Abstract
Objectives
To analyse adverse events (AEs) of special interest across tofacitinib clinical programmes in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO), and to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events are consistent across diseases.
Methods
The analysis included data from patients exposed to ≥1 dose of tofacitinib in phase 1, 2, 3 or 3b/4 clinical trials and long-term extension (LTE) studies (38 trials) in RA (23 trials), PsA (3 trials), UC (5 trials) and PsO (7 trials). All studies were completed by or before July 2019, except for one ongoing UC LTE study (data cut-off May 2019). IRs were obtained for AEs of special interest.
Results
13 567 patients were included in the analysis (RA: n=7964; PsA: n=783; UC: n=1157; PsO: n=3663), representing 37 066 patient-years of exposure. Maximum duration of exposure was 10.5 years (RA). AEs within the ‘infections and infestations’ System Organ Class were the most common in all diseases. Among AEs of special interest, IRs were highest for herpes zoster (non-serious and serious; 3.6, 1.8, 3.5 and 2.4 for RA, PsA, UC and PsO, respectively) and serious infections (2.5, 1.2, 1.7 and 1.3 for RA, PsA, UC and PsO, respectively). Age-adjusted and sex-adjusted mortality ratios (weighted for country) were ≤0.2 across cohorts.
Conclusions
The tofacitinib safety profile in this analysis was generally consistent across diseases and with longer term follow-up compared with previous analyses.
Keywords: arthritis, rheumatoid, arthritis, psoriatic, autoimmune diseases, therapeutics
Key messages.
What is already known about this subject?
Long-term extension studies and integrated analyses of data from the tofacitinib clinical programmes for rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO) have demonstrated that the safety profile of tofacitinib is stable over time and is consistent across the studies for each of these indications.
What does this study add?
This study compares and contrasts adverse events (AEs) of special interest for tofacitinib across the RA, PsA, UC and PsO clinical programmes using data from randomised controlled clinical trials and long-term extension studies.
How might this impact on clinical practice or future developments?
The data from this analysis of the RA, PsA, UC and PsO clinical programmes demonstrate a consistent safety profile across indications.
The findings reinforce the recommendations on screening, testing and monitoring given in the tofacitinib prescribing information.
Continued surveillance is required to monitor the incidence of AEs of special interest with longer term use of tofacitinib in clinical practice and registries.
Introduction
Janus kinase (JAK) inhibitors join a growing number of advanced targeted therapies that are indicated for multiple immune-mediated inflammatory diseases.1 Evaluation of the safety risks associated with long-term exposure across diseases is important because the patient populations under treatment differ in many respects (eg, age, use of concomitant immunosuppressive agents, degree of inflammation and the prevalence of other factors such as smoking, alcohol use and obesity). These factors may be responsible for potential differences in a drug’s risk–benefit profile across disease populations, which might affect patient management.
Tofacitinib is an oral JAK inhibitor. Tofacitinib is approved for use in adults with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis (UC) and in children with polyarticular course juvenile idiopathic arthritis,2 but not for psoriasis (PsO), with the exception of Russia where it is approved for use in moderate to severe plaque PsO.3
Long-term extension (LTE) studies of tofacitinib included patients with RA, PsA, UC and PsO, with exposures up to 9.5, 3, 5.9 and 5.5 years, respectively, and demonstrated a consistent safety profile over time.4–7 The objectives of this analysis were to provide a comparison of adverse events (AEs) of special interest from integrated pooled studies of the tofacitinib clinical programmes in RA, PsA, UC and PsO8–11; to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events remain consistent across diseases after longer term exposure to tofacitinib; and to understand what factors might contribute to any differences.
Methods
Patients and studies
This exploratory analysis includes pooled data for patients who received ≥1 dose of tofacitinib in clinical trials and open-label LTE studies across each disease. Full details of the individual studies have been published previously (online supplemental table S1).
rmdopen-2021-001595supp001.pdf (936.9KB, pdf)
All cohorts included patients aged ≥18 years who received tofacitinib as monotherapy (RA, UC and PsO) or with background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; RA, PsA). All studies had been completed by July 2019, with the exception of one ongoing LTE study in the UC cohort (data cut-off 27 May 2019). Final data for the RA and PsA cohorts are from 18 April 2019 and 31 July 2019, respectively. Final data for the PsO cohort are from 18 August 2016, as the programme was terminated when the objectives of characterising long-term safety and tolerability were met.
All patients provided written, informed consent.
Dosing
Patients received tofacitinib 0.5, 1, 2, 3, 5, 10, 15 or 30 mg two times per day or 20 mg once a day in phase 1/2 studies, and tofacitinib 5 or 10 mg two times per day or 11 mg extended-release once a day in phase 3 and phase 3b/4 studies (online supplemental table S1). In LTE studies, the tofacitinib dose could be switched for efficacy or safety reasons. Data are reported for the following treatment groups: tofacitinib 5 mg two times per day (average total daily dose <15 mg); tofacitinib 10 mg two times per day (average total daily dose ≥15 mg); and all tofacitinib doses (ie, average tofacitinib 5 mg two times per day and average tofacitinib 10 mg two times per day populations pooled).
Analysis of AEs
The analyses for each disease have been described previously.8–11 Data on AEs and serious AEs (SAEs) were collected and coded using Medical Dictionary for Regulatory Activities (MedDRA) V.22.0 (RA, PsA and UC) or V.20.0 (PsO). AEs, SAEs and deaths occurring on treatment or within 28 days after discontinuation of tofacitinib were reported. Adjudication of tuberculosis, opportunistic infections (OIs; excluding tuberculosis), malignancies (excluding non-melanoma skin cancer (NMSC)), NMSC, melanoma, lymphoma/lymphoproliferative disorders, gastrointestinal perforation events and major adverse cardiovascular events (MACEs; total MACE defined as composite of myocardial infarction, stroke and cardiovascular deaths) has been described previously.8
Statistical analyses
IRs for AEs, SAEs, discontinuations due to AEs, deaths and AEs of special interest were reported as the number of unique patients with events per 100 patient-years. Total follow-up time was calculated up to the day of the first event, subject to a risk period of 28 days beyond the last dose or to the data cut-off date, whichever occurred earlier. Events occurring after the 28-day post-treatment period are not included in the IR calculation. Exact Poisson, adjusted for exposure, was used to calculate 95% CIs for the crude IR. Kaplan-Meier curves and cumulative probability plots were generated for analysis of time to events.
Age-adjusted and sex-adjusted standardised mortality ratios (SMRs) were calculated using the observed rates weighted by country, compared with the expected rates for the general population based on the WHO country-specific mortality rates for 2012.12
For malignancies, standardised incidence ratios (SIRs) were calculated as the ratio of observed adjudicated malignancies to expected malignancies, based on rates reported by the US National Cancer Institute Surveillance and Epidemiology and End Results (SEER) database, 2013–2017 (RA, PsA and UC) and 2008–2012 (PsO)13; 95% CIs for SIRs were calculated based on a Poisson distribution.
Patient and public involvement
Patients and the public were not involved in the design, analysis or data interpretation of this study.
Results
Patients
A total of 13 567 patients received tofacitinib and were included in the analysis (RA: n=7964; PsA: n=783; UC: n=1157; PsO: n=3663). Total tofacitinib exposure (patient-years) and median (range) length of exposure by cohort were as follows: 23 497 patient-years, with median exposure of 2.1 years (0–10.5 years) for RA; 2038 patient-years, with median exposure of 3.0 years (0–4.8 years) for PsA; 2581 patient-years, with median exposure of 1.7 years (0–6.8 years) for UC; and 8950 patient-years, with median exposure of 2.4 years (0–5.7 years) for PsO.
Baseline characteristics and demographics for each disease are shown in table 1. The RA cohort had a higher proportion of females than other cohorts (81.9% vs 54.7%, 41.3% and 30.5% in the PsA, UC and PsO cohorts, respectively) and an approximately twofold to fivefold higher proportion of patients who had enrolled at centres in Asia. Patients with RA were also older than those in the other cohorts, with 15.9% of patients aged ≥65 years, vs 6.0%–9.2% for the other cohorts. Approximately 40% of patients in the PsA and PsO cohorts had body mass index ≥30 kg/m2, and a ≥2-fold higher proportion of patients with PsO were current smokers versus other cohorts. Mean disease duration was approximately 8 years for all cohorts except for PsO, for which the mean duration was 18.3 years. C-reactive protein levels were highest in the RA cohort; there was a wide range of C-reactive protein concentrations for all diseases. The range of permitted concomitant medications administered was as expected for each disease, except for PsO, for which the study protocols did not permit background corticosteroid use. Almost all patients in the RA and PsA cohorts had previously received methotrexate, and approximately half of patients in the PsA and UC cohorts had previously received tumour necrosis factor inhibitors (TNFi). Mean corticosteroid dose was highest in the UC cohort (16.0 mg/day) and lowest in the PsA cohort (1.4 mg/day), in which only 21.8% of patients were receiving concomitant corticosteroids.
Table 1.
Baseline characteristics and demographics
| Characteristics | RA (N=7964) | PsA (N=783) | UC (N=1157) | PsO (N=3663) |
| Age, years | ||||
| Mean (SD) | 52.6 (12.1) | 48.7 (12.0) | 41.3 (13.9) | 44.8 (12.9) |
| Median (range) | 53.0 (18–86) | 50.0 (18–78) | 39.0 (18–81) | 45.0 (18–82) |
| <65 at baseline, n (%) | 6694 (84.1) | 711 (90.8) | 1080 (93.3) | 3443 (94.0) |
| ≥65 at baseline, n (%) | 1270 (15.9) | 72 (9.2) | 77 (6.7) | 220 (6.0) |
| Female, n (%) | 6522 (81.9) | 428 (54.7) | 478 (41.3) | 1117 (30.5) |
| Region, n (%) | ||||
| Europe | 2180 (27.4) | 542 (69.2)* | 686 (59.3) | 1563 (42.7) |
| USA/Canada | 2021 (25.4) | 158 (20.2) | 241 (20.8) | 1559 (42.6) |
| Asia | 1775 (22.3)† | 15 (1.9) | 123 (10.6) | 185 (5.1) |
| Latin America | 1246 (15.6) | 68 (8.7) | NA | 356 (9.7) |
| Rest of the world | 742 (9.3) | NA | 107 (9.2) | NA |
| BMI (kg/m2), mean (range) | 27.1 (12.1–70.8) | 29.6 (17.0–54.6) | 24.8 (15.8–55.0) | 29.9 (15.4–64.8) |
| BMI ≥30 kg/m2, n (%) | 2138 (26.8) | 333 (42.5) | 159 (13.8) | 1544 (42.2) |
| Disease duration (years), mean (range) | 8.1 (0.0–65.7) | 7.7 (0.2–43.4) | 8.2 (0.4–42.5) | 18.3 (0.6–68.1) |
| CRP (mg/L), median (Q1–Q3) | 9.2 (3.8–22.8) | 4.8 (1.7–12.6) | 4.5 (1.7–11.5) | 2.7 (1.1–6.5) |
| Smoking status, n (%) | ||||
| Never smoked | 4996 (62.7) | 485 (61.9) | 740 (64.0) | 1412 (38.5) |
| Smoker | 1366 (17.2) | 140 (17.9) | 59 (5.1) | 1380 (37.7) |
| Ex-smoker | 1388 (17.4) | 158 (20.2) | 357 (30.9) | 871 (23.8) |
| Unknown | 214 (2.7) | 0 (0.0) | 1 (0.1) | 0 (0.0) |
| Prior therapy, n (%) | ||||
| Methotrexate | 6657 (83.6) | 725 (92.6) | NA | 1157 (31.6) |
| Non-bDMARD (non-methotrexate) | 3739 (46.9) | 372 (47.5) | NA | 390 (10.6) |
| Thiopurines | NA | NA | 823 (73.2) | NA |
| TNFi | 1245 (15.6) | 377 (48.1) | 612 (54.4) | 580 (15.8) |
| Non-TNFi bDMARD | 414 (5.2) | 46 (5.9) | NA | 214 (5.8) |
| Concomitant medications | ||||
| Corticosteroids, n (%) | 4254 (53.4) | 171 (21.8) | 523 (45.2) | NA‡ |
| Corticosteroids dose (mg/day), mean (range) | 6.5 (0.01–200.0) | 1.4 (0.0–20.0) | 16.0 (2.0–30.0) | NA‡ |
*Also includes Australia and Russia.
†East/South Asia.
‡Concomitant corticosteroid use was not permitted in the PsO studies.
bDMARD, biologic disease-modifying antirheumatic drug; BMI, body mass index; CRP, C-reactive protein; N, number of patients in the disease cohort (note that N varies for some variables); n, number of patients with each characteristic; NA, not applicable; PsA, psoriatic arthritis; PsO, psoriasis; Q, Quarter; RA, rheumatoid arthritis; TNFi, tumour necrosis factor inhibitor; UC, ulcerative colitis.
AEs, SAEs, discontinuations and deaths
For details of AEs, see the online supplemental material.
The IRs for SAEs and discontinuations due to AEs for the all tofacitinib groups were highest for the RA cohort (SAEs: 9.0 vs 5.5–8.5; discontinuations due to AEs: 7.2 vs 3.8–5.7 for the other diseases; table 2).
Table 2.
IRs (95% CI) of AEs and SAEs (all cause)
| RA (N=7964) | PsA (N=783) | UC (N=1157) | PsO (N=3663) | |
| Total tofacitinib exposure, patient-years | 23 497 | 2038 | 2581 | 8950 |
| Median exposure, years | 2.1 | 3.0 | 1.7 | 2.4 |
| Discontinuations due to AEs, IR (95% CI) (n) | 7.2 (6.9 to 7.6) (1705) | 3.8 (3.0 to 4.8) (80) | 4.1 (3.3 to 4.9) (108) | 5.7 (5.3 to 6.3) (530) |
| SAEs,* IR (95% CI) (n) | 9.0 (8.6 to 9.4) (1913) | 7.0 (5.8 to 8.2) (135) | 8.5 (7.4 to 9.8) (210) | 5.5 (5.0 to 6.0) (484) |
| Mortality,* IR (95% CI) (n) | 0.2 (0.2 to 0.3) (59) | 0.1 (0.0 to 0.3) (2) | 0.1 (0.0 to 0.3) (2) | 0.2 (0.1 to 0.3) (17) |
*Within 28 days of the last dose of study drug.
AE, adverse event; IR, incidence rate (unique patients with events per 100 patient-years); n, unique number of patients with event; N, number of patients in the disease cohort; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; SAE, serious adverse event; UC, ulcerative colitis.
All-cause mortality risk was similar across cohorts (table 2) and tofacitinib doses (online supplemental figures S1A, B). The most common cause of death within the 28-day risk period (by MedDRA System Organ Class) was cardiac, for both RA (n/N=20/7964; 0.3%) and PsO (n/N=7/3663; 0.2%). Two deaths occurred within the 28-day risk period in the PsA (cardiac arrest and chronic obstructive pulmonary disease) and UC (aortic dissection and pulmonary embolism (PE)) cohorts. Age-adjusted and sex-adjusted SMRs (95% CI) were as follows: 0.2 (0.2–0.3) for RA, 0.2 (0.0–0.4) for PsA, 0.1 (0.0–0.5) for UC and 0.2 (0.1–0.4) for PsO.
Infections and serious infection events (SIEs)
The SIEs IR was highest for the RA cohort (2.5; 95% CI 2.3 to 2.7; table 3). The five most common SIEs per cohort were pneumonia (n=131), herpes zoster (HZ; n=44), urinary tract infection (n=31), cellulitis (n=31) and gastroenteritis (n=24) for RA; pneumonia (n=4), gastroenteritis (n=3), appendicitis, cellulitis and influenza (all n=2) for PsA; HZ (n=8), anal abscess (n=4), appendicitis (n=4), gastroenteritis (n=3), and cellulitis, sinusitis and Clostridium difficile (all n=2) for UC; and pneumonia (n=27), appendicitis (n=11), HZ (n=10), diverticulitis (n=9) and cellulitis (n=7) for PsO. Subanalyses of SIEs, according to age and by concomitant corticosteroid use, are shown in table 4. Across cohorts, the SIEs IR was highest in the ≥65 years age group; within this age group, the IR was higher in the RA versus PsA, UC and PsO cohorts. The IR for SIEs with concomitant corticosteroid use was higher in the RA versus PsA and UC cohorts. When no concomitant corticosteroids were used, IRs for SIEs were similar between the RA and UC cohorts, and lower in the PsA cohort.
Table 3.
IRs (95% CI) for AEs of special interest
| RA (N=7964) | PsA (N=783) | UC (N=1157) | PsO (N=3663) | |
| Total tofacitinib exposure, patient-years | 23 497 | 2038 | 2581 | 8950 |
| Serious infections, IR (95% CI) (n) | 2.5 (2.3 to 2.7) (592) | 1.2 (0.7 to 1.7) (24) | 1.7 (1.2 to 2.3) (45) | 1.3 (1.1 to 1.5) (119) |
| All HZ (non-serious and serious), IR (95% CI) (n) | 3.6 (3.3 to 3.8) (795) | 1.8 (1.2 to 2.4) (36) | 3.5 (2.8 to 4.3) (87) | 2.4 (2.0 to 2.7) (209) |
| Adjudicated OIs excluding tuberculosis, IR (95% CI) (n) | 0.4 (0.3 to 0.5) (95) | 0.3 (0.1 to 0.7) (7) | 1.6 (1.1 to 2.1) (40)* | 0.3 (0.2 to 0.5) (29) |
| Adjudicated tuberculosis, IR (95% CI) (n) | 0.2 (0.1 to 0.2) (38) | 0.0 (0.0 to 0.2) (0) | 0.0 (0.0 to 0.1) (0)* | 0.0 (0.0 to 0.1) (1) |
| Adjudicated malignancies excluding all NMSC, IR (95% CI) (n) n1 (%) |
0.7 (0.6 to 0.9) (179) 211 (2.6) |
0.7 (0.4 to 1.2) (15) 18 (2.3) |
0.6 (0.3 to 1.0) (16)* 20 (1.8)* |
0.7 (0.5 to 0.8) (60) 74 (2.0) |
| Adjudicated NMSC, IR (95% CI) (n) n1 (%) |
0.6 (0.5 to 0.7) (133) 135 (1.7) |
0.8 (0.4 to 1.3) (16) 16 (2.0) |
0.7 (0.4 to 1.1) (19)* 19 (1.7)* |
0.7 (0.5 to 0.9) (63) 67 (1.8) |
| Adjudicated melanoma, IR (95% CI) (n) n1 (%) |
0.1 (0.0 to 0.1) (14) 14 (0.2) |
0.0 (0.0 to 0.2) (0) 0 (0.0) |
0.1 (0.0 to 0.3) (2)* 2 (0.2)* |
0.1 (0.0 to 0.1) (5) 5 (0.1) |
| Adjudicated lymphoma/lymphoproliferative disorders, IR (95% CI) (n) n1 (%) |
0.1 (0.0 to 0.1) (12) 19 (0.2) |
0.1 (0.0 to 0.3) (1) 1 (0.1) |
0.1 (0.0 to 0.3) (2)* 2 (0.2)* |
0.02 (0.0 to 0.1) (2) 4 (0.1) |
| Adjudicated gastrointestinal perforation, IR (95% CI) (n) | 0.1 (0.1 to 0.2) (27) | 0.1 (0.0 to 0.3)(1) | 0.2 (0.1 to 0.5) (6)* | 0.1 (0.0 to 0.2) (7) |
| Adjudicated MACE,† IR (95% CI) (n) | 0.4 (0.3 to 0.5) (85)‡ | 0.3 (0.1 to 0.6) (6) | 0.3 (0.1 to 0.5) (7)* | 0.3 (0.2 to 0.4) (23) |
| DVT,§ IR (95% CI) (n) | 0.2 (0.1 to 0.2) (37) | 0.1 (0.0 to 0.3) (1) | 0.0 (0.0 to 0.2) (1) | 0.1 (0.0 to 0.1) (6) |
| PE,§ IR (95% CI) (n) | 0.1 (0.1 to 0.2) (31) | 0.1 (0.0 to 0.3) (1) | 0.2 (0.0 to 0.4) (4) | 0.1 (0.0 to 0.2) (9) |
*N=1124.
†Composite MACE defined as any myocardial infarction, stroke or cardiovascular death.
‡N=7311.
AE, adverse event; DVT, deep vein thrombosis; HZ, herpes zoster; IR, incidence rate (unique patients with events per 100 patient-years); MACE, major adverse cardiovascular events; N, number of patients in the disease cohort; n, unique number of patients with event (events are counted up to 28 days beyond the last dose or to the data cut-off date, and are included in the calculation of IR); n1, all events, including those occurring outside the 28-day risk period; NMSC, non-melanoma skin cancer; OI, opportunistic infection; PE, pulmonary embolism; PsA, psoriatic arthritis; PsO psoriasis; RA, rheumatoid arthritis; UC, ulcerative colitis.
Table 4.
IRs (95% CI) for serious infections according to age and concomitant corticosteroid use
| RA | PsA | UC | PsO | |
| Age | ||||
| <65 years, IR (95% CI) | N=6694 2.2 (2.0 to 2.4) (n=452) |
N=711 1.1 (0.7 to 1.7) (n=21) |
N=1080 1.7 (1.2 to 2.3) (n=41) |
N=3443 1.2 (1.0 to 1.5) (n=108) |
| ≥65 years, IR (95% CI) | N=1270 4.6 (3.8 to 5.4) (n=140) |
N=72 1.7 (0.3 to 4.8) (n=3) |
N=77 2.1 (0.6 to 5.3) (n=4) |
N=220 2.2 (1.1 to 3.9) (n=11) |
| Corticosteroid use | ||||
| Yes, IR (95% CI) | N=4254 3.0 (2.7 to 3.3) (n=390) |
N=171 1.6 (0.7 to 3.4) (n=7) |
N=523 1.3 (0.7 to 2.2) (n=14) |
–* |
| No, IR (95% CI) | N=3710 1.9 (1.6 to 2.1) (n=202) |
N=612 1.0 (0.6 to 1.6) (n=17) |
N=634 2.0 (1.4 to 2.8) (n=31) |
–* |
*Concomitant corticosteroid use was not permitted in the PsO studies.
IR, incidence rate (unique patients with events per 100 patient-years); n, number of patients with the event (events are counted up to 28 days beyond the last dose or to the data cut-off date); N, number of patients per category in the disease cohort; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; UC, ulcerative colitis.
HZ IRs (non-serious and serious) ranged from 1.8 for PsA to 3.6 and 3.5 for RA and UC, respectively (table 3). Adjudicated HZ infection types included 49 multidermatomal (ie, non-adjacent dermatomes or >2 adjacent dermatomes) and 8 disseminated (ie, >6 dermatomes or other organ involvement) cases out of 795 HZ cases for RA; 4 multidermatomal and 2 disseminated cases out of 36 HZ cases for PsA; 17 multidermatomal and 7 disseminated cases out of 87 HZ cases for UC; and 23 multidermatomal and 3 disseminated cases out of 209 HZ cases for the PsO cohort.
Cases of adjudicated active tuberculosis were observed in the RA (n=38; IR: 0.2) and PsO (n=1; IR: 0.0) cohorts only (table 3). Eighteen patients in the RA cohort had extrapulmonary/disseminated tuberculosis within the 28-day risk period. Most cases of tuberculosis among patients with RA occurred in patients receiving the average 10 mg two times per day dose and in regions of high prevalence of tuberculosis. Four patients in the RA cohort with a positive test for tuberculosis at screening who were receiving adequate prophylactic treatment went on to develop active tuberculosis infection. The single case of adjudicated tuberculosis in the PsO cohort was reported in a patient receiving the average tofacitinib 10 mg two times per day dose and was a de novo infection.
The IR for adjudicated OIs (excluding tuberculosis) was fourfold to fivefold higher in the UC cohort (1.6 vs 0.3 (PsA and PsO) and 0.4 (RA); table 3), and this was largely accounted for by adjudicated HZ events.
For additional details on SIEs, HZ and adjudicated OIs, see online supplemental figures S1C–F, S2 and table S2.
Malignancies
IRs for adjudicated malignancies (excluding NMSC), NMSC, melanoma and lymphoma/lymphoproliferative disorders were similar across cohorts (table 3). The most common malignancies, including those reported outside the 28-day risk period, are summarised in the online supplemental material, a listing of malignancies is provided in online supplemental table S3, and time to malignancies, NMSC, melanoma and lymphoma/lymphoproliferative disorders data are shown in online supplemental figure S1G–N.
Age-adjusted and sex-adjusted SIRs based on SEER data for malignancies (excluding NMSC), melanoma and lymphoma are shown in figure 1. The 95% CI for most SIRs included 1.0. SIRs for all malignancies (excluding NMSC) were ≤1.0 for the RA and PsA cohorts. SIRs were generally highest for the UC cohort; however, comparisons are limited by the small number of events and wide CIs.
Figure 1.
Age-adjusted and sex-adjusted SIRs (95% CI) using SEER registry data for (A) malignancies excluding NMSC, (B) melanoma and (C) lymphoma. n, unique number of patients with event; NMSC, non-melanoma skin cancer; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; SEER, Surveillance, Epidemiology, and End Results; SIR, standardised incidence ratio; UC, ulcerative colitis.
Other AEs of special interest
IRs for adjudicated gastrointestinal perforation were similar across diseases (table 3) and in patients receiving concomitant non-steroidal anti-inflammatory drugs or corticosteroids (online supplemental table S4).
Adjudicated MACE was reported at similar incidence across the different diseases (table 3). Additional details on MACE for tofacitinib are provided in the online supplemental material.
IRs for DVT ranged from 0.0 (UC) to 0.2 (RA), and IRs for PE ranged from 0.1 (RA, PsA and PsO) to 0.2 (UC) (table 3).
Discussion
This analysis of tofacitinib safety across RA, PsA, UC and PsO demonstrates a generally consistent long-term safety profile, despite differences in patient populations for each cohort in terms of age, region of study enrolment, smoking status, tofacitinib dosing, concomitant use of corticosteroids and prior use of bDMARDs and immunosuppressants. Age-adjusted and sex-adjusted mortality rates indicated no excess mortality, and the overall safety profile was consistent compared with previous analyses for each indication. Additionally, the average tofacitinib 5 and 10 mg two times per day doses were similar in terms of time to mortality, SIEs, all HZ (non-serious and serious) and malignancies (online supplemental figures S1 and S2).
Infections and infestations were the most common treatment-emergent AEs observed across the cohorts, a finding consistent with data for other therapies approved across multiple indications, for example, bDMARDs (eg, adalimumab, etanercept, infliximab, tocilizumab)14–17 and for other JAK inhibitors approved for the treatment of RA.18 19 The SIEs IR (2.5) for the RA cohort in this analysis was slightly higher compared with the other disease cohorts, consistent with a long-term safety analysis of adalimumab across these indications.14 In the RA cohort, the SIEs IR was higher in patients aged ≥65 years versus younger patients, and also higher in those taking concomitant corticosteroids, compared with those not. It is therefore possible that patient characteristics may have contributed to the higher rate of SIEs in the RA cohort compared with the other cohorts (eg, the higher proportion of patients aged ≥65 years in the RA cohort, with prior methotrexate use and with concomitant corticosteroids and/or csDMARDs), although formal statistical analyses of the relationships between baseline characteristics and risk of events were not conducted. Another recent pooled analysis of tofacitinib RA clinical trials identified a higher incidence of SIEs for patients aged ≥65 versus <65 years receiving tofacitinib, consistent with the TNFi comparator arm, and with patients receiving bDMARDs in an RA registry.20 The SIEs IR in the RA cohort is observed to be similar to that reported in an integrated safety analysis of baricitinib18 21 and lower than that reported for upadacitinib.19
Across diseases, most HZ infections were monodermatomal, consistent with previous studies.22–24 Rates of all HZ (non-serious and serious) were higher in the RA and UC cohorts versus PsA and PsO. The higher HZ rate in these cohorts is not unexpected, as patients with RA or UC are at increased risk of HZ, compared with the general population.25 The RA and UC cohorts had the highest proportions of patients who were enrolled at sites in Asia, or were receiving concomitant corticosteroids, characteristics that were associated with an elevated risk of HZ, compared with placebo, in the global tofacitinib clinical development programme and in studies of other JAK inhibitors (enrolment in Asia only).21–24 26 The HZ IR with tofacitinib reported in this analysis is observed to be similar to that reported for baricitinib and upadacitinib in a meta-analysis of infection risk with JAK inhibitors in RA.27 However, expression of HZ is reduced with available vaccines, and clinical practice guidelines for rheumatologists and gastroenterologists recommend immunisation before initiating bDMARD or JAK inhibitor treatment.28–30 The IR for adjudicated OI was several-fold higher for the UC cohort, but this was accounted for by higher incidence of adjudicated OI of HZ among those patients, compared with other cohorts, which may also have been related to the higher mean dose of concomitant corticosteroids for the UC cohort. Adjudicated events of tuberculosis were only reported in the RA and PsO cohorts, and IRs for adjudicated tuberculosis were <1.0 and similar to those previously reported for adalimumab across inflammatory conditions and for baricitinib in RA.14 18 21 Consistent with a previous analysis,31 the majority (76%) of tuberculosis AEs reported in the RA cohort occurred in countries with high background prevalence, that is, Brazil, China, India, Korea, the Philippines and Thailand,32 and most (71%) occurred with the average 10 mg two times per day dose (10 mg two times per day is not the approved dose for RA in most countries). There were no adjudicated events of active tuberculosis in the UC cohort, in which more patients received the average tofacitinib 10 mg two times per day dose than the 5 mg two times per day dose, although smaller cohort sizes and differences in geographical distribution may have also accounted for differences in tuberculosis events between the RA and other cohorts.
Factors that contribute to an increased risk of developing malignancies include age, obesity and immune-mediated inflammatory conditions.13 33 34 Overall, the age-adjusted and sex-adjusted SIRs based on the SEER registry did not indicate an increasing risk for malignancy with tofacitinib relative to the general USA population, even though numerical differences in baseline risk factors (eg, age, smoking and obesity) were apparent between cohorts. However, the number of patients, length of follow-up and number of events for the PsA, UC and PsO cohorts were substantially less than that for the RA cohort, particularly for UC and PsA; continued surveillance is required to determine the risk of malignancies in patients receiving tofacitinib. SIRs for tofacitinib in this analysis were generally consistent with those reported in previous integrated safety analyses of adalimumab (malignancies excluding NMSC (95% CI): RA 0.84 (0.73 to 0.96), PsA 0.68 (0.22 to 1.59), UC 1.47 (0.95 to 2.17), PsO 0.86 (0.58 to 1.22); lymphoma: RA 2.97 (2.05 to 4.17), PsA 5.88 (0.66 to 21.2), UC 3.52 (0.71 to 10.3), PsO 0.58 (0.01 to 3.22)) and baricitinib (malignancies excluding NMSC (95% CI): RA 1.04 (0.79 to 1.36)), which also used the SEER registry for comparison, but differed in drug exposure and length of follow-up.14 18 Real-world evidence from the Corrona RA registry has also demonstrated comparable rates of malignancies for tofacitinib and bDMARDs.35
Rates of gastrointestinal perforation were <0.3 and were consistent across the tofacitinib RA, PsA, UC and PsO cohorts. The corresponding rate reported in the integrated safety analysis of baricitinib in RA was 0.05 per 100 patient-years (95% CI 0.01 to 0.13),18 and the IR from clinical trials of tocilizumab in RA was 0.19 per 100 patient-years (95% CI 1.3 to 2.7).36 However, comparison across study cohorts is limited due to variation in factors known to increase the risk of gastrointestinal perforation, including smoking, non-steroidal anti-inflammatory drug use, corticosteroids and older age.36 37
IRs for adjudicated MACE in this analysis were also <0.5 across all cohorts and were consistent with rates reported for bDMARDs38 39 and other JAK inhibitors.18 19 Comprehensive analyses of thromboembolic events with tofacitinib treatment across the RA, PsA, UC and PsO clinical programmes are published elsewhere.40 41 Importantly, data from a large, randomised, prospective, post-authorisation safety study (Study A3921133; NCT02092467) comparing tofacitinib with TNFi in patients with RA who were aged ≥50 years and had ≥1 additional cardiovascular risk factor showed an increased rate for tofacitinib relative to TNFi regarding VTE, MACE and malignancies.42 43 Given that the underlying mechanism(s) for these AEs remain unknown, the effect of JAK inhibitors on cardiovascular disease and malignancy risk requires further research.
These findings provide the opportunity to compare the long-term safety profile of tofacitinib in different immune-mediated inflammatory diseases. The results of this analysis also reinforce the recommendations given in the tofacitinib prescribing information regarding testing and monitoring for infections (including latent tuberculosis), ensuring that all patients are up to date with HZ and pneumococcal vaccination before initiating tofacitinib in line with current immunisation guidelines, and using tofacitinib with caution in patients at risk of gastrointestinal perforations.2
Limitations of the analysis include the shorter exposure time and relatively small tofacitinib treatment groups in patients with PsA, UC and PsO, compared with the larger safety database available for RA. This limits the precision and interpretation of the IRs determined for events with long latency, that is, malignancies. An additional limitation is the lack of placebo comparison due to the designs of some studies in which patients were exposed to placebo for a short period of 3 months before advancing to tofacitinib. Also, use of the average daily dose is not the best way to show a dose relationship for AEs and does not account for dose switching during individual studies, or a change in dose between the index studies and LTEs. Finally, the use of the WHO and SEER data for calculation of SMRs and SIRs, respectively, may be confounded even after adjusting for age and gender. Longer term follow-up in the UC LTE study, and real-world data in patients with RA, PsA and UC, will provide further information on the safety profile of tofacitinib across indications.
Conclusions
The tofacitinib safety database used for this analysis provides the largest clinical database for a JAK inhibitor to date, with >13 000 tofacitinib-treated patients across four diseases, including >7000 patients with RA with exposure to tofacitinib for up to 10.5 years and accounting for 37 066 patient-years of tofacitinib exposure. This analysis is the first presentation of tofacitinib safety across RA, PsA, UC and PsO, providing the opportunity to compare long-term safety in different inflammatory diseases. The safety profile of tofacitinib in this analysis was consistent with previous analyses from the individual tofacitinib clinical programmes. An increased risk of certain AEs, such as HZ, was evident, consistent with current tofacitinib prescribing recommendations on screening and prevention of infections in patients considered to be at risk. AEs of special interest occurred at comparable rates across diseases, except for SIEs, which were more common in the RA cohort, and HZ, which was more common in the RA and UC cohorts. The variation of risk factors across diseases, such as age and concomitant corticosteroid and/or csDMARD use, may have contributed to this, and clinicians should take these risk factors into consideration when treating patients. This has also been observed for VTE, which has been identified as an important risk of treatment with tofacitinib. Prescribers should review information pertaining to VTE and tofacitinib in their current local product labelling and individualise treatment decisions by considering risk factors for VTE. In conclusion, this analysis demonstrates a generally consistent safety profile for tofacitinib across indications, and highlights the importance of determining the risk–benefit profile on an individual patient basis before initiating tofacitinib therapy.
Acknowledgments
Medical writing support, under the guidance of the authors, was provided by Jennifer Higginson, PhD, CMC Connect, McCann Health Medical Communications, and Kirsteen Munn, PhD, on behalf of CMC Connect, and was funded by Pfizer Inc, New York, New York, USA, in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med 2015;163:461–4).
Footnotes
Contributors: GRB, BES and HT conceived and designed the study/analyses. GRB, BES, SBC, PN and KP were involved in patient recruitment and/or data acquisition. AM and HT performed the data and statistical analyses. All authors critically reviewed the manuscript, interpreted the results, approved the final draft and had the final decision to submit the manuscript for publication.
Funding: This study was sponsored by Pfizer Inc.
Competing interests: GRB has received consulting fees and honoraria for lectures from AbbVie, Eli Lilly, Gilead and Pfizer Inc. PN has received research grants and consulting fees from, and is a member of the speakers’ bureau for, AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi and UCB. BES has received consulting fees from 4D Pharma, AbbVie, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Capella Biosciences, Celgene, Celltrion Healthcare, Eli Lilly, EnGene, F. Hoffmann‑La Roche, Ferring, Genentech, Gilead, Immunic, Ironwood Pharmaceuticals, Janssen, Lyndra, MedImmune, Morphic Therapeutic, Oppilan Pharma, OSE Immunotherapeutics, Otsuka, Palatin Technologies, Pfizer Inc, Progenity, Prometheus Laboratories, Redhill Biopharma, Rheos Medicines, Seres Therapeutics, Shire, Synergy Pharmaceuticals, Takeda, Target PharmaSolutions, Theravance Biopharma R&D, TiGenix, Vivelix Pharmaceuticals; honoraria for speaking in CME programmes from Eli Lilly, Genentech, Gilead, Janssen, Pfizer Inc and Takeda; and research grants from Celgene, Janssen, Pfizer Inc, Takeda and Theravance Biopharma R&D. KP has received consulting fees from AbbVie, Akros, Amgen, Arcutis, Astellas, Bausch Health, Baxalta, Boehringer Ingelheim, Bristol-Myers Squibb, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Evelo, Galapagos, Galderma, Genentech, Janssen, Kyowa Hakko Kirin, LEO Pharma, Meiji Seika Pharma, Merck (MSD), Merck Serono, Mitsubishi Pharma, Novartis, Pfizer Inc, PRCL Research, Regeneron, Roche, Sanofi/Genzyme, Takeda and UCB; is an investigator for AbbVie, Akros, Amgen, Anacor, Arcutis, Astellas, Bausch Health, Baxalta, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Galderma, Genentech, Gilead, GlaxoSmithKline, Janssen, Kyowa Hakko Kirin, LEO Pharma, MedImmune, Merck (MSD), Merck Serono, Moberg Pharma, Novartis, Pfizer Inc, PRCL Research, Regeneron, Roche, Sanofi/Genzyme, Sun Pharma, Takeda and UCB; is a scientific officer for Akros, Anacor and Kyowa Hakko Kirin; is an advisory board participant for AbbVie, Amgen, Astellas, Bausch Health, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dow Pharma, Eli Lilly, Galderma, Janssen, Merck (MSD), Novartis, Pfizer Inc, Regeneron, Sanofi/Genzyme, Sun Pharma and UCB; is a steering committee member for AbbVie, Amgen, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Kyowa Hakko Kirin, Merck (MSD), Merck Serono, Novartis, Pfizer Inc, Regeneron, Sanofi/Genzyme; and is a speaker for AbbVie, Amgen, Astellas, Bausch Health, Celgene, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, LEO Pharma, Merck (MSD), Novartis, Pfizer Inc and Sanofi/Genzyme. LS, HT, AM and HV are employees and shareholders of Pfizer Inc. TVJ was an employee and shareholder of Pfizer Inc at the time of this analysis. SC has received research grants and consulting fees from AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Eli Lilly, Genentech, Gilead, Janssen, Novartis, Pfizer Inc, Roche and Sandoz.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement
On request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual deidentified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the USA and/or EU, or (2) in programmes that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The deidentified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
All studies were conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines, along with applicable local country regulations and laws. The study protocols were approved by the Institutional Review Boards and/or Independent Ethics Committee at each centre.
References
- 1.Novosad SA, Winthrop KL. Beyond tumor necrosis factor inhibition: the expanding pipeline of biologic therapies for inflammatory diseases and their associated infectious sequelae. Clin Infect Dis 2014;58:1587–98. 10.1093/cid/ciu104 [DOI] [PubMed] [Google Scholar]
- 2.Pfizer Inc . Xeljanz® (tofacitinib): highlights of prescribing information, 2020. Available: http://labeling.pfizer.com/ShowLabeling.aspx?id=959 [Accessed 8 Jan 2021].
- 3.Ministry of Healthcare of the Russian Federation . Instructions for medical use of the medicinal product Jaqinus, 2018. [Google Scholar]
- 4.Wollenhaupt J, Lee E-B, Curtis JR, et al. Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study. Arthritis Res Ther 2019;21:89. 10.1186/s13075-019-1866-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Valenzuela F, Korman NJ, Bissonnette R, et al. Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study. Br J Dermatol 2018;179:853–62. 10.1111/bjd.16798 [DOI] [PubMed] [Google Scholar]
- 6.Nash P, Coates LC, Kivitz AJ, et al. Safety and efficacy of tofacitinib in patients with active psoriatic arthritis: interim analysis of OPAL Balance, an open-label, long-term extension study. Rheumatol Ther 2020;7:553–80. 10.1007/s40744-020-00209-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Lichtenstein GR, Loftus Jr EV, Wei SC. DOP61 tofacitinib, an oral, small-molecule Janus kinase inhibitor, in the treatment of ulcerative colitis: analysis of an open-label, long-term extension study with up to 5.9 years of treatment [abstract]. J Crohns Colitis 2020;14:DOP61. [Google Scholar]
- 8.Cohen SB, Tanaka Y, Mariette X, et al. Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme. RMD Open 2020;6:e001395. 10.1136/rmdopen-2020-001395 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Burmester GR, Curtis JR, Yun H, et al. An integrated analysis of the safety of tofacitinib in psoriatic arthritis across phase III and long-term extension studies with comparison to real-world observational data. Drug Saf 2020;43:379–92. 10.1007/s40264-020-00904-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sandborn WJ, Panés J, D’Haens GR, et al. Safety of tofacitinib for treatment of ulcerative colitis, based on 4.4 years of data from global clinical trials. Clin Gastroenterol Hepatol 2019;17:1541–50. 10.1016/j.cgh.2018.11.035 [DOI] [PubMed] [Google Scholar]
- 11.Strober BE, Gottlieb AB, van de Kerkhof PCM, et al. Benefit-risk profile of tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: pooled analysis across six clinical trials. Br J Dermatol 2019;180:67–75. 10.1111/bjd.17149 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.World Health Organization . Global Health Observatory data repository: life tables by country 2018, 2020. Available: https://apps.who.int/gho/data/?theme=main&vid=60050 [Accessed 5 Nov 2020].
- 13.Howlader N, Noone AM, Krapcho M. SEER Cancer Statistics Review,1975-2017, 2020National Cancer Institute. Available: https://seer.cancer.gov/csr/1975_2017/ [Accessed 4 Nov 2020]. [Google Scholar]
- 14.Burmester GR, Gordon KB, Rosenbaum JT, et al. Long-term safety of adalimumab in 29,967 adult patients from global clinical trials across multiple indications: an updated analysis. Adv Ther 2020;37:364–80. 10.1007/s12325-019-01145-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.US Food and Drug Administration . ACTEMRA® (tocilizumab) injection for intravenous/subcutaneous use: highlights of prescribing information 2013. Available: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125276s092lbl.pdf [Accessed 29 Oct 2020].
- 16.Janssen Biotech Inc . REMICADE® (infliximab): highlights of prescribing information, 2020. Available: http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/REMICADE-pi.pdf [Accessed 9 Dec 2020].
- 17.US Food and Drug Administration . ENBREL® (etanercept): highlights of prescribing information 2020. Available: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/103795s5574s5577lbl.pdf [Accessed 4 Nov 2020].
- 18.Smolen JS, Genovese MC, Takeuchi T, et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol 2019;46:7–18. 10.3899/jrheum.171361 [DOI] [PubMed] [Google Scholar]
- 19.Cohen S, van Vollenhoven R, Winthrop K. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT Phase 3 clinical program. Arthritis Rheumatol 2019;71:509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Winthrop KL, Citera G, Gold D, et al. Age-based (<65 vs ≥65 years) incidence of infections and serious infections with tofacitinib versus biological DMARDs in rheumatoid arthritis clinical trials and the US Corrona RA registry. Ann Rheum Dis 2021;80:134–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Winthrop KL, Harigai M, Genovese MC, et al. Infections in baricitinib clinical trials for patients with active rheumatoid arthritis. Ann Rheum Dis 2020;79:1290–7. 10.1136/annrheumdis-2019-216852 [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;24:2258–65. 10.1093/ibd/izy131 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Winthrop KL, Lebwohl M, Cohen AD, et al. Herpes zoster in psoriasis patients treated with tofacitinib. J Am Acad Dermatol 2017;77:302–9. 10.1016/j.jaad.2017.03.023 [DOI] [PubMed] [Google Scholar]
- 24.Winthrop KL, Curtis JR, Lindsey S, et al. Herpes zoster and tofacitinib: clinical outcomes and the risk of concomitant therapy. Arthritis Rheumatol 2017;69:1960–8. 10.1002/art.40189 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Yun H, Yang S, Chen L, et al. Risk of herpes zoster in autoimmune and inflammatory diseases: implications for vaccination. Arthritis Rheumatol 2016;68:2328–37. 10.1002/art.39670 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Curtis JR, Xie F, Yang S, et al. Risk for herpes zoster in tofacitinib-treated rheumatoid arthritis patients with and without concomitant methotrexate and glucocorticoids. Arthritis Care Res 2019;71:1249–54. 10.1002/acr.23769 [DOI] [PubMed] [Google Scholar]
- 27.Bechman K, Subesinghe S, Norton S, et al. A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis. Rheumatology 2019;58:1755–66. 10.1093/rheumatology/kez087 [DOI] [PubMed] [Google Scholar]
- 28.Singh JA, Saag KG, Bridges Jr SL. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2016;68:1–26. [DOI] [PubMed] [Google Scholar]
- 29.Baumrin E, Van Voorhees A, Garg A, et al. A systematic review of herpes zoster incidence and consensus recommendations on vaccination in adult patients on systemic therapy for psoriasis or psoriatic arthritis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol 2019;81:102–10. 10.1016/j.jaad.2019.03.017 [DOI] [PubMed] [Google Scholar]
- 30.Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG clinical guideline: preventive care in inflammatory bowel disease. Am J Gastroenterol 2017;112:241–58. 10.1038/ajg.2016.537 [DOI] [PubMed] [Google Scholar]
- 31.Winthrop KL, Park S-H, Gul A, et al. Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis. Ann Rheum Dis 2016;75:1133–8. 10.1136/annrheumdis-2015-207319 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.World Health Organization . Global tuberculosis report 2020, 2020. Available: https://www.who.int/tb/publications/global_report/en/ [Accessed 29 Oct 2020].
- 33.Franks AL, Slansky JE. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res 2012;32:1119–36. [PMC free article] [PubMed] [Google Scholar]
- 34.Lin C-J, Chang Y-C, Cheng T-Y, et al. The association between metabolically healthy obesity and risk of cancer: a systematic review and meta-analysis of prospective cohort studies. Obes Rev 2020;21:e13049. 10.1111/obr.13049 [DOI] [PubMed] [Google Scholar]
- 35.Kremer J, Bingham C, Cappelli L. Comparison of malignancy and mortality rates between tofacitinib and biologic DMARDs in clinical practice: five-year results from a US-based rheumatoid arthritis registry [abstract]. Arthritis Rheumatol 2019;71:2874. [Google Scholar]
- 36.Monemi S, Berber E, Sarsour K, et al. Incidence of gastrointestinal perforations in patients with rheumatoid arthritis treated with tocilizumab from clinical trial, postmarketing, and real-world data sources. Rheumatol Ther 2016;3:337–52. 10.1007/s40744-016-0037-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Curtis JR, Lanas A, John A, et al. Factors associated with gastrointestinal perforation in a cohort of patients with rheumatoid arthritis. Arthritis Care Res 2012;64:1819–28. 10.1002/acr.21764 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Curtis JR, Mariette X, Gaujoux-Viala C, et al. Long-term safety of certolizumab pegol in rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, psoriasis and Crohn’s disease: a pooled analysis of 11 317 patients across clinical trials. RMD Open 2019;5:e000942. 10.1136/rmdopen-2019-000942 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Rao VU, Pavlov A, Klearman M, et al. An evaluation of risk factors for major adverse cardiovascular events during tocilizumab therapy. Arthritis Rheumatol 2015;67:372–80. 10.1002/art.38920 [DOI] [PubMed] [Google Scholar]
- 40.Mease P, Charles-Schoeman C, Cohen S, et al. Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data. Ann Rheum Dis 2020;79:1400–13. 10.1136/annrheumdis-2019-216761 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Sandborn WJ, Panés J, Sands BE, et al. Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme. Aliment Pharmacol Ther 2019;50:1068–76. 10.1111/apt.15514 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.European Medicines Agency . EMA confirms Xeljanz to be used with caution in patients at high risk of blood clots, 2020. Available: https://www.ema.europa.eu/en/documents/referral/xeljanz-article-20-procedure-ema-confirms-xeljanz-be-used-caution-patients-high-risk-blood-clots_en.pdf [Accessed 9 Mar 2020].
- 43.US Food and Drug Administration . Initial safety trial results find increased risk of serious heart-related problems and cancer with arthritis and ulcerative colitis medicine Xeljanz, Xeljanz XR (tofacitinib), 2021. Available: https://www.fda.gov/drugs/drug-safety-and-availability/initial-safety-trial-results-find-increased-risk-serious-heart-related-problems-and-cancer-arthritis [Accessed 1 Mar 2021].
- 44.Sandborn WJ, Panés J, Sands BE, et al. P598 incidence of venous thromboembolic events in patients with ulcerative colitis treated with tofacitinib in the ulcerative colitis clinical development programme: an update as of May 2019. J Crohns Colitis 2020;14:S498–500. 10.1093/ecco-jcc/jjz203.726 [DOI] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
rmdopen-2021-001595supp001.pdf (936.9KB, pdf)
Data Availability Statement
On request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual deidentified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the USA and/or EU, or (2) in programmes that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The deidentified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.