Treatment of Chronic Inflammatory Pouch Conditions With Tofacitinib: A Case Series From 2 Tertiary IBD Centers in the United States

Introduction

Approximately 10% to 15% of patients with ulcerative colitis (UC) undergo restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) due to medically refractory colitis or neoplasia.¹ While IPAA is an excellent alternative to a permanent end ileostomy for patients with UC, up to 50% of patients develop acute pouchitis, and 10% to 15% of patients develop chronic pouch inflammation.¹ Tofacitinib, a Janus kinase 1/3 inhibitor, has been approved for induction and maintenance of remission in patients with moderate to severe UC who failed anti-tumor necrosis factor agents.² To date, 2 case reports showed that tofacitinib was effective for chronic pouchitis (CP)³ or Crohn’s disease–like pouch inflammation (CDLPI).⁴ On the other hand, a recent case series including 6 patients with CP, cuffitis, or CDLPI showed that 1 patient achieved clinical response, but all patients ultimately discontinued tofacitinib due to the lack of efficacy and adverse events.⁵ Therefore, data regarding its effectiveness are still controversial. This study aims to assess the effectiveness and safety of tofacitinib for patients with CP or CDLPI.

Methods

This is a retrospective study of patients who underwent restorative proctocolectomy with IPAA who were subsequently diagnosed with CP or CDLPI and treated with tofacitinib at the University of Chicago Medicine and Mount Sinai Hospital. This study was approved by the Institutional Review Board of the University of Chicago (#16-0061, #15573A) and Mount Sinai Hospital (#16-01321). We retroactively calculated Modified Pouchitis Disease Activity Index (mPDAI)⁶ based on clinical symptoms and endoscopic findings described in the medical charts. Endoscopic findings were defined according to the Chicago classification of pouchitis.⁷ Our definition of CDLPI included presence of fistulae, strictures involving the pouch or afferent limb, or afferent limb inflammation.^8,9 Clinical response was defined as an improvement in clinical symptoms during tofacitinib use (≥2-point improvement from the baseline clinical score of PDAI), and mPDAI response was defined as a ≥2-point reduction from baseline mPDAI.¹ We assessed clinical data at 3 ± 2 and 12 ± 2 months after starting tofacitinib and at the most recent follow-up date during tofacitinib use. If the data were not available, we assigned these data as not available. We compared demographic data between responders and nonresponders to tofacitinib. Categorical data were compared using Fisher’s exact test, while continuous data were compared using the Mann-Whitney U test. P values <.05 were considered statistically significant.

Results

We identified 14 patients with chronic inflammatory pouch conditions treated with tofacitinib between 2016 and 2020. A total of 10 and 4 patients were identified at the University of Chicago and Mount Sinai Hospital, respectively. Clinical characteristics are summarized in Table 1. Included patients had a preoperative diagnosis of UC (n = 13 [93%]) or inflammatory bowel disease unclassified (n = 1 [7%]). The median interval between ileostomy takedown and tofacitinib initiation was 16 (interquartile range [IQR], 10-24) years. The median age at tofacitinib initiation was 44 (IQR, 33-52) years and the majority of patients were men (71%). Thirteen (93%) patients were exposed to at least 1 biologic and were naïve for tofacitinib for chronic inflammatory pouch conditions before starting tofacitinib. Median mPDAI at the baseline was 5 (IQR, 4-7.5), with median clinical and endoscopic scores of 2 (IQR, 2-5) and 2.5 (IQR, 1.3-4.5), respectively. Eleven (79%) patients were diagnosed with CDLPI. The following baseline endoscopic pouch phenotypes were observed: afferent limb inflammation in 9 of 13 (69%), inlet inflammation in 10 of 13 (77%), inlet stenosis in 3 of 13 (23%), diffuse inflammation in 8 of 13 (62%), cuffitis in 6 of 10 (60%), and fistulae in 3 of 13 (23%). Twelve (86%) patients started tofacitinib 10 mg twice daily (BID). Two (14%) patients initiated 5 mg BID and then escalated the dose to 10 mg BID. Four (29%) patients were on combination therapy with tofacitinib and antibiotics. Median duration of tofacitinib use was 12 months (Table 1).

For the analysis of clinical outcomes, 1 patient with a baseline PDAI clinical score of 1 was excluded as clinical response was defined as ≥2-point improvement from the baseline PDAI clinical score. Clinical response was achieved in 3 (23%) of 13 patients at 3 months. Among patients with available PDAI clinical scores at 12 months, 4 (67%) of 6 showed clinical response. Among the 3 patients who achieved clinical response at 3 months, 1 (33%) maintained the clinical response and 2 (67%) had subsequent clinical relapses during the follow-up. Among the 10 patients who did not achieve clinical response at 3 months, 3 (30%) had subsequent clinical response. The total number of patients who ever responded to tofacitinib was 6 (46%) of 13 patients during the follow-up time. No clinical responses were observed in 7 (54%) of 13 patients (Figure 1A).

We compared demographic data between responders (n = 6) and nonresponders (n = 7). Responders had significantly higher baseline PDAI clinical score (5 [IQR, 5-5]) and mPDAI score (9.5 [IQR, 6.5-11]) compared with nonresponders (2 [IQR, 2-2] in PDAI clinical score; P = .003; and 4 [IQR, 2.5-4.5] in mPDAI; P = 0.009). Duration of tofacitinib use was significantly longer in the responders (18 [IQR, 13-27] months) than in the nonresponders (7 [IQR, 3.8-11] months) (P = .046). Otherwise, there were no statistical differences in clinical data described in Table 1 between the 2 groups (data not shown).

A subgroup analysis only including patients who developed diffuse inflammation of the pouch body before starting tofacitinib showed 2 (29%) of 7 patients achieved clinical responses at 3 months and 3 (43%) of 7 patients had clinical responses at a median of 7.5 months after starting tofacitinib. Another subgroup analysis only including patients with available subsequent pouchoscopies and baseline mPDAI ≥2 showed that 3 (60%) of 5 of patients showed mPDAI responses during median 13 months’ follow-up with tofacitinib.

Nine (64%) patients discontinued tofacitinib primarily due to the lack of efficacy or loss of response. Among them, 4 (44%) patients required pouch excision. No patients experienced serious infections or drug-related adverse events.

Discussion

Our case series showed that approximately 50% of patients with CP or CDLPI had clinical response after initiating tofacitinib. Our comparative analysis showed that patients who ever responded to tofacitinib had higher baseline mPDAI and clinical scores and longer duration of tofacitinib use compared with the nonresponders. This suggests that tofacitinib may control active clinical symptoms due to chronic inflammatory pouch conditions, and patients can continuously use tofacitinib if it works for clinical symptoms. Furthermore, we found no serious drug-related adverse events. Thus, our findings support the effectiveness and safety of tofacitinib for chronic inflammatory pouch conditions. There is increasing evidence to suggest that the pathophysiology of pouchitis may be similar to that of UC.¹⁰ The fact that tofacitinib worked in some of our patients with chronic inflammatory pouch conditions adds more support to that evidence. However, given that nearly two-thirds of patients discontinued tofacitinib primarily due to lack of efficacy or loss of response, there also remains the possibility that tofacitinib may have the lack of durability for CP or CDLPI. Given that our cohort predominantly included CDLPI, more data are needed to understand the efficacy of tofacitinib for patients with non-CDLPI.

There were several limitations to this study. First, this study was a retrospective case series and clinical and endoscopic data were not always available, thereby introducing some biases due to missing values. Second, although this study was conducted by 2 tertiary inflammatory bowel disease centers in the United States, the sample size was too small to perform meaningful statistical analyses. Third, median mPDAI score in our cohort was 5, suggesting that not all patients reached the cutoff value of the mPDAI for defining pouchitis. Moreover, this study predominantly included patients with CDLPI, which we have previously identified as having a poor prognostic phenotype,⁷ implying that our data regarding effectiveness of tofacitinib for chronic inflammatory pouch conditions would not necessarily be translatable to other patient types or clinical practices. We propose future prospective studies with larger sample sizes to confirm our findings.

Conclusions

This case series showed that tofacitinib was effective and safe for some patients with CP or CDLPI. Further research is warranted to better understand the efficacy and safety of tofacitinib for chronic inflammatory pouch conditions.

Author Contribution

Study concept and design: S.A., N.A.C., M.K., D.T.R. Acquisition of data: S.A., N.A.C., M.K. Analysis and interpretation of data: S.A., N.A.C., M.K., D.T.R. Drafting of manuscript: S.A., N.A.C., M.K., D.T.R. Critical revision of manuscript: S.A., N.A.C., M.K., M.C.D., J.F.C., D.T.R. All authors have approved the final version.

Funding

Funding in part provided by National Institute of Diabetes and Digestive and Kidney Diseases P30 DK42086 and RC2 DK122394, and the GI Research Foundation of Chicago. M.K. is funded by National Institutes of Health DK127241-01A.

Conflicts of Interest

S.A. has no relevant disclosures. N.A.C. has served as a consultant for Iterative Scopes. M.K. has served as a consultant for GoodRx. M.C.D. has served as a consultant for AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim International, Bristol-Myers Squibb, Celgene, Eli Lilly, F. Hoffman-La Roche, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda, and UCB; has received research grants from Pfizer, AbbVie, Janssen, and Prometheus; and has ownership interest in Trellus and licensing fees from Takeda. J.F.C. has received research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; has received payment for lectures from AbbVie, Amgen, Allergan, Ferring Pharmaceuticals, Shire, and Takeda; has received consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development. D.T.R. has received grant support from Takeda; and has served as a consultant for AbbVie, Abgenomics, Arena Pharmaceuticals, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corp/Syneos, Dizal Pharmaceuticals, Genentech/Roche, Gilead Sciences, Ichnos Sciences, InDex Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Lilly, Pfizer, Prometheus Laboratories, Prometheus Biosciences, Reistone, Takeda, and Techlab.

Data Availability

The data underlying this article will be shared on reasonable request to the corresponding author.