Real-World Effectiveness and Safety of Tofacitinib in Crohn’s Disease and IBD-U: A Multi-Center Study from the TROPIC consortium

Introduction

The safety and efficacy of tofacitinib in Crohn’s disease (CD) has been studied in two phase II trials in patients with moderate-to-severe CD with no new safety signals observed, but no significant difference from placebo in the primary efficacy endpoint of clinical response.^1–3 However, post-hoc analyses and smaller studies have observed clinical and biological response to tofacitinib in patients with CD.^{2, 4, 5} There is a paucity of real-world effectiveness and safety data for tofacitinib in non-FDA label usage in CD and Inflammatory Bowel Disease-Unclassified (IBD-U) patients.

Methods

Data was collected in the Tofacitinib Real-world Outcomes in Patients with ulceratIve colitis and Crohn’s disease (TROPIC) consortium (supplementary methods).⁶ The primary outcome was clinical response (>50% reduction in symptoms) at weeks 8 and/or 16 determined by Physician Global Assessment (PGA). Secondary outcomes included corticosteroid-free response/remission, clinical remission, and endoscopic remission (ulcer resolution).

Results

Seventy-six patients with CD and IBD-U were included with a median follow-up time of 7.6 months (IQR 3.3-12.1). Most patients (98.7%) had previously been treated with a biological therapy prior to initiating tofacitinib, with 48.7% having failed at least two prior classes of biological therapy. The dosing of tofacitinib was 10mg BID in the majority of patients during induction (75.0%) and maintenance (65.3%). The treatment outcomes stratified by CD or IBD-U are shown in figure 1A. Among 73 patients with recorded week 8/16 data, 46.6% were in clinical response, 39.7% in corticosteroid-free clinical response, 15.1% in clinical remission in and 13.7%. in corticosteroid-free clinical remission. Clinical response at last documented assessment (N = 75) was reported in 42.7% (20% in clinical remission), while 57.3% either had no response or lost response. Univariate comparison of baseline characteristics based on clinical response at 8/16 weeks found significant differences in male gender (p=0.002), BMI (p=0.04) and baseline hemoglobin (p=0.01) but not for disease location (ileal vs. ileal/ileocolonic, p = 0. 16) (Supplementary Table 1). In a multivariate analysis, male gender was associated with increased odds of clinical response (aOR 5.4; CI, 1.9 - 15.5, p = 0.002) and corticosteroid-free clinical response (aOR 4.2; CI,1.4-12.5, p = 0.009). Endoscopic remission among those with baseline ulcers was seen after initiation of tofacitinib in 44% (Figure 1A). The treatment outcomes were not statistically different based on the number of failed biologics prior to the initiation of tofacitinib (Figure 1B). Tofacitinib was discontinued in 54.5% of the patients (42/76), most frequently due to no response (30.3%) or loss of response (15.8%).

Figure 1:

Real-world effectiveness of tofacitinib in moderate to severe Crohn’s disease and IBD-U- clinical, endoscopic and laboratory data.

A. Bars showing the percentages of all patients, Crohn’s Disease and IBD-U patients who had clinical response at week 8 and/or week 16, clinical response at last day of follow up (LDF), endoscopic remission (among those with abnormal endoscopy at baseline) and normalization of CRP (among those with elevated CRP at baseline) while on tofacitinib. N represents the total number of patients in each subgroup.

B. Association between number of prior failed biologics and the different outcomes shown in figure 1A. Bars represents proportion of patients in each outcome subgroup who failed one biologic and those who failed two or more biologics. Proportions were compared using Fisher exact test, and P-values are shown. N represents the total number of patients in each subgroup.

C. Kaplan-Meier survivor curve of tofacitinib persistence among all patients (64 CD and 12 IBD-U) and CD patients only during the first year of treatment. Failure event was defined as withdraw due to no response, loss of response or adverse events. All patients still on tofacitinib as at week 52 of treatment were censored. The median times on tofacitinib for all patients and CD patients only were 47.0 weeks and 46.4 weeks respectively.

CD, Crohn’s disease; CRP, C-reactive protein; IBD-U, Inflammatory bowel disease-unclassified; LDF, Last day of follow up.

AEs occurred in 17.1% (13/76) of our patients, with an incidence rate of 20.4 (16.5-26.9) per 100 patient years follow-up (Supplementary Table 2). Serious AEs occurred in 6 patients (7.9%) with a median age of 30 years and a median time to AE of 93 days [IQR, 19 – 329]. One patient developed HZ and there was one case of VTE (Supplementary Table 2). Surgical outcomes in patients undergoing surgery following tofacitinib therapy is included in supplementary table 2.

Discussion

Clinical response during induction in our cohort (46.6%) was lower than the rate of clinical response in prior clinical induction trials with 10mg BID of Tofacitinib in CD (69.8%). A possible explanation is the difference in baseline CD severity between the two cohorts. Our patient population had failed at least one (98.7%) or two (48.7%) classes of biologic therapy prior to initiating tofacitinib, whereas about 25% of the clinical trial cohort had not trialed a prior biologic, and no patients had received two prior biologic classes of therapy. Furthermore, 36.7% of placebo-treated patients in the clinical trial achieved clinical remission at 8 weeks, an unusually high placebo response rate.

In this cohort, male sex was associated with 4 to 5-fold increased odds of clinical response and corticosteroid-free response. Prior data in RA suggests that men may have overall increased response to biologic therapy.⁷ In IBD, the age at onset of IBD has been shown to vary with sex but to our knowledge this is the first report of sex-based difference in response to therapy in IBD⁸. Further prospective studies are needed to assess sex as a predictor of response to tofacitinib.

Limitations of the study include the retrospective design with the use of the PGA for clinical response assessment, and the lack of standardized endoscopic scoring criteria.

In summary, we report that tofacitinib is effective in achieving clinical response in a subset of real-world patients with CD and IBD-U refractory to prior biologic therapy. Additionally, we report no new significant safety signals with the use of tofacitinib in patients with refractory CD and IBD-U.

Abbreviations:

AEs

Adverse events

CI

Confidence interval

CD

Crohn’s disease

CRP

C-reactive protein

DVT

Deep vein thrombosis

FDA

Food and Drug Administration

GI

Gastrointestinal

HZ

Herpes Zoster

IBD

Inflammatory bowel disease

IL

Interleukins

IQR

Interquartile range

IRs

Incidence rates

JAK

Janus Kinase

MACE

Major adverse coronary events

OLE

Open label extension

OR

Odds ratio

PE

Pulmonary embolism

PGA

Physician Global Assessment

PYF

Patient-Years Follow-up

RA

Rheumatoid arteritis

STROBE

Strengthening the Reporting of Observational Studies in Epidemiology

TNF

Tumor Necrosis Factor

TROPIC

Tofacitinib Real-world Outcomes in Patients with ulceratIve colitis and Crohn’s disease

UC

Ulcerative colitis

VTE

Venous thromboembolism