Background: Tofacitinib is effective for refractory ulcerative colitis (UC), a chronic inflammatory disease of the colonic mucosa. However, its use has been associated with an increased risk of thromboembolic events, prompting regulatory restrictions. Understanding the pathophysiological mechanisms contributing to these potential risks is critical for patient safety. We aim to evaluate and compare ex vivo the effects of tofacitinib and anti-TNF on coagulation parameters and platelet function. Methods: Whole blood and platelet-rich plasma from 10 active UC (aUC) and 10 quiescent UC (qUC) patients and 10 healthy controls (HC) were spiked ex vivo with tofacitinib, anti-TNF (as comparator), or a sterile solution. Coagulation kinetics were measured by rotational thromboelastometry (ROTEM), platelet aggregation by aggregometry, and platelet activation by flow cytometry. The study was conducted at Hospital Universitario de La Princesa. Results: Flow cytometry showed increased expression of activation markers CD62P and CD63 and higher PAC-1 binding in platelets from both aUC and qUC patients incubated with either tofacitinib or anti-TNF versus no drug. No differences were found between the drugs. CD63 expression also increased in HC after drug exposure, with no differences between anti-TNF or tofacitinib. Platelet aggregation and coagulation parameters did not differ between tofacitinib, anti-TNF, and no drug in aUC, qUC, and HC. Conclusions: Tofacitinib does not alter platelet function or coagulation in UC patients under ex vivo conditions compared to anti-TNF. The increased thromboembolic risk observed in some populations treated with tofacitinib cannot be attributed to these factors in UC patients.

Tofacitinib has been approved for the treatment of patients with moderate-to-severe ulcerative colitis independently of prior therapies. We aimed to assess the efficacy and safety of tofacitinib in biologic-naive patients.

This was a retrospective analysis of prospectively collected data extracted from the notes of patients with moderate-to-severe ulcerative colitis naive to advanced therapies, who were treated with tofacitinib [10 mg twice daily (b.i.d.) for 8 or 16 weeks followed by a 5 mg b.i.d. maintenance dose] in six Greek Hospitals, who had a follow-up of at least 26 weeks after treatment initiation.

Overall, 48 patients were included. Clinical response was seen in 30 (62.5%) and 32 (66.6%) patients at week 8 and 16, respectively. Clinical remission, corticosteroid-free clinical remission, biochemical response, and endoscopic remission at week 26 was observed in 26 (54.2%), 26 (54.2%), 28 (60.8%), and 29 (60.4%) patients, respectively. No major adverse events or infections were recorded.

In this retrospective ongoing cohort study, tofacitinib demonstrated clinical response at weeks 8 and 16 in more than 60% and steroid-free clinical remission at week 26 in more than 50% of biologic-naive patients with moderate-to-severe ulcerative colitis with a good safety profile, indicating that tofacitinib is an effective first-line treatment for this group of patients.

Janus kinase inhibitors (JAKis) have revolutionized ulcerative colitis (UC) management; however, the consequences of treatment discontinuation in patients achieving clinical remission remain poorly understood. This study investigated the clinical outcomes following JAKi discontinuation and retreatment effectiveness in patients with relapse.

In this multicenter retrospective cohort study, we analyzed 101 patients with UC who received their first JAKi treatment between 2018 and 2024. Among them, 53 who achieved remission (Patient-Reported Outcome 2 = 0) in week 8 were included. The primary endpoint was a comparison of relapse-free survival between the treatment continuation and discontinuation groups (n = 37 and 16, respectively). The secondary endpoints included assessment of post-discontinuation remission maintenance and post-retreatment remission rates.

The proportion of female patients in the discontinuation group (68.8%) was higher (P = .0478) than the continuation group (40.5%). The mean relapse-free survival was significantly longer in the continuation group than in the discontinuation group (1679 vs 882 days, cumulative relapse-free rate 83.3% vs 13.6%, P < .001, respectively). In the latter, 13 patients experienced relapse during follow-up (post-discontinuation mean relapse-free survival: 326 days), although all patients remained in clinical and biological remission. Notably, among patients who received JAKi retreatment, 83.3% achieved remission in week 8.

To our knowledge, this is the first real-world study to evaluate the effects of JAKi discontinuation on the outcomes for patients with UC. JAKi discontinuation in patients in remission was associated with a high relapse risk. JAKi retreatment was highly effective in patients who experienced relapse after treatment discontinuation, providing valuable evidence for managing treatment interruption.

To assess the real-life, long-term effectiveness and safety of tofacitinib in a large cohort of patients with refractory or difficult-to-treat ulcerative colitis (UC).

This multicenter, retrospective, observational cohort study included patients with moderately to severely active UC who received tofacitinib for at least 8 weeks. Clinical remission and response, endoscopic response and remission, biochemical response and remission, steroid-free clinical remission, primary and secondary loss of response, drug discontinuation, the need for dose optimization, the need for colectomy, and adverse events were evaluated over up to 30 months.

We included 127 patients with UC, with a mean age of 40.3 ± 14.2 years; 58.2% were male, 75.6% had pancolitis, and 79.5% had previously failed at least one biological therapy, predominantly anti-TNF agents (70.1%). Clinical remission was observed in 31.5% of patients at weeks 12-16, 46.5% at 26 ± 4 weeks, and 37.0% at 1 year. Steroid-free clinical remission was achieved in 28.6%, 44.8%, and 37.1% of patients at the same time points, respectively. Biochemical remission was achieved in 33.6% of patients at 26 ± 4 weeks and 29.3% at 1 year. Endoscopic response and endoscopic remission within 1 year were observed in 46.0% and 15.3% of patients, respectively. Ten patients (7.9%) required colectomy, and 13 patients (10.2%) required hospitalization, all of whom had been previously exposed to biologics. The colectomy rate was significantly greater in patients with serum albumin levels ≤ 3.5 g/dL (21.4% vs. 4.1%, p = 0.013).

In this large, long-term real-world study involving patients with predominantly biologically refractory UC, tofacitinib effectively induced clinical remission and endoscopic improvement and prevented colectomy for more than 30 months, with a favorable safety profile. Notably, baseline hypoalbuminemia was associated with higher colectomy rates.

Background: Upadacitinib (UPA) is a new oral selective Janus Kinase (JAK) inhibitor that has shown high efficacy in the treatment of ulcerative colitis (UC). We present data from a multicenter real-world study. Methods: To assess efficacy of UPA, Total Mayo Score (TMS), fecal calprotectin (FC), endoscopy, and intestinal ultrasonography (IUS) were performed. Results: The study population included 76 patients. An amount of 26.3% of the patients were biologics and small molecules-naive, while 73.7% were exposed. By Week 8, 93.4% of the patients had achieved a clinical response (94.7% naive vs. 92.9% exposed), 72.4% achieved endoscopic improvement (78.9% vs. 71.4%), and 57.9% had clinical remission (78.9% vs. 51.8%). Endoscopic remission was achieved in 31.6% of patients (35.0% vs. 30.4%) and biochemical remission in 82.1% (53.3% vs. 68.3%). All of the results were not significantly different apart from the steroid-free clinical remission-36.8% (68% vs. 26.8%, p = 0.002) after 8 weeks of follow-up. IUS was performed in 33 patients. Bowel wall thickness (BWT), inflammatory fat (iFAT), color Doppler signal (CDS), loss of bowel wall stratification (BWS), and Milano Ultrasound Criteria (MUC) had decreased significantly by Weeks 4 and 8 (p < 0.005 for all). Correlation between the IUS results and TMS, FC and endoscopic remission in Week 8 was confirmed (p < 0.001). UPA was well tolerated, and no new safety signals were registered in our group. Conclusions: In this study, UPA was confirmed to be safe and highly effective in inducing remission in UC patients in both the naive group and the biologically exposed patients. The correlation between the IUS results and TMS, FC, and endoscopic remission provides valuable information for clinicians.

Tofacitinib has recently been approved for treatment of moderate-to-severe ulcerative colitis (UC) in adults, yet pediatric data are limited. This international multicenter study describes the effectiveness and safety of tofacitinib in pediatric UC.

This is a retrospective review of children diagnosed with UC treated with tofacitinib from 16 pediatric centers internationally. The primary outcome was week 8 corticosteroid-free clinical remission (Pediatric Ulcerative Colitis Activity Index <10). Secondary outcomes were clinical response (≥20-point decrease in Pediatric Ulcerative Colitis Activity Index) at week 8, corticosteroid-free clinical remission at week 24, and colectomy rate and adverse safety events through to last follow-up. The primary outcome was calculated by the intention-to-treat principle.

We included 101 children with a mean age at diagnosis of 12.8 ± 2.8 years and a median disease duration of 20 months (interquartile range [IQR], 10-39 months). All had treatment failure with at least 1 biologic agent, and 36 (36%) had treatment failure with 3 agents. Median follow-up was 24 weeks (IQR, 16-54 weeks). Sixteen (16%) children achieved corticosteroid-free clinical remission at week 8, and an additional 30 (30%) demonstrated clinical response. Twenty (23%) of 88 children achieved corticosteroid-free clinical remission at week 24. A total of 25 (25%) children underwent colectomy by median 86 days (IQR, 36-130 days). No serious drug-related adverse events were reported; there was 1 case of herpes zoster and 2 cases of minor blood test perturbations.

In this largest real-life pediatric cohort to date, tofacitinib was effective in at least 16% of patients with highly refractory UC by week 8. Adverse events were minor and largely consistent with adult data.

One-third of patients with acute severe ulcerative colitis (ASUC) are steroid-refractory. Cyclosporine and infliximab are currently the mainstays of salvage therapy. Janus kinase inhibitors (JAKi) could play a role in the treatment of ASUC.

To review the evidence on JAKi in the management of ASUC.

We performed a bibliographic search to identify studies focusing on the treatment of ASUC with JAKi.

Potential advantages of JAKi for the management of ASUC include their oral administration, rapid onset of action, short half-life, lack of immunogenicity, and effectiveness in patients with prior biologic exposure. Thirty studies (including 373 patients) have evaluated the efficacy of tofacitinib in ASUC, with a response rate (avoidance of colectomy) ranging between 43% and 100%, with a weighted mean of 82%. Experience with upadacitinib is more limited (only 10 studies and 74 patients are available) but also encouraging: mean colectomy-free rate ranging between 67% and 100%, with a weighted mean of 79%. However, experience with filgotinib in ASUC is currently nonexistent. Regarding safety, the available data does not reveal any new safety concerns when JAKi are used in ASUC, although follow-up periods are still short.

JAKi seems to be a promising treatment option for ASUC, with both tofacitinib and upadacitinib achieving colectomy-free rates of approximately 80%. Further studies are essential to define whether JAKi can replace cyclosporine/infliximab as second-line therapy for the medical management of ASUC, or whether they can even be used as initial treatment in place of intravenous corticosteroids.

Janus kinase [JAK] inhibitors are used for treating inflammatory bowel diseases [IBD]. We aimed to identify the molecular effects of JAK inhibition in human intestinal mucosa, considering IBD location and phenotype.

Colonic and ileal explants from patients with ulcerative colitis [UC], Crohn's disease [CD], and non-IBD controls [NC] were assessed for levels of phosphorylated signal transducers and activators of transcription [p-STAT] and expression of inflammatory genes in response to an ex vivo JAK inhibitor [tofacitinib]. Cytokine production by lamina propria lymphocytes in response to tofacitinib was assessed. Human intestinal organoids were used to investigate the effects of JAK inhibitors on inducible nitric oxide synthase [iNOS] expression.

Explants were collected from 68 patients [UC = 20, CD = 20, NC = 28]. p-STAT1/3/5 inhibition rates varied, being higher in colonic compared to ileal explants. p-STAT1/3 inhibition rates negatively correlated with levels of C-reactive protein [CRP]. While significant alterations in 120 of 255 inflammatory genes were observed in colonic explants, only 30 were observed in ileal NC explants. In colonic explants from UC, significant alterations were observed in five genes, including NOS2. JAK inhibition significantly decreased Th1/Th2/Th17-related cytokine production from lamina propria lymphocytes. Various JAK inhibitors reduced the interferon-γ-induced increase in iNOS expression in organoids.

A site-specific anti-inflammatory effect of JAK inhibition by tofacitinib was noted, whereby the colon was more robustly affected than the ileum. The ex vivo response to tofacitinib is individual. JAK inhibition may attenuate inflammation by decreasing iNOS expression. Ex vivo mucosal platforms may be a valuable resource for studying personalized drug effects in patients with IBD.

Background: Few studies have compared the efficacy and safety of Janus kinase (JAK) inhibitors in patients with ulcerative colitis (UC). We compared the real-world effectiveness and safety of tofacitinib (TOF) and filgotinib (FIL) as induction therapy for UC by propensity score-matching analysis. Methods: We enrolled 230 patients with active UC who received either TOF (n = 197) or FIL (n = 33) as induction therapy. The primary outcome was the clinical response at week 8, and the secondary outcomes were the clinical response/remission rates from weeks 2-8, including the course of patients without a clinical response/remission at week 4. Results: Propensity score-matching analysis revealed that the clinical response rate gradually increased to 72.2% at 8 weeks in the TOF group, whereas it tended to decrease to 48.5% in the FIL group. Clinical remission rates increased from 2 (36.7% vs. 36.7%) to 8 weeks (63.6% vs. 48.5%) after treatment in the TOF and FIL groups, respectively. The clinical response rate was higher in the TOF group than in the FIL group at week 8 in patients without a clinical response at week 4 (38.5% vs. 0%; p = 0.011). The clinical remission rate was also higher in the TOF group than in the FIL group at week 8 in patients without clinical remission at week 4 (50.0% vs. 16.7%; p = 0.046). The incident rates of infection and anemia were higher in the TOF group than in the FIL group. Conclusions: TOF may be more effective than FIL at 8 weeks for patients with UC who do not respond to treatment within the first 4 weeks.

This study aimed to evaluate the real-world effectiveness of tofacitinib for treating moderate-to-severe ulcerative colitis (UC).

Systematic review and meta-analysis.

PubMed, EMBASE and Cochrane CENTRAL databases were searched from inception up to 18 July 2023. Reference lists of included studies were manually searched to identify potentially relevant studies not found in the databases.

Eligible studies included real-world observational studies, reported in English, on patients with moderate-to-severe UC treated with tofacitinib, defined by the Partial Mayo Score. Excluded were clinical trials, reviews, letters, conference abstracts, case reports and studies involving patients with mixed Crohn's disease.

Two independent reviewers extracted data and recorded it in Excel. Quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was performed using random-effects models due to high heterogeneity across studies.

19 studies containing a total of 2612 patients were included. Meta-analysis revealed that clinical response rates were 58% at week 8, 61% at weeks 12-16, 51% at weeks 24-26 and 51% at week 52. Clinical remission rates were 39% at week 8, 43% at weeks 12-16, 40% at weeks 24-26 and 43% at week 52. Corticosteroid-free clinical remission rates were 33% at week 8, 37% at weeks 12-16, 32% at weeks 24-26 and 40% at week 52.

This meta-analysis of real-world studies indicates that treatment of UC with tofacitinib is associated with favourable clinical response and remission rates in the induction and maintenance phases.

Ustekinumab (UST) is an anti-interleukin-12/23 antibody used in the treatment of inflammatory bowel disease. This study includes patients treated at four hospitals in Stockholm to provide long-term real-world data.

Retrospective study including patients diagnosed with ulcerative colitis and treated with UST between the years 2019 and 2021. Patients were followed until withdrawal of treatment, or until a predefined end of study, 31 July 2021. Disease activity was assessed with Physician Global Assessment (PGA); Ulcerative Colitis Endoscopic Index of Severity (UCEIS), laboratory parameters, and drug persistence. The primary outcome was steroid-free remission (PGA = 0) and response (decrease PGA ≥ 1 from baseline) at 3 and 12 months, respectively.

A total of 96 patients, 44 women and 52 men were included. The patients had either extensive colitis (69%), left-sided colitis (29%), or proctitis (3%). All but two patients were anti-TNF-experienced; 94 (98%) had failed ≥1, 59 (61%) ≥ 2, and 34 (35%) had failed ≥ 3 anti-TNF drugs. In addition, 28 (29%) had failed vedolizumab. At inclusion, 92/96 patients (96%) had active disease and four patients were in remission. Among patients who were treated with UST, 9/71 (13%) were in steroid-free remission at 3 months, and 26/33 (78%) were at 12 months. Withdrawal rates at 3 and 12 months, were 12 and 26%, respectively, mainly due to persisting disease activity (20%).

In this group of patients with difficult-to-treat ulcerative colitis, UST was shown to be effective in the majority, with high drug persistence at 12 months in combination with a favorable safety profile.

Real-world data on tofacitinib's effectiveness is limited and mainly retrospective or registry-based. We elected to conduct a pragmatic prospective study to assess the efficacy of tofacitinib for moderate to severe ulcerative colitis (UC), aiming to evaluate the ability of intestinal ultrasound (IUS) to discriminate responders vs. non-responders in real-time.

This pragmatic prospective clinical study included consecutive adult patients starting tofacitinib treatment for active moderate to severe UC. Patients were evaluated at baseline and after 8 weeks of tofacitinib (clinical, biomarker, endoscopy, and IUS). The primary outcome was clinical response defined by a decrease in the full Mayo score (fMS) of ≥3 at week 8. Next, we explored ultrasonographic parameters in the sigmoid colon as potential real-time classifiers to differentiate between responders and non-responders at week 8.

Overall, 30 adult patients started tofacitinib; the median age was 26.3 years (IQR 22.5-39.8), and 50% were female. Most patients (86.6%) had left-sided or extensive colitis, 96.7% had previously failed biologic therapy, and 60% (18/30) were on oral corticosteroids at the start of tofacitinib. At week 8, clinical response (a decrease in the fMS ≥ 3) and remission (fMS ≤ 2) rates were 40% (12/30) and 20% (6/30), respectively. Biomarker response (FC < 250µg/g) and biomarker normalization (FC ≤ 100µg/g) were achieved in 47.6% (10/21) and 38.1% (8/21) of patients, respectively. Endoscopic healing (endoscopic Mayo sub-score [EMS] ≤ 1) was achieved in 33.3% (10/30) of patients. Sigmoid bowel wall normalization as assessed by IUS (sBWT ≤ 3) was achieved in 18.2% (4/22). The best sBWT cut-off at week 8 to accurately classify endoscopic healing vs. no healing was a sBWT of 3.6 mm (AUC of 0.952 [95% CI: 0.868-1.036], p < 0.001).

In this real-world pragmatic prospective study, tofacitinib was an effective treatment for moderate to severe UC, and IUS at week 8 accurately discriminated treatment response from non-response.

Real-world data on the effectiveness of upadacitinib for inflammatory bowel disease (IBD) are limited. To assess upadacitinib persistence, effectiveness, and safety in a real-world scenario.

Retrospective multicenter study of patients with IBD who received upadacitinib before 31st December 2022 and at least 12 weeks before the recruitment date. Clinical effectiveness was assessed based on partial Mayo score for ulcerative colitis (UC) and Harvey-Bradshaw index for Crohn's disease (CD).

We included 100 patients (68 with CD, and 32 with UC). Patients had previously received a median of 4 advanced therapies. Twenty-three discontinued the treatment (median follow-up 7.6 months). CD (vs UC) (hazard ratio 3.7; 95% confidence interval [CI]: 1.04-12.9) and age below 40 years at upadacitinib initiation (hazard ratio 2.4; 95% CI: 1.0-5.8) were associated with treatment discontinuation in multivariable analysis. Clinical remission for IBD was achieved in 59% of patients at week 8, 64% at week 12, and 42% at week 52. The proportion of patients with UC previously exposed to tofacitinib (n = 25) who achieved clinical remission was 78% at week 12, and 50% at week 52. Factors associated with clinical remission at week 12 were UC diagnosis (odds ratio [OR] 4.6; 95% CI: 1.3-17), mild or moderate activity at baseline (OR 8; 95% CI: 1.1-56), and not smoking (OR 4.4; 95% CI: 1.5-13). Dose escalation recaptured remission in 60% of patients with relapse. Eighty percent of patients with active immune-mediated diseases or extraintestinal manifestations improved with upadacitinib. Forty-three patients reported adverse events, 11 of them serious.

Upadacitinib is effective and safe for treating patients with highly refractory IBD, even in previously treated with Janus kinase inhibitors.

To evaluate the effectiveness and safety of tofacitinib in patients with ulcerative colitis (UC) in clinical practice in Lebanon.

This was a retrospective cross-sectional study. The data were collected from hospital records. Patients with moderate to severe UC treated with tofacitinib between 2018 and 2021 were included. Patients' demographics, disease-specific characteristics, clinical assessment at three time points (8, 26, and 52 weeks), endoscopic evaluation at 24 weeks, and adverse events were collected.

A total of 60 UC patients with a mean duration of disease of 7.9 ± 4.7 years were enrolled. 61.7% of patients had extensive disease, and 58.3% had received ≥ 1 biologic prior to tofacitinib. Clinical remission was reported in 25, 34, and 31 patients (41.7%, 56.7%, and 56.4%) at 8, 26, and 52 weeks respectively. Endoscopic remission (endoscopic Mayo score 0 or 1) was observed in 58.3% of patients at 52 weeks. About one-third of patients (31.7%) stopped tofacitinib at one year, primarily for lack of efficacy or loss of response, with no significant difference between biologics-naïve and experienced patients (24% vs. 37.1% respectively). No serious adverse events or deaths were reported. Adverse events were reported in 3 patients (5.0%) - one C. difficile infection, one case of reversible lymphopenia, and one case of facial acne. No serious adverse events or deaths were noted. On multivariate analysis, biologic-naïve status and reduction or normalization of CRP were associated with clinical remission (OR = 10.87, 95% CI = 1.57, 100, and OR = 78.47, 95% CI = 2.09, 2940.32 respectively), while reduction or normalization of CRP was associated with endoscopic remission at 1 year (OR = 19.03, 95% CI = 1.64, 221.09).

Tofacitinib was effective in the treatment of moderately severe ulcerative colitis in this real-world cohort in Lebanon. Further, the predictors associated with clinical and endoscopic remissions were found to be biologic-naïve status and reduction in CRP. Observed AEs were consistent with the known safety profile. One of the major limitations of this study is the smaller sample size and the retrospective nature of the study.

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.

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).

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.

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.

Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management.

There are aspects of Janus kinase (JAK) inhibitors, specifically tofacitinib, that distinguish them from other drugs used in the treatment of ulcerative colitis (UC), such as their oral administration, their short half-life and their lack of immunogenicity. With the available evidence, we can highlight tofacitinib's quick action and flexibility of use, and its efficacy in patients, irrespective of whether or not they have previously been exposed to TNF inhibitors (anti-TNF drugs) and other biologic agents. Moreover, their safety profile is known and manageable, with certain considerations and precautions being factored in before and during treatment. In this review, we have defined various scenarios pertaining to this drug, e.g. its use in the event of failure or intolerance to previous treatment with biologics, when a quick response is required or in patients with other concurrent immune-mediated diseases.

Effectiveness and safety of advanced therapies for ulcerative colitis (UC) warrant assessment in the real world.

To perform a systematic review and summarize real-world evidence of advanced therapies approved for moderate-to-severe UC.

A systematic literature review was conducted using real-world studies of biologics or small molecules in UC using Embase, MEDLINE, and MEDLINE-In Process databases. Only products approved in any jurisdiction during the search were included. English-language full-papers (January 2005 to February 2022) and congress abstracts (January 2019 to February 2022) were included. Studies with less than 30 patients or only biologic-naive patients were excluded.

A total of 139 studies were included out of 3,930 identified articles (75%, published between 2019 and 2022; 64%, retrospective observational; 53%, from 5 countries [Italy, United States, Spain, United Kingdom, and Belgium]). Most studies were single agent (highest: vedolizumab = 50, tofacitinib = 24, and adalimumab = 18), and rates of clinical remission (CR) and adverse events varied widely. From the published comparative effectiveness studies (16), the rates of CR were numerically higher with vedolizumab vs anti-tumor necrosis factor (TNF)-α agents. Compared with vedolizumab, the effectiveness of tofacitinib was numerically greater in CR (occasionally significant). Rates of steroid-free CR were comparable between ustekinumab and tofacitinib. Infliximab was the most effective anti-TNFα agent, as reported by 2 studies. Remarkably, adverse events were similar across therapies in comparative studies.

Vedolizumab and tofacitinib were the most assessed therapies. In comparative studies, remission rates were numerically higher with tofacitinib vs vedolizumab and for vedolizumab vs anti-TNFα. Tofacitinib was comparable with ustekinumab for steroid-free CR. Safety was comparable across therapies. Future studies should explore the literature gaps identified, including limited comparative studies with small sample sizes, variations in study designs and patient characteristics, varied definitions of CR, and limited use of patient-reported outcome measures in real-world settings.

Janus kinase (JAK) inhibitors and sphingosine 1 phosphate (S1P) receptor modulators are small molecule drugs (SMDs) approved for IBD treatment. Their use in clinical practice might be limited due to cardiovascular concerns. We aimed to provide guidance on risk assessment, monitoring, and management strategies, aiming to minimize potential cardiovascular risks of SMDs and to facilitate an adequate shared decision-making. A systematic literature search was conducted, and proposed statements were prepared. A virtual consensus meeting was held, in which eleven IBD physicians and two cardiovascular specialists from ten countries attended. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75 % of participants voting as 'agree' with each statement. Consensus was reached for eighteen statements. Available evidence does not show a higher risk of cardiovascular events with JAK inhibitors in the overall IBD population, although it might be increased in patients with an unfavorable cardiovascular profile. S1P receptor modulators may be associated with a risk of bradycardia, atrioventricular blocks, and hypertension. Cardiovascular risk stratification should be done before initiation of SMDs. Although the risk of cardiovascular events in patients with IBD on SMDs appears to be low overall, caution should still be taken in certain scenarios.

Accumulating evidence reveals mitochondrial dysfunction exacerbates intestinal barrier dysfunction and inflammation. Despite the growing knowledge of mitochondrial dysfunction and ulcerative colitis (UC), the mechanism of mitochondrial dysfunction in UC remains to be fully explored.

We integrated 1137 UC colon mucosal samples from 12 multicenter cohorts worldwide to create a normalized compendium. Differentially expressed mitochondria-related genes (DE-MiRGs) in individuals with UC were identified using the "Limma" R package. Unsupervised consensus clustering was utilized to determine the intrinsic subtypes of UC driven by DE-MiRGs. Weighted gene co-expression network analysis was employed to investigate module genes related to UC. Four machine learning algorithms were utilized for screening DE-MiRGs in UC and construct MiRGs diagnostic models. The models were developed utilizing the over-sampled training cohort, followed by validation in both the internal test cohort and the external validation cohort. Immune cell infiltration was assessed using the Xcell and CIBERSORT algorithms, while potential biological mechanisms were explored through GSVA and GSEA algorithms. Hub genes were selected using the PPI network.

The study identified 108 DE-MiRGs in the colonic mucosa of patients with UC compared to healthy controls, showing significant enrichment in pathways associated with mitochondrial metabolism and inflammation. The MiRGs diagnostic models for UC were constructed based on 17 signature genes identified through various machine learning algorithms, demonstrated excellent predictive capabilities. Utilizing the identified DE-MiRGs from the normalized compendium, 941 patients with UC were stratified into three subtypes characterized by distinct cellular and molecular profiles. Specifically, the metabolic subtype demonstrated enrichment in epithelial cells, the immune-inflamed subtype displayed high enrichment in antigen-presenting cells and pathways related to pro-inflammatory activation, and the transitional subtype exhibited moderate activation across all signaling pathways. Importantly, the immune-inflamed subtype exhibited a stronger correlation with superior response to four biologics: infliximab, ustekinumab, vedolizumab, and golimumab compared to the metabolic subtype.

This analysis unveils the interplay between mitochondrial dysfunction and the immune microenvironment in UC, thereby offering novel perspectives on the potential pathogenesis of UC and precision treatment of UC patients, and identifying new therapeutic targets.

The efficacy and safety of tofacitinib for the treatment of refractory ulcerative colitis (UC) has been demonstrated in clinical trials. Although, a series of reports with real-world evidence of its short-term efficacy and safety profiles have already been published, reports of long-term real-world data have been limited. We aimed to show our 3-year evidence on the clinical use of tofacitinib for the treatment of UC, focusing on its efficacy and safety profiles.

A retrospective observational study was conducted on patients who started tofacitinib for active refractory UC at our hospital. The primary outcome was the retention rate until 156 weeks after initiating tofacitinib. The secondary outcomes were short-term efficacy at 4, 8, and 12 weeks; long-term efficacy at 52, 104, and 156 weeks; prognostic factors related to the cumulative retention rate; loss of response; and safety profile, including adverse events.

Forty-six patients who were able to be monitored for up to 156 weeks after tofacitinib initiation, were enrolled in this study. Continuation of tofacitinib was possible until 156 weeks in 54.3%, with > 50% response rates and > 40% remission rates. Among patients in whom response or remission was achieved and tofacitinib was deescalated after 8 weeks of induction treatment, 54.3% experienced relapse but were successfully rescued by and retained on reinduction treatment, except for 1 patient. No serious AEs were observed in the study.

Tofacitinib is effective and safe as long-term treatment in a refractory cohort of UC patients in real-world clinical practice.

Upadacitinib is a Janus kinase inhibitor, which has recently been approved for treating Crohn's disease. There are limited real-world studies on the outcomes of upadacitinib in Crohn's disease.

Our aim was to evaluate the outcomes of upadacitinib in a real-world Crohn's disease cohort.

We conducted a retrospective, multicentre, cohort study over a 2-year period across National Health Service (NHS) Lothian and Royal Devon University Healthcare NHS Foundation Trust. The primary outcome was treatment persistence at week 24. Secondary endpoints were corticosteroid-free clinical remission (Harvey-Bradshaw Index (HBI)<5) and biomarker remission (C-reactive protein (CRP)≤5 mg/L and faecal calprotectin (FCAL)<250 µg/g) at 12, 24 and 52 weeks. We recorded adverse events.

135 patients commenced upadacitinib as of the 1 January 2024, of which 93 patients with active Crohn's disease were included with a minimum of 12 weeks follow-up. The median follow-up time was 25 weeks (IQR 15-42 weeks). 82% of the cohort had exposure to at least two classes of advanced therapies, and 52% had exposure to at least three classes of advanced therapies. Treatment persistence was 87.1% at week 12, 81.7% at week 24 and 62.8% at week 52. Rates of clinical remission were 64% (42/66), 48% (22/46) and 38% (8/21) at weeks 12, 24 and 52, respectively. Significant reductions in HBI, CRP and FCAL were observed during follow-up. 14% (13/91) had a hospitalisation due to Crohn's disease. Adverse events occurred in 40% (37/93) of the cohort, of which 12% (11/93) were serious.

Upadacitinib was effective in a real-world, highly refractory, Crohn's disease cohort with good persistence.

Biological drugs (BD) and Janus kinase inhibitors (JAKi) have revolutionized the treatment of diverse dermatoses. However, there are concerns regarding their safety, especially the risk of cancer and opportunistic infections. Here, we discuss the risk of cancer associated with the BD and JAKi used in dermatology.

A narrative review was carried out. All relevant articles evaluating the risk of cancer associated with BD or JAKi and published between January 2010 and February 2024 were selected.

Multiple large studies have evaluated the association between BD, JAKi and cancer risk. However, there is a lack of prospective, comparative studies. Overall, patients undergoing BD and JAKi present a cutaneous cancer incidence similar to that in the general population. The drugs more strongly associated with non-skin cancer risk were anti-tumor necrosis factor (anti-TNFs) agents and JAKi (especially tofacitinib and oral ruxolitinib). This risk appears to increase with age, the presence of other factors (such as chronic immunosuppression from previous drugs or other comorbidities), and specific diseases such as rheumatoid arthritis (RA) and myelodysplastic syndrome. Conversely, BD such as interleukin (IL)-17 and IL-23 inhibitors may even reduce the risk of some visceral and hematological malignancies. In patients with dermatological conditions such as psoriasis and atopic dermatitis, the risk of malignancies may be lower than in other subgroups, and probably comparable to the general population.

The incidence of cancer in patients undergoing BD or JAKi is generally low. This incidence can be higher in elderly patients with RA or myelodysplastic syndrome, and in those undergoing prolonged therapy with tofacitinib or ruxolitinib (oral), or anti-TNF agents.

Tofacitinib (TFB) appears to be effective in the treatment of ulcerative colitis (UC); however, available real-world studies are limited by cohort size. TFB could be an option in the treatment of acute severe ulcerative colitis (ASUC). We aimed to investigate efficacy and safety of TFB in moderate-to-severe colitis and ASUC.

This retrospective, international cohort study enrolling UC patients with ≥6-week follow-up period was conducted from February 1 to July 31, 2022. Indications were categorized as ASUC and chronic activity (CA). Baseline demographic and clinical data were obtained. Steroid-free remission (SFR), colectomy, and safety data were analyzed.

A total of 391 UC patients (median age 38 [interquartile range, 28-47] years; follow-up period 26 [interquartile range, 14-52] weeks) were included. A total of 27.1% received TFB in ASUC. SFR rates were 23.7% (ASUC: 26.0%, CA: 22.8%) at week 12 and 41.1% (ASUC: 34.2%, CA: 43.5%) at week 52. The baseline partial Mayo score (odds ratio [OR], 0.850; P = .006) was negatively associated with week 12 SFR, while biologic-naïve patients (OR, 2.078; P = .04) more likely achieved week 52 SFR. The colectomy rate at week 52 was higher in ASUC group (17.6% vs 5.7%; P < .001) and decreased with age (OR, 0.94; P = .013). A total of 67 adverse events were reported, and 17.9% resulted in cessation of TFB. One case of thromboembolic event was reported.

TFB is effective in both studied indications. TFB treatment resulted in high rates of SFR in the short and long terms. Higher baseline disease activity and previous biological therapies decreased efficacy. No new adverse event signals were found.

Older adults and patients with underlying conditions such as immunocompromised (IC) populations (e.g., due to medical conditions or immunosuppressive medication) are at increased risk for herpes zoster (HZ). The first HZ recombinant vaccine for IC patients was approved in 2020. Limited evidence exists to inform decision-makers on HZ incidence in high-risk patients in Europe. This systematic literature review (SLR) assessed HZ incidence across 14 high-risk populations in the European Union/European Economic Area, Switzerland, and the United Kingdom.

An SLR (Embase, Medline, 2002-2022, observational studies) was performed to identify HZ incidence (i.e., primary outcomes: rate or cumulative; secondary: relative incidence) in type 1 and 2 diabetes mellitus (DM); chronic obstructive pulmonary disease and asthma; depression; rheumatic disorders (RD); multiple sclerosis (MS); inflammatory bowel diseases (IBD); psoriasis; lupus; human immunodeficiency virus (HIV); solid organ transplantation (SOT); solid organ malignancy (SOM); hematologic malignancy (HM); and stem cell transplantation (SCT).

Of 776 unique records screened, 59 studies were included (24 reported incidence rate per 1000 person-years; two, cumulative incidence per 1000 persons; and 33, relative incidence). The highest incidence rates were reported for SOT (12.1-78.8) and SCT (37.2-56.1); HM (2.9-32.0); RD (0.41-21.5); lupus (11.0-16.5); IC mixed population (11.3-15.5); HIV/AIDS (11.8-13.0); chronic respiratory diseases (4.7-11.4); SOM (8.8-11.0); IBD (7.0-10.8); DM (4.3-9.4); depression (7.2-7.6); MS (5.7-6.3); and psoriasis (5.3-6.1). In many high-risk populations, HZ incidence was higher for older age groups, women, and some treatments.

The HZ incidence rate in Europe increased with age and varied across high-risk populations, with high rates for solid organ and stem cell transplants, cancer, and rheumatoid arthritis. Most studies were retrospective with methodological differences affecting generalizability and comparability. Future studies should stratify data by IC population, age, sex, severity, medication, and study timeframe.

Real-world data on tofacitinib (TOF) covering a period of more than 1 year for a sufficient number of Asian patients with ulcerative colitis (UC) are scarce.

To investigate the long-term efficacy and safety of TOF treatment for UC, including clinical issues.

We performed a retrospective single-center observational analysis of 111 UC patients administered TOF at Hyogo Medical University as a tertiary inflammatory bowel disease center. All consecutive UC patients who received TOF between May 2018 and February 2020 were enrolled. Patients were followed up until August 2020. The primary outcome was the clinical response rate at week 8. Secondary outcomes included clinical remission at week 8, cumulative persistence rate of TOF administration, colectomy-free survival, relapse after tapering of TOF and predictors of clinical response at week 8 and week 48.

The clinical response and remission rates were 66.3% and 50.5% at week 8, and 47.1% and 43.5% at week 48, respectively. The overall cumulative clinical remission rate was 61.7% at week 48 and history of anti-tumor necrosis factor-alpha (TNF-α) agents use had no influence (P = 0.25). The cumulative TOF persistence rate at week 48 was significantly lower in patients without clinical remission than in those with remission at week 8 (30.9% vs 88.1%; P < 0.001). Baseline partial Mayo Score was significantly lower in responders vs non-responders at week 8 (odds ratio: 0.61, 95% confidence interval: 0.45-0.82, P = 0.001). Relapse occurred in 45.7% of patients after TOF tapering, and 85.7% of patients responded within 4 wk after re-increase. All 6 patients with herpes zoster (HZ) developed the infection after achieving remission by TOF.

TOF was more effective in UC patients with mild activity at baseline and its efficacy was not affected by previous treatment with anti-TNF-α agents. Most relapsed patients responded again after re-increase of TOF and nearly half relapsed after tapering off TOF. Special attention is needed for tapering and HZ.

Ulcerative proctitis (UP), though associated with high symptom burden and poor quality of life, is excluded from most of the randomized controlled trials in UC, including the OCTAVE trials. We aimed to analyse the effectiveness of tofacitinib in UP, and compare it to that in left sided colitis (LSC) and pancolitis (PC).

This was a prospective cohort study. Patients with either steroid-dependent or refractory ulcerative colitis, who received tofacitinib, were divided into three groups based on the disease extent [UP, LSC and PC]. The primary outcome was comparison of proportion of patients in clinical remission in the three groups, at weeks 8, 16 and 48. Safety outcomes were reported using incidence rate per patient year of exposure.

Clinical remission was achieved in 47%(15/32), 24%(23/94), and 43%(23/54) of patients at week 8, 56%(18/32), 37%(35/94), and 56%(30/54) of patients at week 16, and 59%(19/32), 38%(36/94), and 24%(13/54) of patients at week 48 in groups UP, LSC and PC, respectively. Corticosteroid-free clinical remission rates were significantly higher in patients in groups UP at week 48. Five (15%) patients with UP were primary non-responders to tofacitinib at week 16, while three (9%) patients had secondary loss of response at week 48. The probability of sustained clinical response was highest in patients with UP. Patients with UP had the lowest incidence of adverse effects.

The effectiveness of tofacitinib in inducing and maintaining clinical remission is greater in patients with UP compared to LSC and PC.