Characteristics, clinical outcomes and patient-reported outcomes of patients with ulcerative colitis receiving tofacitinib: a real-world survey in the United States and five European countries

Ulcerative colitis (UC) is a chronic inflammatory bowel disease, with a prevalence of 286 per 100,000 in the USA, and varying across Europe (per 100,000: Northern 91–505; Southern 15–134; Eastern 2–340; and Western 43–412) [1].

UC is characterized by mucosal inflammation that starts in the rectum and extends proximally for a variable distance through the colon [2, 3]. At presentation, proctitis is most common, found in 30–60% of patients, while 16–45% have left-sided colitis, and 15–35% have extensive disease [4]. Symptoms vary based on severity and extent of disease. UC most commonly presents with blood in the stool (reported by 90% of patients) and diarrhoea [4]. The majority of patients with UC have mild-to-moderate disease [5]. About one-third of patients with UC have extraintestinal manifestations of which spondyloarthritis appears to be the most common [4]. As a consequence, UC has a significant negative impact on many aspects of patients’ quality of life (QoL) [6].

The main intermediate and long-term goal of pharmacotherapy in UC is sustained corticosteroid-free remission, in terms of symptoms and mucosal healing on endoscopy [2, 7, 8]. Guidelines recommend a variety of different therapy classes, including aminosalicylates, corticosteroids, immunomodulators, tumour necrosis factor inhibitors (TNFi), the anti-integrin vedolizumab, interleukin (IL)-12/23 antagonist ustekinumab, and the Janus kinase (JAK) inhibitor tofacitinib, for the induction and maintenance of remission in moderate-to-severe UC [2, 9, 10]. Recently, other JAK inhibitors, filgotinib and upadacitinib, and the sphingosine-1-phosphate (S1P) receptor modulator ozanimod have been approved for the treatment of moderate-to-severe UC. An increasing number of available therapeutic options has led to considerable practice variability in the use of these drugs to treat patients with moderate-to-severe UC [11]. Despite advances in the treatment of UC, clinical and endoscopic endpoints cannot be achieved in a substantial proportion of patients with biologics [12, 13]. Varying persistence profiles [14, 15] suggest that cycling across multiple biologics and novel treatments with different modes of action are warranted.

Tofacitinib is an oral, small molecule, JAK inhibitor for the treatment of moderate-to-severe UC that was approved in Europe and the USA in 2018. Tofacitinib has demonstrated effectiveness including remission, mucosal healing, and patient-reported outcomes in three randomized controlled trials (RCT) [16‐18]. However, RCTs are considered to be ‘gold standard’ regarding evidence-based medicine, but their strict patient inclusion/exclusion criteria means that they do not necessarily reflect real-world patient populations, thus limiting their generalizability. Real-world evidence is therefore important in demonstrating effectiveness during routine clinical practice, where conditions are not so tightly controlled. Physicians and patients can provide unique and independent assessments of disease activity, which can be used in treatment decision making. Therefore, to support the robust tofacitinib clinical trial data, we present data from the well-established Adelphi Ulcerative Colitis Disease Specific Programme™ (DSP) [19]. The objective of this analysis was to describe the variations in treatment patterns, patient-reported outcomes and physician and patient satisfaction, in patients with moderate-to-severe UC treated with tofacitinib in a real-world setting.

This analysis of the Adelphi UC DSP describing clinical characteristics, variations in treatment patterns, and treatment outcomes in patients with UC receiving tofacitinib found that overall, the majority of physicians followed treatment recommendations at induction and through maintenance; that disease activity, symptoms frequency and severity is reduced; and that high rates of remission were achieved. QoL is improved and treatment satisfaction were achieved during treatment over the ≥ 52-weeks assessment period in patients with moderate-to-severe UC treated with tofacitinib in a real-world setting. Our real-life data support the clinical efficacy of tofacitinib as observed in RCTs [16].

Biologics were used early in treatment of moderate-to-severe UC, with the use of TNFi therapy across subsequent lines decreasing as newer therapies became available. A previous analysis of the Adelphi Inflammatory Bowel Disease DSP in 2017 characterised the increase in use of biologic therapy in patients with UC [34]. The cycling across multiple biologics seen from this study may be attributed to patients having both primary non-response and secondary non-response [12]. This was supported by our findings which found that the reason physicians most frequently chose tofacitinib was for its efficacy and for rapid symptom relief, suggesting primary or secondary non-response, particularly to TNFi therapy. Although this study did not capture reasons for previous biologic failure, these reasons may be a factor for how patients will respond to future treatments. In a network meta-analysis of RCTs of patients with inflammatory bowel disease reported that patients who discontinued their first-line TNFi therapy due to primary non-response were less likely to respond to second-line biologics compared to those who had secondary loss of response or intolerance to TNFi [11].

Prescribing dosage of tofacitinib typically followed treatment recommendations, with few dose changes reported, particularly during induction. While the dose remained unchanged for the majority of patients during maintenance, changes in dose typically involved de-escalation to a lower dose or lower dose frequency. It is recommended that the lowest effective dose is typically used, however it is possible that dose changes were due to intolerance, loss of response or non-response, leading to dose de-escalation and dose escalation, respectively. An observational study also noted dose reductions in patients continuing tofacitinib after week 24 [35]. Analysis of data from the randomised, double-blind RIVETING trial of tofacitinib dose reduction to 5 mg twice daily versus remaining on 10 mg twice daily, found that most patients in stable remission on 10 mg twice daily maintenance therapy maintained remission following dose de-escalation [36]. Additionally, in contrast to biologic therapies that are liable to loss of exposure due to substantial disease activity or immunogenicity [37], the pharmacokinetic results in the OCTAVE Induction 1 and 2 and Sustain trials found no indication of a decrease in plasma tofacitinib concentrations during the treatment course at any dose in individual patients [16].

Our analysis demonstrated that the number of patients in remission was positively correlated with length of time on tofacitinib treatment, with the proportion of patients increasing by 54% from initiation to weeks [52+], possibly suggesting that these patients may be those who continued with tofacitinib treatment and were early responders. Specifically, at weeks [4, 8) less than one-third (29.2%) of patients were in remission; the proportion was more than two-thirds (68.3%) of patients at weeks > 52. A meta-analysis of real-world studies evaluating the effectiveness of tofacitinib for moderate-to-severely active UC, remission was achieved in 34.7% (95% confidence interval [CI], 24.4–45.1%), 47.0% (95% CI 40.3–53.6%), and 38.3% (95% CI 29.2–47.5%) of patients at week 8, weeks 12–16, and month 6, respectively [38]. These real-world data also support findings of the OCTAVE Induction 1 and 2 trials, where 18.5% and 16.6% of patients with UC treated with tofacitinib (versus 8.2% and 3.6% receiving placebo), respectively, achieved clinical remission by week 8 [16]. During the maintenance OCTAVE Sustain trial, remission occurred in 34.3% of patients in the 5 mg tofacitinib group and 40.6% in the 10 mg tofacitinib group (versus 11.1% placebo) group at 52 weeks [16].

The gastrointestinal symptoms associated with UC significantly impact on patients’ QoL [6]. There are currently limited real-world studies that have assessed improvement in individual symptoms and QoL with tofacitinib as in our cross-sectional study [39]. Our analysis demonstrated that tofacitinib improves symptoms, symptom severity, and QoL in patients with moderate-to-severe UC, with improvements beginning in the first month of treatment and increasing with length of time on tofacitinib therapy. Thus, we found a reduction in the proportion of patients with more stools than normal and/or with bloody stools, with the vast majority reporting normal non-bloody stools at/after a year of treatment. Similarly, other gastrointestinal symptoms (bloody diarrhea, abdominal pain/cramps, bowel movement urgency, rectal bleeding) and fatigue/tiredness showed improvement with length of time on tofacitinib, and overall severity of symptoms, pain and fatigue/tiredness were substantially reduced from tofacitinib initiation. QoL showed clinically meaningful improvements as early as the second or third month of treatment. Specifically, the improvement in work productivity, amounting to over 40% overall is an important finding for patients with UC of working age. Over 90% of people with IBD who have symptoms during their working life require workplace accommodations to enable them to work, yet many found them difficult to arrange or did not ask for them [40].

Our findings generally concur with RCTs during induction and maintenance, as we found improvement in QoL in both these treatment periods, with the greatest improvements observed during induction. In the OCTAVE induction studies, there were statistically significant and clinically meaningful improvements in HRQoL of patients with moderate-to-severe UC with tofacitinib (versus placebo) as early as Week 4, with sustained improvements in the maintenance study [18]. Similarly, a systematic review with network meta-analysis of RCTs comparing the impact of therapies on HRQL found that induction therapy with tofacitinib improves HRQoL of patients with moderate-to-severe UC, with the improvement maintained during maintenance therapy [41].

The majority of physicians and patients were satisfied with tofacitinib, starting from treatment initiation, and rising to over 90% of individuals from 6 months onwards; similar patterns were seen for physicians and patients over time in terms of satisfaction. A survey of 194 patients with UC receiving tofacitinib 10 mg twice daily for 8 weeks reported that approximately 60% of patients were each at least satisfied with tofacitinib, preferred tofacitinib to their prior treatment, and would use tofacitinib again [42]. In agreement, we found 79% of patients were satisfied with tofacitinib at [4, 8) weeks. Supporting our findings, bowel function has been shown to be important for patient treatment satisfaction with tofacitinib [43].

By design, DSPs are non-interventional and capture data from a large representative patient sample in a real-world setting. Nevertheless, several limitations should be considered in the evaluation of our findings. Participating patients may not reflect the general UC population as they may be the more frequently consulting patients who may have had more active disease. However, identification of patients with UC is based on the judgement of the physician and is representative of physician’s real-world clinical practice. Consecutively presenting patients were included so that a patient consultation is at random, although the patient samples were not truly random as the methodology dictates inclusion of the next ‘n’ number of consecutive consulting patients, and there are no data verification procedures for choosing the consecutive series of patients. Physician inclusion was likely influenced by their willingness to participate. Physician- and patient-reported data may be subject to recall bias; this may have affected responses particularly of time-stamped data such as steroid use, which therefore may be under-estimated. Not all patients completed a PSC, so there is a disconnect between available physician reported and patient reported data. The comparisons are between the independent groups of patients across time. The cross-sectional nature of the DSP means that the data were captured at a single point in time and do not follow individuals up over time; thus, there can be no temporal relationship between exposure and outcome. Note the MCIDs used here to contextualise the mean differences in some patient reported outcomes between patient groups are intended to give context to changes within individual patients. Finally, we cannot rule out any impact on our findings of COVID-19, since data were collected during the pandemic.

In conclusion, this cross-sectional real-world analysis demonstrates that patients with moderate-to-severe UC treated with tofacitinib show considerable improvement in symptoms and HRQoL from tofacitinib initiation though maintenance to one year and beyond, with approximately 60% of patients attaining remission at weeks 24–52. Physicians and patients report satisfaction with UC control at recommended doses early in treatment despite patients’ previous treatment lines. Our findings highlight the importance of real-world studies to demonstrate outcomes of the every-day patient population outside the stringent eligibility criteria of clinical trials.