Clinical and Endoscopic Outcomes Through 78 Weeks of Tofacitinib Therapy for Ulcerative Colitis in a US Cohort

Abstract

Background

Tofacitinib is an oral JAK inhibitor for the treatment of ulcerative colitis (UC). We assessed outcomes through 78 weeks of tofacitinib therapy for UC in a real-world setting.

Methods

This retrospective cohort study included adults initiating tofacitinib for UC from May 1, 2018, to April 1, 2021, at a large academic center in the United States. The primary outcome was steroid-free clinical remission at 78 (+/-4) weeks (SFCR 78; simple clinical colitis activity index ≤2 with no corticosteroid use within 30 days). The secondary outcome was tofacitinib discontinuation due to nonresponse (treatment persistence). Additional outcomes were endoscopic response/remission and adverse events (AEs).

Results

Seventy-three patients initiated tofacitinib, with a median follow-up of 88 weeks. Among patients with available data, 31 of 60 (51.7%) achieved SFCR 78, 21 of 47 (44.7%) achieved endoscopic remission during follow-up, and 25 of 73 (34.2%) discontinued tofacitinib during follow-up due to nonresponse (including 11 patients who required colectomy). Nineteen AEs were reported among 15 patients during follow-up: shingles (n = 4, all without documented vaccinations), deep venous thrombosis (n = 2), elevated liver enzymes (n = 2), skin abscess (n = 2), pneumonia (n = 2), possible miscarriage (n = 2), norovirus (n = 1), COVID-19 (n = 1), lymphopenia (n = 1), Clostridioides difficile infection (n = 1), and heart block (n = 1). One patient discontinued therapy due to an AE (elevated liver enzymes), and no deaths occurred.

Conclusion

Tofacitinib treatment was effective in achieving SFCR for the majority of patients with UC through 78 weeks. Adverse events were consistent with the known safety profile of tofacitinib, and AEs requiring discontinuation were rare. Due to limitations regarding sample size, larger studies are needed to confirm these findings.

Introduction

Medical therapies for moderate to severe ulcerative colitis (UC) have expanded over the last decade to include several distinct mechanisms of action. Tofacitinib is the first oral small molecule Janus kinase inhibitor that was approved for UC in the United States in 2018. What is known about the effectiveness of tofacitinib to maintain clinical and endoscopic remission stems largely from randomized controlled trials due to limited long-term data from real-world cohorts.

The phase 3 OCTAVE clinical trials demonstrated the efficacy of induction and maintenance tofacitinib compared with placebo for patients with UC.¹ A long-term extension study of OCTAVE demonstrated that nearly 60% of patients who were in remission at baseline maintained remission after 36 months and identified a median treatment persistence of 4.0 to 5.6 years depending on initial response to tofacitinib.^2,3 However, clinical trial data may not reflect clinical practice due to the strict enrollment criteria of these studies. There is therefore a need for observational research to assess the effectiveness of tofacitinib in clinical practice.

Cohort studies of tofacitinib therapy for UC have shown variable results and assessed largely short-term clinical outcomes.^4–11 The reported rates of clinical remission have ranged between 21% to 48% at 24 to 26 weeks after tofacitinib initiation,^{4,5,7,8,11,12} and few studies have reported both clinical and endoscopic outcomes beyond 52 weeks.^5,6,12,13 In a recent Spanish cohort study, 74 patients with UC were followed for up to 24 months of tofacitinib therapy.¹² Clinical remission was achieved in 42% of UC patients at 16 weeks, 56% at 78 weeks, and 52% at 104 weeks. However, only 18 and 13 patients were eligible for the 78-week and 104-week end points, respectively. Additionally, there were no long-term data regarding endoscopic remission, which is an increasingly important end point in clinical practice.¹⁴

A better understanding of the long-term effectiveness, durability, and safety of tofacitinib outside of clinical trial settings is needed. We therefore conducted a retrospective cohort study to assess clinical, endoscopic, and safety outcomes through 78 weeks of tofacitinib therapy for UC.

Materials and Methods

Study Design

This was a retrospective cohort study of patients 18 years and older with UC who initiated tofacitinib therapy after May 1, 2018, at Brigham and Women’s Hospital (Boston, MA), Massachusetts General Hospital (Boston, MA), or any affiliated hospitals. Electronic health records were manually reviewed for clinical, laboratory, and endoscopic data. Patients with diagnoses for Crohn’s disease or inflammatory bowel disease unclassified, prior colectomy, a primary indication for tofacitinib other than ulcerative colitis, and those receiving combination therapy of tofacitinib with a biologic agent were excluded. Patients were followed from the time of tofacitinib initiation to tofacitinib discontinuation, total colectomy, or the last available gastroenterology encounter through April 1, 2022. The dates of tofacitinib discontinuation, primary reasons for discontinuation, and clinical disease activity measured by simple clinical colitis activity index (SCCAI)¹⁵ scores were extracted from gastroenterology provider documentation. Simple clinical colitis activity index scores are incorporated in the UC patient note templates in the health system.

Outcomes

The primary outcome was steroid-free clinical remission (SFCR) assessed at 78 (+/-4) weeks after tofacitinib initiation (ie, SFCR 78). Steroid-free clinical remission was defined as an SCCAI ≤2 (when not available, the provider global assessment of clinical remission was used) with no use of oral or intravenous (IV) corticosteroids within 30 days preceding assessment. The secondary outcome was time to tofacitinib discontinuation due to nonresponse (ie, treatment persistence; nonresponse includes drug discontinuation in the setting of colectomy for refractory disease activity but not colectomy due to dysplasia or malignancy) during all available follow-up that is not limited to 78 weeks.

Additional outcomes included SFCR at 12 and 52 weeks (SFCR 12 and 52). Endoscopic response (ie, decrease in Mayo endoscopic subscore¹⁶ by ≥1 point) endoscopic remission (ie, Mayo endoscopic subscore of 0) biochemical response (ie, improvement in C-reactive protein [CRP] or fecal calprotectin by >25% or normalization), and biochemical remission (normalization of CRP or fecal calprotectin) were assessed >8 weeks after tofacitinib initiation.Improvement in arthralgia (if present prior to tofacitinib initiation), all-cause hospitalizations, UC-related hospitalizations, and adverse events (AEs) were assessed at any time during follow-up. AEs were also stratified by age older than 50 years to assess safety in older adults. Hospitalizations related to UC were hospitalizations where UC was listed as the primary discharge diagnosis or the secondary discharge diagnosis with a UC-related complication as the primary discharge diagnosis as previously described.¹⁷ We also assessed sustained SFCR (defined as SFCR at 12, 52, and 78 weeks after tofacitinib initiation) and SFCR 52 weeks after dose de-escalation from 10 mg twice daily to 15 or 10 mg total daily dosing. Dose de-escalation was at the discretion of the prescribing providers.

Independent Variables

Independent variables included age, sex, race, ethnicity, body mass index (BMI), UC duration, concomitant corticosteroid use, concomitant 5-ASA use, concomitant immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate) use, prior biologic therapies, cigarette smoking, current cannabis use, current opioid use, history of malignancy, most recent Mayo endoscopic subscore and Montreal disease extent, UC-related hospitalization within the preceding 12 months, and the most recent values for the following continuous variables within 12 weeks prior to tofacitinib initiation: CRP, serum albumin, fecal calprotectin, daily bowel movement frequency, and SCCAI.

Statistical Analysis

Categorical variables were described by fractions and percentages, while continuous variables were expressed in terms of their median and interquartile range (IQR). Univariable and multivariable logistic regression¹⁸ were used to identify independent variables associated with SFCR 78. Covariates from the univariable analysis associated with SFCR 78 at P < .05 were included in the multivariable model. A higher P value threshold was not chosen in order to limit overfitting. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported in the final model.

A Kaplan-Meier curve of tofacitinib treatment persistence¹⁹ was generated. Univariable and multivariable Cox proportional hazards regression¹⁹ were used to identify all independent variables associated with tofacitinib treatment persistence. Independent variables that were associated with treatment persistence on univariable analysis at P < .05 were included in the multivariable model. Hazard ratios (HRs) with 95% CIs were reported in the final model. Patients were censored at time of colectomy for dysplasia, treatment discontinuation for reasons unrelated to effectiveness (eg, adverse events or nonadherence), or loss to follow-up. The proportional hazards assumption was tested using Schoenfeld residuals.²⁰ Patients with missing data for any independent variables were excluded from multivariable analyses. StataSE 17 (College Station, TX) was used for all analyses.

Subgroup Analysis

As tofacitinib may be utilized after failure of 2 classes of biologics, we separately assessed the proportions of patients with prior antitumor necrosis factor (anti-TNF) and vedolizumab failure who achieved SFCR 12, 52, and 78 after initiating tofacitinib.

Ethical Considerations

This study was approved by the institutional review board of Brigham and Women’s Hospital (Boston, MA, USA).

Results

Cohort Characteristics

The cohort included 73 patients who initiated tofacitinib with a median follow-up of 88 weeks (IQR, 40.9-151.0 weeks); 60.2% were female, 94.5% had prior to exposure to ≥1 anti-TNF agent, 54.7% had prior exposure to ≥2 anti-TNF agents, 74.0% had prior exposure to vedolizumab, and 54.7% were receiving concomitant oral or IV corticosteroids at the time of tofacitinib initiation. Other baseline characteristics are presented in Table 1.

Unadjusted Outcomes

Among patients with sufficient follow-up data, 39 of 71 (54.9%), 40 of 69 (58.0%), and 31 of 60 (51.7%) achieved SFCR 12, 52, and 78, respectively. Among 60 patients with at least 78 weeks of follow-up, 20 (33.3%) had sustained SFCR at 12, 52, and 78 weeks. Among 27 patients with baseline steroid use and at least 78 weeks of follow-up, 14 achieved SFCR 78 (51.9%). In the subgroup of patients with prior anti-TNF and vedolizumab failure, proportions of patients achieving SFCR 12, 52, and 78 with tofacitinib were 26 of 50 (52.0%), 26 of 49 (53.1%), and 21 of 44 (47.7%), respectively.

Tofacitinib was discontinued among 31 of 73 (42.5%) patients during all available follow-up. Discontinuation specifically due to nonresponse or colectomy for refractory disease occurred in 25 of 73 (34.2%) after a median of 27.7 weeks (IQR, 13.0-44.3 weeks). Other reasons for discontinuation were colectomy for dysplasia (n = 2), nonadherence (n = 2), insurance coverage (n = 1), and an AE (elevated liver enzymes, n = 1). Endoscopic response and remission were achieved in 39 of 47 (83.0%) and 21 of 47 (44.7%), respectively. Median time to endoscopy was 58.1 weeks (IQR, 30.7-103.6 weeks) after tofacitinib initiation. Improvement in arthralgia occurred in 13 of 23 (56.5%) patients. Other outcomes are presented in Figure 1.

Adverse Events

There were 19 AEs reported among 15 of 73 (20.5%) patients during the median 88 weeks of follow-up (Figure 2), representing 14 AEs per 100 patients/year. There were fewer AEs among younger (50 years and younger) vs older (over 50 years) adults receiving tofacitinib (16.0% vs 30.4%). Among AEs were 2 “possible miscarriages,” one of which was associated with a positive beta human chorionic gonadotropin (hCG) followed by a negative beta hCG 3 days later. The second involved a patient who reported observation of a miscarriage, but there was no laboratory or other objective documentation to confirm pregnancy. Neither patient intended to become pregnant, and neither discontinued tofacitinib due to these events. Other adverse events included shingles (n = 4; all patients did not have documented vaccination for varicella zoster virus), deep venous thrombosis (DVT; n = 2), elevated liver enzymes (n = 2), skin abscess (n = 2), pneumonia (n = 2), norovirus infection (n = 1), COVID-19 infection (n = 1), lymphopenia (n = 1), Clostridioides difficile infection (n = 1), and heart block (n = 1), which was not clearly attributed to tofacitinib upon review of cardiology consultation notes. One patient discontinued tofacitinib therapy due to the AE (elevated liver enzymes).

SFCR 78 Logistic Regression Analysis

Univariable logistic regression identified significant, positive associations between older age (OR, 1.06; 95% CI, 1.02-1.10), and higher BMI (OR, 1.21; 95% CI, 1.07-1.38) with SFCR 78 (Supplementary Table 1). On multivariable analysis, older age and higher BMI were again positively associated with SFCR 78 (age at initiation: OR, 1.04; 95% CI, 1.00-1.09; BMI: OR, 1.17; 95% CI, 1.02-1.33). Because age and BMI are continuous variables, we examined a quadratic relationship for each using both a linear and squared term. There was no association between BMI² (OR, 1.00; 95% CI, 0.98-1.00) or age at initiation² (OR, 1.00; 95% CI, 1.00-1.00) with SFCR 78, suggesting that both previously observed associations were linear.

Treatment Persistence Analysis

Kaplan-Meier analysis of tofacitinib treatment persistence is presented in Figure 3. Univariable Cox regression identified associations between age at initiation (HR, 0.92; 95% CI, 0.89-0.96), UC duration (HR, 0.92; 95% CI, 0.86-0.99), BMI (HR, 0.87; 95% CI, 0.79-0.95), UC hospitalization within last 12 months (HR, 2.40; 95% CI, 1.05-5.50), and SCCAI (HR, 1.18; 95% CI, 1.06-1.31) with tofacitinib treatment persistence (Supplementary Table 2). On multivariable analysis, only the association of age at initiation persisted (HR, 0.94; 95% CI, 0.91-0.98). Due to this finding, a stratified Kaplan-Meier analysis was performed demonstrating greater treatment persistence among those older than 50 years (P = .01, log-rank test; Figure 4). For Cox analyses, the proportional hazards assumption was confirmed using Schoenfeld residuals.

Dose De-escalation Outcomes

Dose de-escalation from 10 mg twice daily dosing occurred among 38 of 73 (52.1%) patients to 10 or 11 mg (n = 35) or 15 mg (n = 3) total daily dosing after a median of 36.9 weeks (IQR, 20.6-62.3 weeks) from tofacitinib initiation. All patients were in SFCR prior to dose de-escalation. Among these 38 patients, 34 had at least 52 weeks of follow-up, 2 of whom discontinued tofacitinib for reasons unrelated to treatment efficacy (dysplasia requiring colectomy and elevated liver enzymes). Among the remaining 32 patients, 18 (56.3%) were in SFCR at 52 weeks after dose de-escalation. Of the remaining 14 patients, 12 were re-escalated to 10 mg twice daily dosing, and 2 discontinued therapy due to loss of response (Figure 5). Adverse events (elevated liver enzymes and shingles) were observed in 2 of 38 (5.3%) patients after dose de-escalation over a median of 94 weeks of follow-up.

Discussion

With a growing array of treatments for moderate to severe UC, a better understanding of longer-term drug performance beyond clinical trial end points including predictors of remission are needed to tailor therapy. However, real-world clinical data assessing tofacitinib performance for UC beyond 52 weeks are limited. We presented one of largest cohort studies to date assessing tofacitinib outcomes for UC through 78 weeks of therapy in the United States.

In this largely biologic-refractory UC population, we found that tofacitinib treatment was effective in achieving SFCR at 78 weeks for >50% of patients with 34% discontinuing treatment due to nonresponse during follow-up. Proportions of patients achieving SFCR at all time points were unchanged in the subgroup of patients with prior anti-TNF and vedolizumab failure. We also observed endoscopic remission in 45% of patients after a median of 58 weeks of therapy. There were 19 AEs reported among 15 patients during follow-up. One patient discontinued treatment due to an AE (elevated liver enzymes). Adverse events were consistent with the known safety profile of tofacitinib.²¹

Our multivariable analyses found that patients of older age had greater odds of SFCR 78 as well as greater treatment persistence. At least 2 prior studies have reported favorable outcomes for older adults receiving tofacitinib for UC.^8,22 In a post hoc analysis of the OCTAVE Sustain study, age, among other factors, was positively associated with higher odds of clinical remission at week 52 in a multivariable model.²² A multicenter study in the United Kingdom found a positive, independent association between younger age and primary nonresponse to tofacitinib.⁸ However, there was also a correlation between age and disease duration and severity. In our study, there was a significant association between disease duration and treatment persistence on univariable analysis, which was attenuated in the multivariable model including age. Therefore, it is possible that older age is the driver of this association, which may represent later-onset UC patients who are known to have a less severe disease course.²³ While tofacitinib may be more effective in older adults, the decision to treat must be balanced with consideration of AEs, which, as expected, occurred more commonly among adults older than 50 years of age in our cohort.

We also identified an independent and positive association between higher BMI and SFCR 78. There are limited data regarding BMI and clinical outcomes with tofacitinib therapy. A post hoc analysis of OCTAVE did not identify an association between BMI and clinical remission of UC.²⁴ Body mass index also was not associated with tofacitinib efficacy in studies using pooled clinical trial data for both rheumatoid arthritis and psoriatic arthritis.^25,26 We hypothesize that a higher BMI may reflect a more nutritionally optimal status, which may be associated with better treatment outcomes.

Our study provides important data regarding dose de-escalation of tofacitinib. More than 50% of patients in our cohort who underwent dose de-escalation remained in SFCR after 52 weeks of follow-up. Less than 40% of those de-escalated required re-escalation. Likewise, OCTAVE Open identified a sustained remission rate of 75% at 52 weeks after dose de-escalation.²⁷ Similar results were found in a randomized controlled trial of 140 patients at month 6 after de-escalation.²⁸ In one real-world study, only one-third of patients had recurrence of symptoms after de-escalation to 10 mg total daily dosing, after which dose escalation re-captured response in nearly 50% of patients.⁸ In combination, these findings support attempting dose de-escalation for patients who achieve SFCR on 10 mg twice daily dosing to limit the risk of potential AEs.

The strengths of the study include the granular outcome data with regards to endoscopic response and remission, reasons for tofacitinib discontinuation, dose de-escalation, and AEs. To our knowledge, this study also reports the largest number of patients assessed for SFCR 78 weeks after initiation of tofacitinib and 52 weeks after dose de-escalation outside of a clinical trial setting. We were able to perform regression analyses that identified older age and higher BMI as potential subpopulations who may have a more favorable response to tofacitinib treatment; however, larger real-world studies are needed to validate these findings.

Limitations include the retrospective design, potential omissions and errors in clinical documentation, variable follow-up times, inability to detect adverse events that may have occurred outside of our health system, and sample size limitations that precluded additional subgroup analyses. Our primary analysis also depends on physician documentation of SCCAI scores or global assessments, which are subjective and may vary by IBD provider. We therefore included an analysis on treatment persistence, which may be a more objective assessment of the durability of tofacitinib treatment. While our study also provides more endoscopic outcome data compared with other real-world cohort studies,^6–8,12 the sample size is likely insufficient to make conclusions about the effectiveness of tofacitinib to achieve and maintain deep remission in UC. Additionally, as our study focused on outcomes through 78 weeks, our results do not capture the longer-term durability and safety of tofacitinib. The vast majority of patients in our cohort also had multiple biologic failures prior to tofacitinib, and therefore our results may underestimate tofacitinib effectiveness in less refractory populations.

In summary, tofacitinib appears to be an effective and durable treatment for UC through 78 weeks of follow-up in a largely bio-exposed population. Remission appears to be maintained for the majority of patients who undergo dose de-escalation. Adverse evetns were consistent with the known safety profile of tofacitinib. The most commonly reported AE was shingles, and AEs requiring tofacitinib discontinuation were rare. As the treatment algorithms for UC grow in complexity, there is a rising need for both head-to-head clinical trials and comparative effectiveness studies to guide treatment decisions.

Supplementary Data

Supplementary data is available at Inflammatory Bowel Diseases online.

Funding

This study was sponsored by Pfizer.

Conflicts of Interest

JRA serves as a consultant for Abbvie, Janssen, Pfizer, Pandion, Servatus, Finch Therapeutics, Iterative Scopes, BMS, Merck, Summit, Artizan, and Artugen and has grant support from Merck, Pfizer and Janssen. RSD has served as a consultant for Centaur Labs and has grant support from Pfizer and Janssen. PPS is an employee of Pfizer Inc. KB and JC have no financial or personal conflicts of interest to disclose.

Writing assistance: none

Author Contributions

R.S.D.: study concept and design, acquisition of data, analysis and interpretation of data, drafting of manuscript

K.B. and J.C.: critical revision of the manuscript for important intellectual content

P.S. and J.R.A.: study concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, study supervision

The final manuscript was reviewed and approved by Pfizer.

References