Abstract
Background
Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). This analysis assessed the impact of cigarette smoking on tofacitinib efficacy and safety in the UC clinical program.
Methods
Efficacy endpoints and adverse events (AEs) were evaluated by smoking status (ever smokers [current and ex-smokers] and never smokers) in the phase (P)2 induction study (baseline demographics and safety only), P3 studies (OCTAVE Induction 1&2, OCTAVE Sustain, OCTAVE Open), and P3/4b RIVETING study.
Results
This post hoc analysis included 1156 patients (ever smokers, n = 416 [36.0%; current smokers, n = 59 (5.1%); ex-smokers, n = 357 (30.9%)]; never smokers, n = 740 [64.0%]; median [range] treatment duration 654 [1–2712] and 615.5 [1–2850] days, respectively). Similar proportions of ever smokers and never smokers achieved efficacy endpoints. AEs were reported in 88.7% of ever smokers and 83.8% of never smokers. Overall, 60.6% of ever smokers had an infection (serious infections, 5.5%; herpes zoster [nonserious and serious], 10.8%; Clostridioides difficile infection, 12.0%; lower respiratory tract infection, 19.5%: corresponding values among never smokers were 53.1%, 3.9%, 6.8%, 8.5%, and 11.4%). Major adverse cardiovascular events were reported in 1.0% of ever smokers and 0.7% of never smokers and thromboembolism events (venous and arterial) in 1.0% of ever smokers and 0.9% never smokers. Deaths, malignancies (excluding non-melanoma skin cancer [NMSC]), and NMSC occurred infrequently in ever smokers (0.5%, 2.5%, and 3.7%, respectively) and never smokers (0.1%, 1.5%, and 1.0%, respectively). Colorectal cancer was reported in 0.6% of never smokers; no cases occurred in ever smokers.
Conclusions
Efficacy and safety of tofacitinib were generally similar in ever smokers and never smokers. Overall, serious AEs and, as expected, infections were more frequent in ever smokers versus never smokers. This may inform treatment selection and monitoring strategies.
ClinicalTrials.gov
NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304
Keywords: cigarette, inflammatory bowel disease, Janus kinase inhibitor, ulcerative colitis
Graphical Abstract
Graphical Abstract.
Introduction
Inflammatory bowel disease is a chronic intestinal disorder comprising Crohn’s disease and ulcerative colitis (UC), which results from interactions between genetic and environmental factors, and influences the intestinal immune response.1 Cigarette smoking is an environmental factor known to interfere with the development and clinical course of UC and Crohn’s disease in opposite ways. UC has been shown to predominantly affect nonsmokers and ex-smokers, and smoking has consistently been shown to have a protective effect against the development and severity of UC, while smokers with Crohn’s disease have a worse disease course.2 However, the protective effects of smoking are temporary, and the relative risk of developing UC increases following smoking cessation.3 Smoking represents a major cause of preventable mortality,4 and patients with inflammatory bowel disease should be advised to stop smoking due to overall harm to health.5
In several studies of biologic therapies for the treatment of inflammatory bowel disease, smoking has been recognized as a risk factor for the development of extraintestinal manifestations,6 infections,7 and colorectal cancer.8 However, it is less clear whether smoking status affects the efficacy of therapeutic options in patients with UC, with the majority of studies finding no relationship between smoking and treatment outcome.9–11 Moreover, there is anecdotal evidence to suggest that ex-smokers may have medication-resistant UC, compared with never smokers.12,13
Tofacitinib is an oral Janus kinase inhibitor for the treatment of UC. The efficacy and safety of tofacitinib were evaluated in a series of clinical trials, including a phase 2 induction study (NCT00787202), 2 identical phase 3 induction studies (OCTAVE Induction 1 and 2; NCT01465763 and NCT01458951), a phase 3 maintenance study (OCTAVE Sustain; NCT01458574), an open-label, long-term extension study (OCTAVE Open; NCT01470612), and a phase 3b/4 study (RIVETING; NCT03281304).14–18 Here, we investigated the impact of smoking status on the efficacy and safety of tofacitinib 5 or 10 mg twice-daily (BID) treatment in the UC clinical program.
Methods
Patients and Studies
This post hoc analysis included data from the tofacitinib UC clinical program, and the detailed study design of each study has previously been reported.14–18 Briefly, in the phase 2 induction study, patients (aged ≥18 years) with moderately to severely active UC were randomized to receive placebo or tofacitinib 0.5, 3, 10, or 15 mg BID.14 Only patients who received tofacitinib 10 mg BID in the phase 2 induction study are included in this analysis. In OCTAVE Induction 1 and 2, patients (aged ≥18 years) with moderately to severely active UC, who had previously failed, or were intolerant to, treatment with corticosteroids, immunosuppressants, and/or tumor necrosis factor inhibitors (TNFi), were randomized to receive placebo or tofacitinib 10 or 15 mg BID. Randomization to tofacitinib 15 mg BID was discontinued following a protocol amendment; therefore, this analysis only included those patients in the OCTAVE Induction 1 and 2 studies randomized to receive placebo or tofacitinib 10 mg BID.15 Patients who completed OCTAVE Induction 1 and 2 with a clinical response (a decrease from induction study baseline Mayo score of ≥3 points and ≥30%, plus a decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1) were eligible to enroll into OCTAVE Sustain. In OCTAVE Sustain, patients were re-randomized to receive placebo or tofacitinib 5 or 10 mg BID.15 OCTAVE Open was an open-label, long-term extension study (≤7.0 years of treatment) that enrolled patients who completed OCTAVE Induction 1 or 2 without a clinical response (nonresponders), and patients who had either completed OCTAVE Sustain or withdrawn early after experiencing treatment failure (an increase from OCTAVE Sustain baseline total Mayo score of ≥3 points, plus an increase in rectal bleeding subscore and endoscopic subscore of ≥1 point, after ≥8 weeks of treatment).16 Dose assignment in OCTAVE Open was based on remission (total Mayo score of ≤2 with no individual subscore >1, and a rectal bleeding subscore of 0) status at baseline; patients in remission received tofacitinib 5 mg BID, and all others received 10 mg BID. Patients from OCTAVE Open who had received tofacitinib 10 mg BID for ≥2 consecutive years, were in stable remission for ≥6 months, and corticosteroid free for ≥4 weeks, were eligible to enroll in RIVETING, and were randomized to receive tofacitinib 5 or 10 mg BID.17
Efficacy Assessments
Efficacy endpoints were derived from Mayo scores and were based on centrally read endoscopic subscores in OCTAVE Induction 1 and 2, and OCTAVE Sustain, and were derived from locally read endoscopic subscores in OCTAVE Open and RIVETING. Efficacy endpoints were reported at week 8 of OCTAVE Induction 1 and 2, week 52 of OCTAVE Sustain, month 36 of OCTAVE Open, and month 6 of RIVETING.
Efficacy endpoints in all trials included clinical response, endoscopic improvement (Mayo endoscopic subscore of 0 or 1; defined as mucosal healing in the study protocols), remission, and partial Mayo score remission (partial Mayo score of ≤2 with no individual subscore >1). Efficacy endpoints were summarized by initial treatment allocation.
Safety Assessments
Safety endpoints evaluated in this analysis included treatment-emergent adverse events (AEs), serious AEs (SAEs; an AE that was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, or resulted in a persistent or significant disability/incapacity, a congenital anomaly/birth defect, or death), and selected AEs of interest in cigarette smokers (which included serious infections [infections meeting SAE-reporting criteria or that required parenteral antimicrobial therapy], opportunistic infections [excluding tuberculosis and herpes zoster with 2 adjacent dermatomes], herpes zoster, tuberculosis, malignancies [excluding non-melanoma skin cancer (NMSC)], NMSC, major adverse cardiovascular events [MACE], venous thromboembolic events, and arterial thromboembolic events). Opportunistic infections, tuberculosis, malignancies, and cardiovascular events were evaluated by adjudication committees.
Safety was assessed in all patients who received ≥1 dose of tofacitinib 5 or 10 mg BID in any study included in the analysis. Patients were characterized based on the average daily tofacitinib dose: A predominant dose (PD) of tofacitinib 5 mg BID (an average daily dose <15 mg) and a PD of tofacitinib 10 mg BID (an average daily dose ≥15 mg).
Statistical Analysis
Data are described descriptively. Efficacy and safety data were summarized by induction study baseline cigarette smoking status; patients were classified as ever smokers (current smoker or ex-smoker) or never smokers.
The proportions of patients meeting efficacy endpoints are reported for the full analysis set (all patients who received ≥1 dose of placebo or tofacitinib 5 or 10 mg BID in any study, excluding the phase 2 induction study). Patients with missing data in OCTAVE Induction 1 and 2, OCTAVE Sustain, and RIVETING were treated as nonresponders. In OCTAVE Open, patients with missing data were treated as nonresponders, but with the last observation carried forward after a patient advanced to a follow-up study.
The proportion of patients with treatment-emergent AEs, SAEs, and selected AEs of interest was calculated. Events were counted up to 28 days after the last dose of study treatment.
Results
Baseline Demographics and Clinical Characteristics
This analysis included 1156 patients; at induction study baseline, 416 (36.0%) were ever smokers (current smokers, n = 59 [5.1%]; ex-smokers, n = 357 [30.9%]) and 740 (64.0%) were never smokers (Table 1). Overall, in current smokers, the mean duration of smoking was 15.4 years and the majority (53.4%) had smoked for >10 years (Table S1). Overall, in ex-smokers, patients had stopped smoking for a mean duration of 12.3 years; more patients had stopped smoking for >10 years (42.9%) than >0–5 years (32.0%) and >5–10 years (25.1%). Moreover, overall, ex-smokers had smoked for a mean duration of 15.5 years, with the majority (62.1%) smoking for >10 years (Table S1). Baseline disease activity characteristics were generally similar between ever smokers and never smokers, although ever smokers were more often male, older, more likely to have longer disease duration, prior TNFi use, a prior history of myocardial infarction, diabetes mellitus, or ischemic or coronary heart disease, and more likely to have comorbid chronic obstructive pulmonary disease (COPD), compared with never smokers (Table 1).
Table 1.
Baseline demographics and clinical characteristics in the tofacitinib UC clinical program, by cigarette smoking status.
| Ever smokers | Never smokers | |||||
|---|---|---|---|---|---|---|
| PD tofacitinib 5 mg BID | PD tofacitinib 10 mg BID | Tofacitinib all | PD tofacitinib 5 mg BID | PD tofacitinib 10 mg BID | Tofacitinib all | |
| Female, n/N (%)a | 25/63 (39.7) | 126/353 (35.7) | 151/416 (36.3) | 61/139 (43.9) | 266/601 (44.3) | 327/740 (44.2) |
| Age (years), mean (SD)b | 50.3 (14.3) | 46.4 (13.5) | 47.0 (13.6) | 41.9 (13.8) | 37.2 (12.6) | 38.0 (12.9) |
| [N] | [63] | [353] | [416] | [139] | [601] | [740] |
| Race, n/N (%) | ||||||
| White | 45/63 (71.4) | 283/353 (80.2) | 328/416 (78.8) | 115/139 (82.7) | 483/601 (80.4) | 598/740 (80.8) |
| Black | 0/63 (0.0) | 3/353 (0.8) | 3/416 (0.7) | 1/139 (0.7) | 6/601 (1.0) | 7/740 (0.9) |
| Asian | 11/63 (17.5) | 43/353 (12.2) | 54/416 (13.0) | 17/139 (12.2) | 73/601 (12.1) | 90/740 (12.2) |
| Other | 5/63 (7.9) | 7/353 (2.0) | 12/416 (2.9) | 4/139 (2.9) | 26/601 (4.3) | 30/740 (4.1) |
| Unknown | 2/63 (3.2) | 17/353 (4.8) | 19/416 (4.6) | 2/139 (1.4) | 13/601 (2.2) | 15/740 (2.0) |
| BMI (kg/m2), mean (SD)b | 26.8 (6.5) | 25.9 (4.8) | 26.1 (5.1) | 24.5 (4.7) | 24.1 (4.8) | 24.2 (4.8) |
| [N] | [63] | [353] | [416] | [139] | [600] | [739] |
| Total Mayo scoreb | ||||||
| Mean (SD) | 7.9 (2.6) | 8.9 (1.9) | 8.7 (2.0) | 7.8 (2.5) | 8.7 (1.7) | 8.5 (1.9) |
| [N] | [63] | [352] | [415] | [139] | [600] | [739] |
| ≥3, n/N (%) | 58/63 (92.1) | 346/352 (98.3) | 404/415 (97.3) | 131/139 (94.2) | 595/600 (99.2) | 726/739 (98.2) |
| Partial Mayo scoreb | ||||||
| Mean (SD) | 5.5 (2.1) | 6.3 (1.6) | 6.1 (1.7) | 5.5 (2.0) | 6.1 (1.5) | 6.0 (1.6) |
| [N] | [63] | [352] | [415] | [139] | [600] | [739] |
| ≥2, n/N (%) | 57/63 (90.5) | 344/352 (97.7) | 401/415 (96.6) | 128/139 (92.1) | 593/600 (98.8) | 721/739 (97.6) |
| Mayo endoscopic scoreb | ||||||
| Mean (SD) | 2.4 (0.7) | 2.6 (0.5) | 2.6 (0.6) | 2.4 (0.7) | 2.6 (0.5) | 2.6 (0.6) |
| [N] | [63] | [353] | [416] | [139] | [601] | [740] |
| ≥2, n/N (%) | 58/63 (92.1) | 347/353 (98.3) | 405/416 (97.4) | 128/139 (92.1) | 595/601 (99.0) | 723/740 (97.7) |
| Baseline C-reactive protein, mg/La | ||||||
| Mean (SD) | 4.2 (5.2) | 11.8 (18.4) | 10.6 (17.2) | 10.7 (19.4) | 11.1 (17.8) | 11.0 (18.1) |
| [N] | [63] | [347] | [410] | [136] | [594] | [730] |
| >3, n/N (%) | 25/63 (39.7) | 241/347 (69.5) | 266/410 (64.9) | 78/136 (57.4) | 377/594 (63.5) | 455/730 (62.3) |
| >6, n/N (%) | 14/63 (22.2) | 170/347 (49.0) | 184/410 (44.9) | 45/136 (33.1) | 252/594 (42.4) | 297/730 (40.7) |
| Extent of disease, n/N (%)a | ||||||
| Proctosigmoiditis | 12/62 (19.4) | 59/344 (17.2) | 71/406 (17.5) | 22/139 (15.8) | 70/576 (12.2) | 92/715 (12.9) |
| Left-sided colitis | 26/62 (41.9) | 116/344 (33.7) | 142/406 (35.0) | 43/139 (30.9) | 195/576 (33.9) | 238/715 (33.3) |
| Extensive colitis/pancolitis | 24/62 (38.7) | 168/344 (48.8) | 192/406 (47.3) | 74/139 (53.2) | 311/576 (54.0) | 385/715 (53.8) |
| Proctitis | 0/62 (0.0) | 1/344 (0.3)c | 1/406 (0.2)c | 0/139 (0.0) | 0/576 (0.0) | 0/715 (0.0) |
| Disease duration ≥6 years, n/N (%)b | 35/63 (55.6) | 208/353 (58.9) | 243/416 (58.4) | 72/139 (51.8) | 289/601 (48.1) | 361/740 (48.8) |
| Baseline corticosteroid use, n/N (%)b | 26/63 (46.0) | 157/353 (44.5) | 186/416 (44.7) | 53/139 (38.1) | 284/601 (47.3) | 337/740 (45.5) |
| Prior corticosteroid use, n/N (%)a | 59/63 (93.7) | 311/353 (90.1) | 370/416 (90.7) | 126/139 (90.6) | 520/601 (90.1) | 646/740 (90.2) |
| Prior TNFi use, n/N (%)a,d | 29/63 (46.0) | 218/345 (63.2) | 247/408 (60.5) | 62/139 (44.6) | 303/577 (52.5) | 365/16 (51.0) |
| Prior TNFi failure, n/N (%)a,d | 26/63 (41.3) | 211/345 (61.2) | 237/408 (58.1) | 58/139 (41.7) | 288/577 (49.9) | 346/16 (48.3) |
| Prior immunosuppressant use, n/N (%)a,d | 48/63 (76.2) | 269/345 (78.0) | 317/408 (77.7) | 89/139 (64.0) | 432/577 (74.9) | 521/16 (72.8) |
| Prior immunosuppressant failure, n/N (%)a,d | 46/63 (73.0) | 262/345 (75.9) | 308/408 (75.5) | 85/139 (61.2) | 420/577 (72.8) | 505/16 (70.5) |
| Medical historyb | ||||||
| History of myocardial infarction, n/N (%) | 3/63 (4.8) | 5/353 (1.4) | 8/416 (1.9) | 1/139 (0.7) | 2/601 (0.3) | 3/740 (0.4) |
| History of diabetes mellitus, n/N (%) | 6/63 (9.5) | 23/353 (6.5) | 29/416 (7.0) | 4/139 (2.9) | 14/601 (2.3) | 18/740 (2.4) |
| History of ischemic heart disease, n/N (%) | 3/63 (4.8) | 9/353 (2.5) | 12/416 (2.9) | 2/139 (1.4) | 7/601 (1.2) | 9/740 (1.2) |
| History of coronary heart disease, n/N (%) | 0/63 (0.0) | 6/353 (1.7) | 6/416 (1.4) | 0/139 (0.0) | 1/601 (0.2) | 1/740 (0.1) |
| Smoking history | ||||||
| Time since started smoking (years), mean (SD); median [min–max]d,e |
12.4 (6.8); 13.0 [5.0–20.0] |
15.7 (10.2); 15.0 [3.0–50.0] |
15.4 (10.0); 14.5 [3.0–50.0] |
NA | NA | NA |
| [N] | [5] | [53] | [58] | |||
| Time since stopped smoking (years), mean (SD); median [min–max]d,f | 14.7 (11.2); 13.0 [1.0–48.0] |
12.4 (10.0); 10.0 [0.0–46.0] |
12.8 (10.2); 10.0 [0.0–48.0] |
NA | NA | NA |
| [N] | [58] | [292] | [350] | |||
| COPD status, n/N (%)b | ||||||
| Yes | 1/63 (1.6) | 9/353 (2.5) | 10/416 (2.4) | 0/139 (0.0) | 1/601 (0.2) | 1/740 (0.1) |
| No | 62/63 (98.4) | 344/353 (97.5) | 406/416 (97.6) | 139/139 (100) | 600/601 (99.8) | 739/740 (99.9) |
Abbreviations: BID, twice daily; BMI, body mass index; COPD, chronic obstructive pulmonary disease, N, number of patients treated in the treatment group; n, number of patients in the specified category; NA, not applicable; PD, predominant dose; SD, standard deviation; TNFi, tumor necrosis factor inhibitor; UC, ulcerative colitis.
aData are from screening of phase 2 or phase 3 induction studies (OCTAVE Induction 1 and 2).
bData are from day 1 (start of active treatment in the tofacitinib UC clinical program).
cThis patient was enrolled as a protocol deviation.
dExcludes phase 2.
eCurrent smokers only.
fEx-smokers only.
Efficacy
For both ever smokers and never smokers, a numerically higher proportion of tofacitinib-treated patients achieved efficacy endpoints, compared with placebo-treated patients, at week 8 of OCTAVE Induction 1 and 2 and week 52 of OCTAVE Sustain (Figure 1A and 1B). When stratified by smoking status, the proportions of tofacitinib-treated patients who achieved efficacy endpoints at week 8 of OCTAVE Induction 1 and 2 and week 52 of OCTAVE Sustain, were generally similar in ever smokers and never smokers. In OCTAVE Induction 1 and 2, the treatment effect of tofacitinib 10 mg BID versus placebo for remission was greater in never smokers versus ever smokers.
Figure 1.
Proportion of patients who achieved efficacy endpoints in (A) OCTAVE Induction 1 and 2, (B) OCTAVE Sustain, (C) OCTAVE Open, and (D) RIVETING, by smoking status (full analysis set). Abbreviations: BID, twice daily; N, number of patients in the specified category with nonmissing data; n, number of patients with the specified response within the given category; PMS, partial Mayo score. Cigarette smoking status was determined at the baseline of the induction studies. aCentral read endoscopy. bNonresponder imputation was applied after a patient discontinued. cLocal read endoscopy. dNonresponder imputation, last observation carried forward was applied after a patient discontinued and the patient advanced to a subsequent study up to the visit they would have reached if that had stayed in the study. ePatients with missing scores were treated as nonresponders. Patients in the tofacitinib 5 mg BID group with dose escalation were treated as nonresponders for visits after dose escalation.
At month 36 of OCTAVE Open, a numerically higher proportion of patients treated with tofacitinib 5 mg BID achieved efficacy endpoints compared with tofacitinib 10 mg BID (Figure 1C). Conversely, at month 6 of RIVETING, a numerically higher proportion of patients treated with tofacitinib 10 mg BID achieved efficacy endpoints compared with tofacitinib 5 mg BID (Figure 1D). However, smoking status did not affect the achievement of efficacy endpoints in OCTAVE Open and RIVETING.
When stratified by prior TNFi exposure status, the proportion of patients who achieved efficacy endpoints was generally higher in patients without prior TNFi exposure than those with prior TNFi exposure, regardless of smoking status (Figure S1, Supplementary Data Content). This observation was consistent across OCTAVE studies, regardless of treatment (tofacitinib 5 or 10 mg BID, or placebo).
Safety
SAEs occurred with similar frequency among treatment groups (tofacitinib 5 mg BID and tofacitinib 10 mg BID), regardless of smoking status. Overall, SAEs occurred with a higher frequency in ever smokers versus never smokers (Table 2).
Table 2.
Summary of safety in the tofacitinib UC clinical program, by cigarette smoking status.
| Ever smokers | Never smokers | |||||
|---|---|---|---|---|---|---|
| PD tofacitinib 5 mg BID N = 63 |
PD tofacitinib 10 mg BID N = 353 |
Tofacitinib all N = 416 |
PD tofacitinib 5 mg BID N = 139 |
PD tofacitinib 10 mg BID N = 601 |
Tofacitinib all N = 740 |
|
| Total patient-years of exposure | 249.1 | 854.3 | 1103.4 | 534.0 | 1362.1 | 1896.1 |
| Treatment duration (days), median (range) | 1504 (52–2712) |
506 (1–2694) |
654 (1–2712) |
1,684 (57–2850) |
376 (1–2758) |
615.5 (1–2850) |
| Treatment-emergent AEs | ||||||
| Patients with AEs, n (%) | 62 (98.4) | 307 (87.0) | 369 (88.7) | 127 (91.4) | 493 (82.0) | 620 (83.8) |
| Patients with SAEs, n (%) | 16 (25.4) | 88 (24.9) | 104 (25.0) | 25 (18.0) | 106 (17.6) | 131 (17.7) |
| Deaths, n (%) | 0 (0.0) | 2 (0.6) | 2 (0.5) | 0 (0.0) | 1 (0.2) | 1 (0.1) |
| Discontinuation due to AEs, n (%) | 12 (19.0) | 99 (28.0) | 111 (26.7) | 27 (19.4) | 141 (23.5) | 168 (22.7) |
| Most common reasons for discontinuation: | ||||||
| Worsening UC | 2 (3.2) | 53 (15.0) | 55 (13.2) | 12 (8.6) | 69 (11.5) | 81 (10.9) |
| Lymphopenia | 0 (0.0) | 2 (0.6) | 2 (0.5) | 2 (1.4) | 4 (0.7) | 6 (0.8) |
| Anemia | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.7) | 4 (0.7) | 5 (0.7) |
| Anal abscess | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 4 (0.7) | 4 (0.5) |
Abbreviations: AE, adverse event; BID, twice daily; N, number of patients treated in the treatment group; n, number of patients in the specified category; PD, predominant dose; SAE, serious AE; UC, ulcerative colitis.
Deaths
Overall, there were 3 deaths: 2 patients were ever smokers and 1 patient had never smoked; all patients were in the PD of tofacitinib 10 mg BID group. The cause of death in the never smoker was an aortic dissection (not considered to be treatment related). The 2 ever smoker patients were ex-smokers, and causes of death (considered to be treatment related) were recorded as hepatic angiosarcoma in the first patient and pulmonary embolism secondary to metastatic cholangiocarcinoma in the second patient.
Selected AEs of interest in cigarette smokers
Extraintestinal manifestations were reported in 101 (24.8%) ever smokers and 148 (20.7%) never smokers (Table 3).
Table 3.
Proportions of selected AEs of interest in cigarette smokersa in the tofacitinib UC clinical program.
| Ever smokers | Never smokers | |||||
|---|---|---|---|---|---|---|
| PD tofacitinib 5 mg BID N = 63 |
PD tofacitinib 10 mg BID N = 353 |
Tofacitinib all N = 416 |
PD tofacitinib 5 mg BID N = 139 |
PD tofacitinib 10 mg BID N = 601 |
Tofacitinib all N = 740 |
|
| Extraintestinal manifestations, n (%)b | 15 (23.8) | 86 (24.9) | 101 (24.8) | 32 (23.0) | 116 (20.1) | 148 (20.7) |
| Infections, n (%) | ||||||
| All infections | 47 (74.6) | 205 (58.1) | 252 (60.6) | 89 (64.0) | 304 (50.6) | 393 (53.1) |
| Serious infections | 4 (6.3) | 19 (5.4) | 23 (5.5) | 6 (4.3) | 23 (3.8) | 29 (3.9) |
| Herpes zoster (nonserious and serious) | 8 (12.7) | 37 (10.5) | 45 (10.8) | 14 (10.1) | 36 (6.0) | 50 (6.8) |
| Opportunistic infectionsb,c,d | 4 (6.3) | 9 (2.6) | 13 (3.2) | 4 (2.9) | 14 (2.4) | 18 (2.5) |
| Clostridioides difficile infection | 8 (12.7) | 42 (11.9) | 50 (12.0) | 13 (9.4) | 50 (8.3) | 63 (8.5) |
| Lower respiratory tract infection | 18 (28.6) | 63 (17.8) | 81 (19.5) | 24 (17.3) | 60 (10.0) | 84 (11.4) |
| MACE, n (%)b,c | 2 (3.2) | 2 (0.6) | 4 (1.0) | 2 (1.4) | 3 (0.5) | 5 (0.7) |
| Malignancies, n (%)b,c,e | ||||||
| Malignancies (excluding NMSC) | 2 (3.2) | 8 (2.3) | 10 (2.5) | 1 (0.7) | 10 (1.7) | 11 (1.5) |
| Colorectal cancer | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 4 (0.7) | 4 (0.6) |
| Lung cancer | 0 (0.0) | 1 (0.3) | 1 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Breast cancer | 1 (1.6) | 1 (0.3) | 2 (0.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Lymphoma and lymphoproliferative disease | 0 (0.0) | 1 (0.3) | 1 (0.2) | 1 (0.7) | 0 (0.0) | 1 (0.1) |
| Melanoma | 0 (0.0) | 1 (0.3) | 1 (0.2) | 0 (0.0) | 1 (0.2) | 1 (0.1) |
| NMSC | 4 (6.3) | 11 (3.2) | 15 (3.7) | 1 (0.7) | 6 (1.0) | 7 (1.0) |
| Thromboembolic events, n (%) | ||||||
| Thromboembolism | 1 (1.6) | 3 (0.8) | 4 (1.0) | 2 (1.4) | 5 (0.8) | 7 (0.9) |
| Deep vein thrombosisf | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.2) | 1 (0.1) |
| Pulmonary embolismf | 0 (0.0) | 2 (0.6) | 2 (0.5) | 0 (0.0) | 4 (0.7) | 4 (0.5) |
| Arterial thromboembolismg | 1 (1.6) | 1 (0.3) | 2 (0.5) | 2 (1.4) | 0 (0.0) | 2 (0.3) |
Abbreviations: AE, adverse event; BID, twice daily; MACE, major adverse cardiovascular events; MedDRA, Medical Dictionary for Regulatory Activities; N, number of patients treated in the treatment group; n, number of patients in the specified category; NMSC, non-melanoma skin cancer; PD, predominant dose; UC, ulcerative colitis.
aEvents that occurred >28 days after the last dose of study drug were excluded.
bExcludes data from phase 2 (ever smokers: PD tofacitinib 10 mg BID, N = 345; tofacitinib all, N = 408; and never smokers: PD tofacitinib 10 mg BID, N = 577; tofacitinib all, N = 716).
cAdjudicated events.
dExcludes tuberculosis and herpes zoster with 2 adjacent dermatomes.
eNo events of pancreatic cancer or prostate cancer.
fAdjudicated events from OCTAVE Open and RIVETING, plus selected events from the phase 2 induction study, OCTAVE Induction 1 and 2, and OCTAVE Sustain, from the narrow Standardized MedDRA query for embolic and thrombotic events.
gSelected events from the narrow Standardized MedDRA query for embolic and thrombotic events (v23.0).
Overall, 252 (60.6%) ever smokers and 393 (53.1%) never smokers had an infection (classified as any infection), of which 23 (5.5%) and 29 (3.9%) were serious infections, respectively. In total, 45 (10.8%) ever smokers and 50 (6.8%) never smokers had herpes zoster (nonserious and serious); 50 (12.0%) ever smokers and 63 (8.5%) never smokers had a Clostridioides difficile infection; and 81 (19.5%) ever smokers and 84 (11.4%) never smokers had a lower respiratory tract infection. Adjudicated opportunistic infections (excluding tuberculosis and herpes zoster with 2 adjacent dermatomes) were reported in 13 (3.2%) ever smokers and 18 (2.5%) never smokers; there were no reported cases of tuberculosis.
Adjudicated MACE were reported in 4 (1.0%) ever smokers and 5 (0.7%) never smokers. Among the ever smokers, 2 (0.5%) patients had a pulmonary embolism, and, among never smokers, 1 (0.1%) patient had a deep vein thrombosis and 4 (0.5%) patients had a pulmonary embolism; all patients were in the PD of tofacitinib 10 mg BID group. Two (0.5%) ever smokers and 2 (0.3%) never smokers had arterial thromboembolism.
Malignancies (excluding NMSC) occurred in 10 (2.5%) ever smokers and 11 (1.5%) never smokers. Malignancies in patients who were ever smokers included 2 patients with breast cancer and 1 patient each with lung cancer, lymphoma or lymphoproliferative disease, and melanoma; and in never smokers included 4 patients with colorectal cancer, and 1 patient each with lymphoma or lymphoproliferative disease and melanoma. Overall, NMSC was reported in 15 (3.7%) ever smokers and 7 (1.0%) never smokers.
Discussion
In this post hoc descriptive analysis of data from the tofacitinib UC clinical program (including 1156 patients), we demonstrated that tofacitinib efficacy and safety were generally similar in ever smokers and never smokers of cigarettes, but it is noted that overall, SAEs and infections were more frequent in ever smokers versus never smokers.
Cigarette smoking is recognized to interfere with the course of UC; some studies have noted that active smoking results in a more benign course of disease compared with nonsmokers, and smoking cessation may be associated with new-onset UC and may negatively impact the course of the disease.3 Smoking was not predictive of the primary response to TNFi or vedolizumab in a systematic review of patients with inflammatory bowel disease.19 Conversely, real-world data from patients with UC treated with vedolizumab demonstrated that current or former smoking was significantly associated with clinical remission at week 14.20
The treatment effect of tofacitinib compared with placebo in OCTAVE Induction 1 and 2, and OCTAVE Sustain, has previously been reported.15 The data reported here demonstrate that, when stratified by smoking status, generally similar proportions of patients achieved efficacy endpoints.
In the general population, smoking is a known risk factor for infections.21 A retrospective review of safety data from patients with inflammatory bowel disease treated with vedolizumab noted that active smokers were more likely to have respiratory infections and active smoking was independently associated with developing an infection; active smokers also had a 3-fold increased risk for infections with vedolizumab.7 In contrast, a numerically similar proportion of ever smokers and never smokers had lower respiratory tract infections in this study, although it should be noted that the ever smoker group consisted predominantly of ex-smokers and not current smokers. Previous analyses of data from the tofacitinib UC clinical program showed an elevated risk of herpes zoster in patients with UC receiving tofacitinib compared with placebo and, in univariate analyses but not in a multivariate analysis, smoking was identified as a risk factor for herpes zoster.22 However, in this study, the proportion of patients who had herpes zoster (nonserious and serious) was numerically similar in ever smokers and never smokers. Inflammatory bowel disease itself has been shown to be an independent risk factor for the development of C. difficile infection.23,24 In addition, the incidence rates of C. difficile infection have been reported to be higher in current smokers compared with ex-smokers and never smokers, and similar between ex-smokers and never smokers.25 In comparison, in this analysis, a numerically similar proportion of ever smokers and never smokers had a C. difficile infection.
Smoking is also associated with a risk of serious chronic disorders, including cardiovascular disorders, lung disease, COPD, and many forms of cancer.26–28 Malignancies (excluding NMSC), NMSC, MACE, and venous thromboembolic events occurred infrequently in the tofacitinib UC clinical program, details of which have previously been reported.17,18,29–31 In our study, the proportions of patients with these AEs were numerically similar between ever smokers and never smokers. Of note, the small sample size, duration of follow-up, and the relatively young age of patients, without a prominent risk profile, render the patient population suboptimal to explore the impact of smoking on MACE and pulmonary embolism events. Colorectal cancer is a severe complication of UC, and in a retrospective cohort study of patients with UC, smoking was identified as the main risk factor for the development of colorectal cancer.8 Interestingly, in our study cohort, 4 never smokers had colorectal cancer, although this finding should be interpreted with caution due to the small number of patients included in this analysis.
An important component of the impact of UC is the development of extraintestinal manifestations,32 and these have been shown to be associated with active smoking.6 Data from a retrospective safety analysis of patients with UC treated with vedolizumab reported that active smokers at the time of vedolizumab initiation had an increased risk of noninfectious AEs; however, in this study, a numerically similar proportion of ever smokers and never smokers reported extraintestinal manifestations.
This study has some limitations. The studies included in this analysis were not designed to assess the impact of smoking status, and all assessments are descriptive, with no formal statistical analysis. Most patients in the ever smoker group were ex-smokers, and the number of current smokers was low; therefore, a robust analysis of the ever smokers stratified by current smokers and ex-smokers was not feasible (Tables S2 and S3, Supplementary Data Content). Consequently, these data should be interpreted with caution. However, it is noteworthy that the baseline clinical characteristics for the ever smoker group show that within the current smoker and ex-smoker subgroups, the time since smoking initiation, and the time since smoking cessation, respectively, varied widely. Therefore, this also suggests that analysis of data stratified by current and ex-smokers should be interpreted with caution, due to the heterogeneity within subgroups. Additionally, factors such as the degree of smoking (pack-years or dose exposure), time between smoking cessation and UC diagnosis, time between smoking cessation and initiation of tofacitinib, and smoking of other substances beyond cigarettes (eg, e-cigarettes, noncommercial tobacco) were not collected during the studies. Efficacy analyses were not adjusted for characteristics such as age and disease duration, and the low number of some AEs limits the interpretation of these data. Baseline differences between the ever smokers and never smokers in factors known to impact infection risk (eg, age, disease duration, treatment history, and comorbid COPD) were not adjusted for in this analysis.
Conclusions
This post hoc analysis of data from the tofacitinib UC clinical program suggested that tofacitinib efficacy and safety in patients with UC were generally similar in ever smokers and never smokers. Overall, SAEs and infections were more frequent in ever smokers versus never smokers; however, at baseline, there were differences in factors known to impact infection risk between the 2 groups. These findings may inform treatment selection and monitoring strategies in patients with UC and support the recommendation to stop or refrain from cigarette smoking.
Supplementary Material
Contributor Information
David T Rubin, Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA.
Joana Torres, Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal; Division of Gastroenterology, Hospital da Luz, Lisbon, Portugal; Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
Miguel Regueiro, Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, OH, USA.
Walter Reinisch, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Lani Prideaux, Department of Gastroenterology and Hepatology, Monash Medical Centre, Melbourne, Victoria, Australia.
Paulo G Kotze, IBD Outpatient Clinics, Colorectal Surgery Unit, Catholic University of Paraná, Curitiba, Brazil.
Fiona H Tan, Pfizer Australia, Melbourne, Victoria, Australia.
Sean Gardiner, Pfizer Inc, New York, NY, USA.
Rajiv Mundayat, Pfizer Inc, New York, NY, USA.
Mary Jane Cadatal, Pfizer Inc, Manila, Philippines.
Siew C Ng, Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, Chinese University of Hong Kong, Sha Tin, Hong Kong, China.
Author Contributions
F.H.T. and S.G. conceived and designed the study. R.M. and M.J.C. analyzed and interpreted the data. All authors critically revised the manuscript for important intellectual content and approved the final version of the manuscript for submission.
Funding
This study was sponsored by Pfizer. Medical writing support was funded by Pfizer.
Conflicts of Interest
D.T.R. has received grant support from Takeda and has served as a consultant for AbbVie, AltruBio, Arena Pharmaceuticals, Bellatrix Pharmaceuticals, Boehringer Ingelheim Ltd., Bristol Myers Squibb, Dizal Pharmaceuticals, Galapagos, Ichnos Sciences, InDex Pharmaceuticals, Iterative Health, Janssen Pharmaceuticals, Lilly, Pfizer Inc, Prometheus Biosciences, Reistone, S.A., and Syneos.
J.T. has served as an advisory board member for AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Galapagos, Janssen, and Pfizer Inc, has received research funding from AbbVie and Janssen, and has received lecture fees from AbbVie, Galapagos, Janssen, and Pfizer Inc.
M.R. has served as an advisory board member or consultant for AbbVie, Amgen, Celgene, Janssen, Miraca Labs, Pfizer Inc, Seres Therapeutics, Takeda, and UCB, has received research funding from AbbVie, Janssen, and Takeda, and has received unrestricted educational grants from AbbVie, Janssen, Pfizer Inc, Salix, Shire, Takeda, and UCB.
W.R. has served as a speaker for AbbVie, Celltrion, Falk Pharma GmbH, Ferring, Galapagos, Janssen, MSD, Pfizer Inc, Pharmacosmos, Roche, Shire, Takeda, and Therakos, has served as a consultant for AbbVie, Amgen, AOP Orphan, Arena Pharmaceuticals, Astellas, AstraZeneca, Bioclinica, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celgene, Celltrion, Eli Lilly, Falk Pharma GmbH, Ferring, Galapagos, Gatehouse Bio Inc, Genentech, Gilead Sciences, Grünenthal, ICON, InDex Pharmaceuticals, Inova, Janssen, Landos Biopharma, MedAhead, MedImmune, Microbiotica, Mitsubishi Tanabe Pharma Corporation, MSD, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pfizer Inc, Pharmacosmos, Protagonist, Provention, Quell Therapeutics, Sandoz, Seres Therapeutics, SetPoint Medical, Sigmoid, Sublimity, Takeda, Teva Pharmaceuticals, Therakos, Theravance, and Zealand, has served as an advisory board member for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Galapagos, Janssen, Mitsubishi Tanabe Pharma Corporation, MSD, Pharmacosmos, Pfizer Inc, Sandoz, and Takeda, and has received research funding from AbbVie, Janssen, MSD, Sandoz, Sanofi, and Takeda.
L.P. has no conflicts of interest to declare.
P.G.K. has served as a consultant or speaker for AbbVie, Janssen, Pfizer Inc, and Takeda, and has received research funding from Pfizer Inc and Takeda.
F.H.T., S.G., R.M., and M.J.C. are employees and stockholders of Pfizer Inc.
S.C.N. has served as a speaker for AbbVie, Ferring, Janssen, Menarini, Pfizer Inc, Takeda, and Tillotts, has received research funding from AbbVie, Ferring, and Olympus, and holds a directorship with Microbiota I-Center.
Ethical Considerations
All patients provided written informed consent, and all studies were conducted in accordance with the Declaration of Helsinki, International Council for Harmonisation Guidelines for Good Clinical Practice, and local regulations. Participating institutions provided Institutional Review Board approval prior to participation. All authors had access to the study data and reviewed and approved the final manuscript. This analysis included data from the following studies registered at ClinicalTrials.gov: phase 2 induction study (baseline demographics and safety only; NCT00787202); phase 3 studies OCTAVE Induction 1 and 2 (NCT01465763 and NCT01458951), OCTAVE Sustain (NCT01458574), and OCTAVE Open (NCT01470612); and the phase 3/4b RIVETING study (NCT03281304).
Data Availability
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results.
References
- 1. Seyedian SS, Nokhostin F, Malamir MD.. A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. J Med Life. 2019;12(2):113–122. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Lakatos PL, Szamosi T, Lakatos L.. Smoking in inflammatory bowel diseases: good, bad or ugly? World J Gastroenterol. 2007;13(46):6134–6139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Lunney PC, Leong RWL.. Review article: ulcerative colitis, smoking and nicotine therapy. Aliment Pharmacol Ther. 2012;36(11-12):997–1008. [DOI] [PubMed] [Google Scholar]
- 4. Samet JM. Tobacco smoking: the leading cause of preventable disease worldwide. Thorac Surg Clin. 2013;23(2):103–112. [DOI] [PubMed] [Google Scholar]
- 5. Lamb CA, Kennedy NA, Raine T, et al. ; IBD Guidelines eDelphi Consensus Group. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68(Suppl 3):s1–s106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Severs M, van Erp SJH, van der Valk ME, et al. ; Dutch Initiative on Crohn and Colitis. Smoking is associated with extra-intestinal manifestations in inflammatory bowel disease. J Crohns Colitis. 2016;10(4):455–461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Meserve J, Aniwan S, Koliani-Pace JL, et al. Retrospective analysis of safety of vedolizumab in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2019;17(8):1533–1540.e2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. de Campos Silva EF, Baima JP, de Barros JR, et al. Risk factors for ulcerative colitis-associated colorectal cancer: a retrospective cohort study. Medicine (Baltimore). 2020;99(32):e21686. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. García-Bosch O, Gisbert JP, Cañas-Ventura A, et al. Observational study on the efficacy of adalimumab for the treatment of ulcerative colitis and predictors of outcome. J Crohns Colitis. 2013;7(9):717–722. [DOI] [PubMed] [Google Scholar]
- 10. Angelison L, Almer S, Eriksson A, et al. ; Swedish Organization for the Study of Inflammatory Bowel diseases (SOIBD). Long-term outcome of infliximab treatment in chronic active ulcerative colitis: a Swedish multicentre study of 250 patients. Aliment Pharmacol Ther. 2017;45(4):519–532. [DOI] [PubMed] [Google Scholar]
- 11. Shelton E, Allegretti JR, Stevens B, et al. Efficacy of vedolizumab as induction therapy in refractory IBD patients: a multicenter cohort. Inflamm Bowel Dis. 2015;21(12):2879–2885. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Ribaldone DG, Dileo I, Pellicano R, et al. Severe ulcerative colitis: predictors of response and algorithm proposal for rescue therapy. Ir J Med Sci. 2018;187(2):385–392. [DOI] [PubMed] [Google Scholar]
- 13. Calabrese E, Yanai H, Shuster D, Rubin DT, Hanauer SB.. Low-dose smoking resumption in ex-smokers with refractory ulcerative colitis. J Crohns Colitis. 2012;6(7):756-762. [DOI] [PubMed] [Google Scholar]
- 14. Sandborn WJ, Ghosh S, Panes J, et al. ; Study A3921063 Investigators. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367(7):616–624. [DOI] [PubMed] [Google Scholar]
- 15. Sandborn WJ, Su C, Sands BE, et al. ; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723–1736. [DOI] [PubMed] [Google Scholar]
- 16. Sandborn WJ, Lawendy N, Danese S, et al. Safety and efficacy of tofacitinib for treatment of ulcerative colitis: final analysis of OCTAVE Open, an open-label, long-term extension study with up to 7.0 years of treatment. Aliment Pharmacol Ther. 2022;55(4):464–478. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Vermeire S, Su C, Lawendy N, et al. Outcomes of tofacitinib dose reduction in patients with ulcerative colitis in stable remission from the randomised RIVETING trial. J Crohns Colitis. 2021;15(7):1130–1141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Sandborn WJ, D’Haens GR, Sands BE, et al. Tofacitinib for the treatment of ulcerative colitis: an integrated summary of up to 7.8 years of safety data from the global clinical programme. J Crohns Colitis. 2023;17(3):338–351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Gisbert JP, Chaparro M.. Predictors of primary response to biologic treatment [anti-TNF, vedolizumab, and ustekinumab] in patients with inflammatory bowel disease: from basic science to clinical practice. J Crohns Colitis. 2020;14(5):694–709. [DOI] [PubMed] [Google Scholar]
- 20. Baumgart DC, Bokemeyer B, Drabik A, Stallmach A, Schreiber S; Vedolizumab Germany Consortium. Vedolizumab induction therapy for inflammatory bowel disease in clinical practice—a nationwide consecutive German cohort study. Aliment Pharmacol Ther. 2016;43(10):1090–1102. [DOI] [PubMed] [Google Scholar]
- 21. Arcavi L, Benowitz NL.. Cigarette smoking and infection. Arch Intern Med. 2004;164(20):2206–2216. [DOI] [PubMed] [Google Scholar]
- 22. Winthrop KL, Melmed GY, Vermeire S, et al. Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib. Inflamm Bowel Dis. 2018;24(10):2258–2265. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Rahier JF, Magro F, Abreu C, et al. ; European Crohn's and Colitis Organisation (ECCO). Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8(6):443–468. [DOI] [PubMed] [Google Scholar]
- 24. Kucharzik T, Ellul P, Greuter T, et al. ECCO guidelines on the prevention, diagnosis, and management of infections in inflammatory bowel disease. J Crohns Colitis. 2021;15(6):879–913. [DOI] [PubMed] [Google Scholar]
- 25. Rogers MAM, Greene MT, Saint S, et al. Higher rates of Clostridium difficile infection among smokers. PLoS One. 2012;7(7):e42091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Mannino DM, Buist AS.. Global burden of COPD: risk factors, prevalence, and future trends. Lancet. 2007;370(9589):765–773. [DOI] [PubMed] [Google Scholar]
- 27. Baka Z, Buzás E, Nagy G.. Rheumatoid arthritis and smoking: putting the pieces together. Arthritis Res Ther. 2009;11(4):238. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Gandini S, Botteri E, Iodice S, et al. Tobacco smoking and cancer: a meta-analysis. Int J Cancer. 2008;122(1):155–164. [DOI] [PubMed] [Google Scholar]
- 29. Lichtenstein GR, Rogler G, Ciorba MA, et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancy (excluding nonmelanoma skin cancer) events across the ulcerative colitis clinical program. Inflamm Bowel Dis. 2021;27(6):816–825. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Sandborn WJ, Panés J, Sands BE, et al. Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme. Aliment Pharmacol Ther. 2019;50(10):1068–1076. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Sands BE, Colombel JF, Ha C, et al. Lipid profiles in patients with ulcerative colitis receiving tofacitinib-implications for cardiovascular risk and patient management. Inflamm Bowel Dis. 2021;27(6):797–808. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Levine JS, Burakoff R.. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2011;7(4):235–241. [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results.