use within the last 30 days prior to the year-3 visit. Initiation was assessed separately in patients who did not receive MTX or GC at baseline, and was defined as initiating MTX or GC on or before the year-3 visit.

Clinical efficacy was assessed at year 3 using the Clinical Disease Activity Index (CDAI). Remission was defined as CDAI ≤ 2.8, low disease activity (LDA) as CDAI > 2.8 to ≤ 10, and incomplete response as CDAI > 10. For maintenance analyses, patients receiving MTX or GC at LTE baseline were stratified by CDAI clinical response 3 months after LTE study entry and evaluated for maintenance of response through year 3.

For patients who initiated treatment with MTX or GC during the LTE studies, the proportion of patients with CDAI response (remission, LDA, or incomplete response) and RA disease parameters [tender joint count (TJC), swollen joint count (SJC), Patient Assessment of Arthritis Pain, assessed by visual analog scale (Pain VAS), Patient’s Global Assessment of disease activity (PtGA) and Physician’s Global Assessment of disease activity (PGA) assessed by VAS, Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue Scale, and C-reactive protein (CRP) levels] were evaluated. Assessments were recorded at baseline, last post-baseline visit prior to initiating MTX or GC, and at the year-3 visit.

Descriptive and summary statistics are presented.

Results

Patients Discontinuing MTX or GC

Of 4867 tofacitinib-treated patients, 2796 (57.4%) were receiving MTX at baseline and 1608/2796 (57.5%) had efficacy measurements at year 3. Of these patients, 186/1608 (11.6%) had discontinued MTX by year 3 and were evaluated in the analysis: 49/186 (26.3%) patients receiving tofacitinib 5 mg BID and 137/186 (73.7%) receiving tofacitinib 10 mg BID. Among all tofacitinib-treated patients who discontinued MTX, the mean (median) number of days spent off MTX prior to the year-3 visit was 577 (563) days.

Of 4867 tofacitinib-treated patients, 2553 (52.5%) were receiving GC at baseline and 1434/2553 (56.2%) had efficacy measurements through year 3. Of these patients, 319/1434 (22.2%) discontinued GC by year 3 and were evaluated in the analysis: 114/319 (35.7%) receiving tofacitinib 5 mg BID and 205/319 (64.3%) receiving tofacitinib 10 mg BID. Among all tofacitinib-treated patients who discontinued GC, the mean (median) number of days after GC discontinuation was 568 (547) days.

Patient demographics and disease characteristics were generally similar irrespective of whether patients discontinued or continued MTX or GC (Table 1).

Table 1 Patient demographics and disease characteristics for patients receiving MTX or GC at baseline by MTX or GC use prior to the year-3 visit
Full size table

MTX Discontinuation and CDAI Response

At year 3, 63/186 (33.9%) patients receiving tofacitinib who discontinued MTX achieved CDAI remission (CDAI ≤ 2.8), compared with 355/1422 (25.0%) who continued background MTX (Fig. 1a). Overall, 131/186 patients (70.4%) who discontinued MTX and 983/1422 patients (69.1%) who continued MTX were either in CDAI remission or LDA at year 3.

Fig. 1
figure 1

a CDAI response at year 3 in patients who were receiving tofacitinib with background MTX at baseline and subsequently discontinued or continued MTX; b maintenance of month-3 CDAI response at year 3 among patients who were receiving tofacitinib with background MTX at baseline and at the month-3 visit, who discontinued or continued MTX prior to the year-3 visit; c CDAI response at the last post-baseline visit prior to and following initiation of MTX at year 3 among patients who were receiving tofacitinib without MTX at baseline and subsequently initiated MTX. CDAI remission: ≤ 2.8; CDAI LDA: CDAI > 2.8 to ≤ 10; CDAI incomplete response as CDAI > 10. Year-3 data were missing from one patient who discontinued MTX, two patients who continued MTX, and one patient after initiation of MTX. CDAI Clinical Disease Activity Index, LDA low disease activity, MTX methotrexate

Full size image

In the maintenance of efficacy analysis, of 41 patients who achieved CDAI remission at month 3 and later discontinued MTX (from month 3 to year 3), 28 (68.3%) maintained CDAI remission at year 3 (Fig. 1b); compared with 171/284 (60.2%) who continued MTX. A similar trend was observed for CDAI LDA or incomplete response, with the majority of patients maintaining month-3 CDAI response at year 3, regardless of MTX discontinuation.

Glucocorticoid Discontinuation and CDAI Response

At year 3, 109/319 patients (34.2%) who discontinued GC were in CDAI remission, while 226/1115 (20.3%) who continued GC were in CDAI remission (Fig. 2a). Overall, 232/319 patients (72.7%) who discontinued GC and 735/1115 (65.9%) who continued GC achieved either CDAI remission or LDA at year 3.

Fig. 2
figure 2

a CDAI response at year 3 in patients who were receiving tofacitinib with GC at baseline and subsequently discontinued or continued GC; b maintenance of month-3 CDAI response at year 3 among patients who were receiving tofacitinib with GC at baseline and at the month 3 visit, who discontinued or continued GC prior to the year-3 visit; c CDAI response at the last post-baseline visit prior to and following initiation of GC at year 3 among patients who were receiving tofacitinib without GC at baseline and subsequently initiated GC. CDAI remission: ≤ 2.8; CDAI LDA: CDAI > 2.8 to ≤ 10; CDAI incomplete response as CDAI > 10. Year-3 data were missing from one patient who discontinued GC, two patients who continued GC, four patients prior to initiation of GC, and three patients after initiation of GC. CDAI Clinical Disease Activity Index, GC glucocorticoid, LDA low disease activity

Full size image

Of 54 patients who achieved CDAI remission at month 3 and later discontinued GC (from month 3 to year 3), 38 (70.4%) maintained CDAI remission at year 3, compared with 98/187 (52.4%) who continued GC (Fig. 2b). A similar trend was observed for CDAI LDA or incomplete response; the majority of patients maintained month-3 CDAI response at year 3, regardless of GC discontinuation.

Initiation of MTX or GC During the LTE Studies

Of 1044 patients in the LTE studies who were not receiving MTX at LTE baseline and had any efficacy measurement at year 3, 65 (6.2%) initiated MTX prior to/at year 3: 22/423 (5.2%) patients receiving tofacitinib 5 mg BID and 43/621 (6.9%) receiving tofacitinib 10 mg BID.

Of 1218 patients in the LTE studies who were not receiving GC at LTE baseline and had any efficacy measurement at year 3, 306 (25.1%) patients initiated GC prior to/at year 3: 82/417 (19.7%) patients receiving tofacitinib 5 mg BID and 224/801 (28.0%) receiving tofacitinib 10 mg BID.

Patient demographics and disease characteristics at baseline for those who initiated MTX or GC during the LTEs prior to the year-3 visit, and had a post-baseline visit prior to initiation, are presented in Table 2. Prior to initiation of MTX or GC, 40/58 (69.0%) and 128/282 (45.4%) patients, respectively, had a CDAI incomplete response (Figs. 1c, 2c). In patients who initiated MTX, CDAI remission or LDA was achieved in 18/58 (31.0%) patients at last post-baseline visit prior to initiation and in 29/58 (50.0%) after initiation at year 3 (Fig. 1c). In patients who initiated GC, CDAI remission or LDA was achieved in 150/282 (53.2%) patients at last post-baseline visit prior to initiation and in 155/282 (55.0%) after initiation at year 3 (Fig. 2c).

Table 2 Patient demographics and disease characteristics for patients who did not receive MTX at baseline and initiated it later, and for patients who did not receive GC at baseline and initiated it later
Full size table

Overall, some improvements in CDAI remission/LDA rates and other RA disease parameters (TJC, SJC, Pain, PtGA, PGA, FACIT–Fatigue Scale Score, and CRP) were observed in patients receiving tofacitinib who initiated MTX; only modest improvement was observed in patients who initiated GC (Figs. 1c, 2c; Table 3).

Table 3 Disease parameters at baseline, last post-baseline visit prior to initiation of MTX or GC, and at year 3, in patients who did not receive MTX or GC at baseline
Full size table

Discussion

This post hoc, pooled analysis from two LTE studies evaluated how discontinuation of concomitant MTX or GC may impact the maintenance of clinical efficacy with tofacitinib 5 or 10 mg BID. In addition, the potential effect of MTX or GC initiation was investigated.

Previous analyses of these LTE studies demonstrated consistent efficacy and safety of tofacitinib over time (up to 114 months), when administered as monotherapy or in combination with csDMARDs [18–20]. In addition, in a vaccine sub-study of patients enrolled in the ORAL Sequel LTE, discontinuation of tofacitinib treatment for 2 weeks resulted in worsening of disease activity and physical function, which then showed improvement back to baseline levels approximately 1 month after reinitiation of tofacitinib [27]. However, this is the first analysis of the effect of discontinuation or initiation of concomitant treatment of either MTX or GC.

Overall, 11.6% of patients receiving tofacitinib with background MTX at LTE baseline discontinued MTX treatment prior to year 3; 22.2% who were receiving GC at LTE baseline discontinued GC. In patients not receiving MTX at baseline, 6.2% initiated MTX before year 3; 25.1% of patients not receiving GC at baseline initiated GC.

Similar CDAI response levels at year 3 between patients who discontinued MTX and those who continued use (among patients receiving background MTX at baseline) suggested that discontinuing concomitant MTX may not have a detrimental effect on response to tofacitinib in the majority of patients. Furthermore, at year 3, patients receiving tofacitinib generally maintained the same response to treatment achieved at month 3, irrespective of whether they discontinued MTX or not. Similarly, discontinuation of concomitant GC did not negatively impact CDAI response at year 3 or maintenance of month-3 CDAI response at year 3.

A phase IIIb/IV study (ORAL Strategy, NCT02187055) compared the efficacy and safety of tofacitinib monotherapy with tofacitinib in combination with MTX (and also adalimumab in combination with MTX), and showed that while both treatments provided improvement in clinical and functional responses, tofacitinib monotherapy was not non-inferior to tofacitinib combination therapy based on the primary endpoint of ACR50 response rate [17]. Although non-inferiority of monotherapy to combination therapy was not shown in this previous study based on ACR50 response rate, the results presented here suggest that in most patients receiving combination therapy who achieve remission, response can be maintained if MTX is then discontinued.

Further aims of this post hoc analysis were to investigate the proportions of patients who initiated treatment with MTX or GC during the two LTE studies, and the potential impact of MTX or GC initiation on the clinical efficacy of tofacitinib. For patients not receiving MTX at LTE baseline, the majority of those who initiated MTX were classified as CDAI incomplete responders at last post-baseline visit prior to initiating MTX. Although this suggests that the addition of another agent was likely due to limited efficacy of previous tofacitinib-based therapy, specific reasons for initiation were not captured during the LTE studies. In general, a numerical improvement in disease activity was observed after MTX initiation, suggesting that patients who experience an initial improvement with tofacitinib yet remain as CDAI-incomplete responders may derive some clinical benefit from the addition of MTX. However, the small number of patients who initiated MTX may limit the value of this finding. For patients not receiving GC at LTE baseline, prior to initiating GC, just under half were CDAI-incomplete responders. Overall, initiation of GC resulted in modest improvement in disease parameters.

This was a post hoc analysis of data from two open-label studies, which were not specifically designed to study the impact of concomitant MTX or GC discontinuation or initiation on tofacitinib; therefore, conclusions may be limited and should be interpreted with caution. In particular, the very small patient numbers in some analysis groups (e.g., patients used to investigate the impact of initiating MTX) limit this analysis to being exploratory in nature. It should be noted that patients had additional/differing exposure to tofacitinib in qualifying phase I–III studies prior to enrollment into the LTE studies evaluated in this analysis. The analysis is also limited by the definition of discontinuation and initiation used, which grouped together patients with different durations of MTX or GC treatment over 3 years. Also, patients receiving concomitant MTX and GC were not analyzed separately, which may confound results; however, similar proportions were observed in the continued vs. discontinued group for MTX or GC use separately among MTX or GC users at LTE baseline. A controlled study that includes a larger number of patients and is specifically designed to examine concomitant MTX/GC discontinuation and initiation with tofacitinib is needed; a prospective study investigating the effect of MTX discontinuation in LDA-responders initiated on tofacitinib in combination with MTX is ongoing (NCT02831855).

Conclusions

Patients achieving CDAI remission or LDA with tofacitinib may be able to discontinue MTX or GC and maintain their response to treatment. Moreover, patients who have an initial improvement with tofacitinib-based therapy but remain CDAI-incomplete responders (CDAI > 10) may benefit from the addition of MTX. Additional studies are required to support these findings.