The safety profile of tofacitinib in RA has been mainly characterized in extensive RCTs, LTE studies (ORAL SEQUEL up to 9.5 years), and the phase IV Oral Surveillance trial [
11]. The summary of safety results from studies in the tofacitinib clinical development program is shown in Table
1. The most frequent adverse events (AEs) reported are headache, upper respiratory tract infections, diarrhea, nasopharyngitis, hypertension, and nausea. Serious AEs (SAEs) included infections, mainly pneumonia, urinary tract infections, cellulitis, herpes zoster (HZ), appendicitis, and diverticulitis. HZ and pneumonia were the infections that most frequently led to the discontinuation of the treatment. Cohen et al. [
11], in an ISS of 9.5 years of experience with tofacitinib and 7061 patients (22,875 PYs of exposure), described an incidence rate (IR) for SAEs of 9.0 [95% confidence interval, (CI): 8.6–9.4]. Wollenhaupt et al. [
12], in a LTE study of up to 9.5 years of experience, showed that 52% of patients (from a total of 4481) discontinued the treatment with tofacitinib, 24% due to AEs and 4% because of inadequate response. The IR causing discontinuation was 6.8 (95% CI 6.4–7.2). Kivitz et al. [
39], in a post-hoc, pooled study involving phase III studies with 3881 patients with RA and designed to compare tofacitinib in monotherapy and in combination with cDMARDs, revealed that the IR for SAEs (6.2–6.7), discontinuation due to AEs (5.5–6.2), and severe infections (1.6–1.7) was lower in monotherapy than in combination (10.2–13.5, 10.8–11.0, and 3.4–3.6, respectively). Curtis et al. [
40] analyzed characteristics associated with the discontinuation of the treatment and reported that the patients who discontinued had a longer disease duration at baseline, had greater use of glucocorticoids (GCC), were smokers/ex-smokers, and came from the USA and Canada. Infections and all-cause mortality were evaluated in clinical trials in a data cut, including 4789 patients who received tofacitinib in phase II, III, and LTE studies (8460 PYs of exposure) [
41]. Factors associated with an increased risk of serious infections were: age (≥ 65 years versus < 65; hazard ratio, HR, 2.2; 95% CI 1.6–2.9), diabetes (with versus without; HR 2.0; 95% CI 1.4–2.9), dose of GCC (≥ 7.5 mg versus < 7.5 mg of prednisone or equivalent; HR 1.4; 95% CI 1.1–1.9), and dose of tofacitinib (10 mg versus 5 mg, BID; HR 1.4; 95% CI 1.1–1.8). In another post-hoc analysis, Curtis et al. [
42] analyzed the efficacy and safety of tofacitinib in older and younger patients with RA by using data from five phase III and two LTE studies. Compared with patients aged < 65 years, the exposure to tofacitinib was lower in patients aged ≥ 65 years (
n = 475/3111; 15.3%) in phase III studies (259 versus 1555 PYs) and LTE studies (962 versus 5072 PYs). Moreover, patients aged ≥ 65 years had a higher IR for SAEs and discontinuation due to AEs than those aged < 65 years. In the phase IV ORAL Surveillance, RA patients were ≥ 50 years old and had at least one of the following CV risk factors: current cigarette smoker, diagnosis of hypertension, diabetes mellitus, family history of premature coronary heart disease, history of coronary artery disease including a history of revascularization procedure, coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronary syndrome, and presence of extra-articular disease associated with RA [
1]. Patients receiving tofacitinib 10 mg BID had to stop and switch to 5 mg BID because of a dose-dependent signal of venous thromboembolic events (VTE).
Table 1
Summary of safety results from studies in the tofacitinib clinical development program
Overall safety profile | | Manuscript | Pool of phase III trials | 3881 | Lower IR with tofacitinib monotherapy than in combination: for SAEs (6.2–6.7 versus 10.2–13.5), discontinuation due to AEs (5.5–6.2 versus 10.8–11.0) and severe infections (1.6–1.7 versus 3.4–3.6) |
| Abstract | Pool of LTE studies | 4934 | Characteristics of patients who discontinued tofacitinib: longer disease duration at baseline, higher use of GCC, smokers/ex-smokers, and from the USA/Canada |
| Manuscript | LTE study (up to 9.5 years) | 4481 | Treatment discontinuation = 52% of patients: (24% due to AEs and 4% due to inadequate response); IR for AEs leading to discontinuation = 6.8 |
| Manuscript | ISS data (up to 9.5 years) | 7061 | Treatment discontinuation due to AEs = 23.1% of patients (IR = 7.1) |
| SmPC | Phase IV study: ORAL surveillance Special population ≥ 50 years + ≥ 1 CVRF | 4362 | IR were: pulmonary embolism 0.27 (0.12–0.52), deep vein thrombosis 0.30 (0.14–0.55), mortality 0.57 (0.34–0.89), and non-fatal serious infections 3.35 (2.78–4.01)a |
Infections | | Manuscript | Systematic review and meta-analysis: phase II and III trials | 5888 | IR for serious infections = 1.97 |
| Abstract | Meta-analysis; RCTs and LTE studies | NA | IR for serious infections = 1.70 (5 mg BID) and 1.79 (10 mg BID) with tofacitinib monotherapy and were 3.44 and 3.42, respectively, when combined with methotrexate |
van Vollenhoven et al. [ 43] | Manuscript | Pool of phase I, II, III trials and LTE studies | 7061 | Tofacitinib led to an initial elevation of ALC but decreased (stabilized) in 48 months; ALC < 500 cells/mm3 was associated with serious infections |
| Letter | Pool of phase II, III, and IIIb/IV with a TNFi control/comparator arm (< 65 vs. ≥ 65 years) | 2180 | IR for serious infections Aged < 65 years: tofa 5 mg BID 2.35 (1.42, 3.67); tofa 10 mg BID 2.00 (0.55, 5.13); ADA 1.48 (0.60, 3.06) Aged ≥ 65 years: tofa 5 mg BID 4.55 (1.67, 9.91); tofa 10 mg BID 11.31 (3.08, 28.95); ADA 2.44 (0.3, 8.81) |
Herpes zoster | | Manuscript | Pool of phase I, II, III trials and LTE studies | 6192 | IRs for herpes zoster = 0.56 (5 mg BID tofacitinib monotherapy) versus 5.44 (10 mg BID, csDMARD and GCC) |
Opportunistic infections and tuberculosis | | Manuscript | Systematic review and meta-analysis: RCTs and LTE studies | 75,000 in RCTs | 119 cases of active tuberculosis in LTE studies; IR of tuberculosis > 40/100,000 |
| Manuscript | Pool of phase II, III trials and LTE studies | 5671 | 60 opportunistic infections; IR for tuberculosis = 0.21; concurrent treatment of isoniazid and tofacitinib was associated with no tuberculosis infection |
| Manuscript | Basic research | – | Tofacitinib increased susceptibility to Candida albicans infection in BALB/c mice |
Malignancies | | Manuscript | ISS data | 5671 | Malignancies in 107 patients; mainly lung cancer, breast cancer, lymphoma, and gastric cancer |
| | Manuscript | ISS data | 6194 | Lymphoma occurred in 19 patients (IR = 0.10) |
| Manuscript | Systematic review, meta-analysis, and network meta-analysis | – | Odds ratio for overall malignancies = 1.15; treatment with tofacitinib is not associated with an increased risk for malignancies |
Interstitial lung disease | | Abstract | ISS data | 7061 | Interstitial lung disease in 42 patients (0.6%); characteristics of patients associated with the event: aged ≥ 65 and from Asia |
Cardiovascular AEs | | Manuscript | Systematic review and meta-analysis: RCTs | 11,799 | Odds ratio for cardiovascular AEs = 0.63; tofacitinib is not associated with risk for cardiovascular AEs, MACEs, or VTEs |
| Manuscript | Phase II trial | 111 | Atorvastatin reduces significantly the elevated levels of total and LDL-cholesterol and triglycerides increased by tofacitinib |
| Manuscript | Systematic review and meta-analysis: RCTs | NA | Tofacitinib is significantly associated with hypercholesterolemia (odds ratio 4.64), increased levels of HDL (2.25), and LDL (4.80) cholesterol |
Charles-Schoeman et al. [ 70] | Manuscript | Pool of phase III and LTE studies | 4827 from LTE | IR for MACEs was 0.4 per 100 PYs). Increased HDL cholesterol level after 24 weeks of treatment |
| Manuscript | Pool of phase I, II, and III RCTs and LTE studies | 7964 | IRs of venous thromboembolism and arterial thromboembolism are generally higher in patients with cardiovascular or VTE risk factors |
| SmPC | Phase IV study: ORAL Surveillance Special population ≥ 50 years + ≥ 1 CVRF | 4362 | IR for CV mortality within 28 days of the last treatment were 0.5 per 100 PYs (95% CI 0.2–0.8) for tofacitinib 10 mg, 0.2 per 100 PYs (95% CI 0.1–0.5) for tofacitinib 5 mg, and 0.2 per 100 PYs (95% CI 0.1–0.4) for TNF inhibitors |
Mortality | | Manuscript | Pool of phase II, III trials and LTE studies | 4789 | All-cause mortality rate = 0.3 per 100 patients-years |
The safety profile of tofacitinib observed in real-world settings is in concordance with the one found during the clinical development program. The summary of safety results from studies in real-world settings using tofacitinib for RA is shown in Table
2. Cohen et al. [
24], in a 3-year post-marketing study involving data from 102,214 patients worldwide and 34,223 PYs follow-up receiving tofacitinib, reported a total of 25,417 AEs, 4352 SAEs, and 102 fatal cases. Of all AEs, 83% were considered as non-serious. No new safety signals were identified in this study compared with the previously described ones. Data from the US Corrona Registry have been presented in recent years. The IR for AEs for up to 5 years was compared among patients who started treatment with tofacitinib 5 mg BID, bDMARD, or cDMARD [
22]. Propensity scores (PS)-trimmed and PS-matched were used for comparison purposes. Patients who started with tofacitinib or bDMARDs had similar IRs for major adverse CV events (MACE), serious infectious events and VTE rates. Nevertheless, the IR for HZ was higher in those starting with tofacitinib. These results are consistent with long-term clinical trial findings. Characteristics, treatment patterns and persistence in Canadian RA patients treated with tofacitinib have also been described in 4276 patients enrolled from 2014 to 2017 [
36]. In this period, 1226/3678 (33.3%) discontinued, mostly from lack of efficacy (35.7%) and AEs (26.9%). Persistence was 62.7% and 49.6% after 1 and 2 years of treatment, respectively.
Table 2
Summary of safety results from studies in real-world settings using tofacitinib for rheumatoid arthritis
Overall safety profile | | Abstract | Corrona Registry (5 years) | 1544 | Similar rates of MACE and serious infection events between initiating with tofacitinib and bDMARD; IR for herpes zoster higher for tofacitinib |
| Brief report | Post-marketing surveillance experience (3 years) | 34,223 PYs | 25,417 AEs, 4352 SAEs, and 102 fatal cases Of AEs, 83% were considered non-serious |
| Abstract | Case series: St. Gallen and-Aarau RA cohorts | 144 | Main reasons for discontinuation: inadequate response, gastrointestinal symptoms, and infection |
| Abstract | Retrospective case series: drug-based registry | 211 | Incidence rate of all-cause AEs higher in tofacitinib initiators (44.9 events/100 patient-years) versus TNFi (33.1 events/100 patient-years) |
| Letter | Corrona Registry | 10,357 | Age-/gender-standardized SIE IRs were higher in older versus younger patients, and similar between tofacitinib and bDMARD initiators for both age groups |
Herpes zoster | | Abstract | Post-marketing surveillance experience (3 years) | 3929 | Herpes zoster was the most frequently reported AE by preferred term (3.7%); tuberculosis in 3 patients; IR for herpes zoster = 6.81 and for serious infection events = 5.38 |
| Manuscript | Healthcare insurance data (5 years) | 2526 | Crude incidence of herpes zoster = 3.87/100 patient-years. Characteristics associated with infection: age (older), sex (female), prednisone (> 7.5 mg/day), prior infection, and higher number of hospitalizations |
| Manuscript | Healthcare insurance data (6 years) | 8030 | Incidence of herpes zoster lowest without GCC (3.4/100 patient-years with methotrexate versus 3.7 without). An increased risk associated with age (older), and sex (female) |
Hepatitis | | Letter | Retrospective case Series | 32 | Tofacitinib does not interfere with hepatitis C viral replication |
| Letter | Retrospective case series | 116 | 6 patients with previous hepatitis B infection were considered carriers and the remaining 75 had resolved the infections (normal levels of alanine aminotransferase) |
| Letter | Retrospective case series | 20 | No hepatitis B virus reactivation in patients with resolved infection receiving tofacitinib over 3 years |
Malignancies | | Abstract | Post-marketing surveillance experience (3 years) | 3929 | 25 cases of malignancies within first 6 months of treatment (12 associated with the treatment); IR for malignancy = 1.25 |
Gastrointestinal perforation | | Manuscript | Healthcare insurance data | 4755 | Incidence of lower tract gastrointestinal perforation = 1.29; predictors of risk were: age (older), diverticulitis/other gastrointestinal conditions, and prednisone (> 7.5 mg/day) |
Interstitial lung disease | | Abstract | Healthcare insurance data | 1310 and 1540 PYs | IR for interstitial lung disease = 3.05 |
Cardiovascular AEs | | Manuscript | Prospective case series | 46 | Improvement of the atherosclerosis, reduction of the disease activity, and limitation of the vascular damage |
| Abstract | Healthcare insurance data (6 years) | 2155 | 20 venous thrombotic events occurred in patients. IR for venous thrombotic events = 1.31 |
| | Manuscript | Healthcare insurance data | 2905 | IR for venous thromboembolism = 0.60 and 0.34; infrequent incidence of deep vein thrombosis |
DVT and PE | | Manuscript | FDA’s Adverse Event Reporting System | 317 | No raised rates for DVT and PE with tofacitinib |
Mortality | | Abstract | 3-Year Canadian experience | 4276 | 27 patients (out of 1226 of those who discontinued tofacitinib) died during tofacitinib treatment |
Malignancies
There is concern about the risk of malignancies associated with immunosuppression [
56]. Considering data from clinical trials and LTE studies, the risk of malignancies in patients with RA receiving 5 mg tofacitinib BID is similar to that reported for bDMARDs and cDMARDs. Data from clinical trials and LTE studies (5671 patients, and 12,664 PYs of exposure) have shown that the rate of malignancies does not increase with time exposure to tofacitinib, and the global risk for malignancies was similar to that expected in the RA population [
59]. Diverse ISS data from the tofacitinib clinical development program for RA, meta-analysis, and network meta-analysis have confirmed such results [
60,
61]. The risk of JAK/STAT inhibitor treatment for recurrent cancer in patients with previous malignancies is unknown (because these patients were excluded from clinical trials). The number of lymphoma events during the tofacitinib clinical development program (phase I, II, III clinical trials and LTE studies) has been published [
62]. Lymphoma is the most frequent malignancy in patients with RA. Its IR was 0.10, and it did not increase over the time of exposure (19 cases of 6194 patients; 19,406 PYs of exposure; 3.4 years of mean treatment duration). In data coming from the ISS up to 9.5 years, malignancies (excluding NMSC) occurred in 177 patients [2.5%; IR: 0.8 (95% CI 0.7–0.9)], NMSC in 129 patients [1.8%; IR: 0.6 (95% CI 0.5–0.7)] and lymphomas in 12 patients [0.2%; IR: 0.05 (95% CI 0.03–0.09)] [
11].
Regarding real-world data, Tamura et al. [
26], in the interim analysis of post-marketing reported cases in Japanese patients with RA treated with tofacitinib (3 years, up to November 2017), found that the rate of malignancies and deaths was similar to those in the clinical development program. A total of 3929 patients received tofacitinib and 25 developed a malignancy during the first 6 months of treatment (12 cases associated with the treatment), being the second-leading cause of death (5 out of 21 deaths). In the US Corrona register, Kremer et al. [
63] compared the 5-year IRs of events of special interest, including malignancy, among patients who initiated tofacitinib (1999; 4505 PYs) or bDMARDs (6354 patients; 16,670 PYs). Of patients initiating tofacitinib and bDMARD, 88% and 59% had received previously a bDMARD. The IRs were similar between groups and for trimmed/matched analyses, in total 1.0 (95% CI 0.7–1.6) for total cancer excluding NMSC and 1.0 (95% CI 0.7–1.5) for NMSC. The adjusted HR was 1.04 (95% CI 0.7–1.6) for total cancer excluding NMSC and 1.0 (95% CI 0.7, 1.5) for NMSC. Data from a 3-year post-marketing study [
24] [
24] showed an estimated IR for neoplasm events by 6-month intervals ranging from 0.14 to 0.69 per 100 patient years, with an overall rate of 0.5 per 100 patient-years, which was highest after the first year and stabilized subsequently.
Gastrointestinal Perforations
Data from the ORAL Sequel (LTE) study [
12], with an up to 9.5-year follow-up, reported 22 cases of gastrointestinal (GI) perforations. Perforations occurred in the large intestine (excluding the anus and rectum,
n = 13), gastroduodenal area (
n = 3), anus and rectum (
n = 2), small intestine (
n = 1), and other non-specified locations (
n = 3). All patients received concomitant treatment with nonsteroidal anti-inflammatory drugs or GCC, medications known to be associated with the development of GI perforations. In the last report from ISS, GI perforations occurred in 28 patients (0.4%; IR: 0.1; 95% CI 0.1–0.2) [
11].
Xie et al. [
16] described the risk of GI perforations in RA patients receiving various therapies in real-world settings. The incidence with tofacitinib was 1.3/1000 PYs, which was higher than for TNFi (0.8/1000 PYs). The incidence with tocilizumab, abatacept, and rituximab was 1.6, 1.1, and 0.7, respectively. The risk of lower GI perforations remained high after adjusting for age, sex, nonsteroidal anti-inflammatory drugs, GCC, peptic ulcer, and other GI conditions. This increased risk could be related to IL-6 inhibition. Real-world data from the US Corrona Registry showed an age- and gender-standardized IR for GI perforations of 0.05 in patients receiving tofacitinib, similar to those treated with bDMARDs (IR: 0.05) and cDMARDs (IR: 0.04) [
64].
Interstitial Lung Disease
Interstitial lung disease (ILD) is an important extra-articular manifestation of RA. Different clinical trials have reported cases of ILD in patients with RA receiving tofacitinib, some of them fatal [
1]. The relationship between JAK/STAT inhibition and ILD is so far unknown. In a pooled post hoc analysis of data from the tofacitinib clinical development program, Citera et al. [
65], analyzed the IR of ILD in patients with active RA receiving tofacitinib. A total of 42 patients (0.6%, out of 7061; 23,394 PYs) had an ILD event during treatment with tofacitinib. Incidence rates were higher in patients older than 65 years and from Asia (compared with non-Asian ones). In phase I, II, III, IV and LTE studies, the incidence of ILD events reported after tofacitinib treatment was 0.18, and ILD events were associated with known risk factors for ILD in RA. In patients with ILD events (case-matched control analysis), the ILD group had a numerically higher proportion of patients with some characteristics such as Asian (31.0% versus 17.6% non-Asian), smokers (50.0% versus 39.5% ex-smokers), rheumatoid factor positive (89.2% versus 71.0% negative), anti-CCP antibody positive (54.8% versus 46.7% negative), higher baseline erythrocyte sedimentation rate (57.0 versus 46.9 mm/h, control) and C-reactive protein (25.4 versus 15.4 mg/L control) and previous MTX treatment (90.5% versus 79.5%, without), csDMARDs (61.9% versus 55.2%), TNF inhibitors (26.2% versus 18.6%), and concomitant GCC (71.4% versus 52.9%).
Regarding real-world data, Xie et al. [
17], in a comparative study, evaluated the risk of ILD in 150,225 patients with RA receiving biologic agents or csDMARD with data from Medicare 2006–2014 and Market Scan (2010–2015). The overall IR for ILD was 4.8 per 1000 PYs. Crude IRs varied between 3.1 (95% CI 1.2–8.1) for tofacitinib and 8.4 (95% CI 7.3–9.6) for infliximab in Medicare and between 0.6 (95% CI 0.1–4.1) for certolizumab and 3.9 (95% CI 2.1–7.2) for infliximab in Market Scan. Case series have also been published reporting RA patients with previous ILD who received tofacitinib to treat the disease [
66,
67]. Conversely, Sendo et al. [
68], in a study with SKG mice (animal model of RA that develops ILD), demonstrated that tofacitinib increased the myeloid-derived suppressor cells (MDSCs) and decreased the progression of ILD compared with controls. This potential benefit of tofacitinib on ILD in an experimental model of RA merits further evaluation in patients with RA, so it will be evaluated in the PULMORA phase IV study [
69], a randomized, actively controlled, open-label, assessor-blinded, multicenter 48-week phase IV independent trial to evaluate the effects of tofacitinib versus methotrexate on interstitial pulmonary abnormalities.
Cardiovascular AEs
Data from the ISS for up to 9.5 years indicated that MACEs were reported in 85 patients (1.3%; IR: 0.4 [95% CI 0.3–0.5]) [
11]. Charles-Schoeman et al. [
70] evaluated the risk for CV events with tofacitinib using pooled data from six phase III studies and two LTE studies over 7 years in RA patients. The IR for MACE was 0.4 per 100 PYs. A protective association with subsequent MACEs was found with an increased HDL cholesterol level and decreased total cholesterol to HDL cholesterol ratio, but no impact was shown for LDL cholesterol or total cholesterol. McInnes et al. [
71], in a randomized phase II, placebo controlled, multicenter phase II study, open-label for tofacitinib and blinded for atorvastatin, revealed that atorvastatin can decrease the increased levels of lipids induced by tofacitinib, without reducing its efficacy in RA. Nurmohamed et al. [
72], in a systematic review on the impact of biologic agents and tofacitinib in CV risk factors, found no increase in number of CV events with these medications. Similarly, Xie et al. [
73], in another systematic review and meta-analysis, compared the impact of JAK inhibitors on risk of CV events in patients with RA. They analyzed data from 26 RCTs and 11,799 patients and showed that there is no significant association between tofacitinib and risk of CV events (Odds ratio 1.0; 95% CI 0.6–1.8). Souto et al. [
74], in a systematic review and meta-analysis of RCTs, demonstrated that the mean increase in the HDL and LDL cholesterol levels was higher in patients with RA receiving tofacitinib than biologic agents. In ORAL Surveillance, the IR for CV mortality within 28 days of the last treatment was 0.5 per 100 PYs (95% CI 0.2–0.8) for tofacitinib 10 mg, 0.2 per 100 PYs (95% CI 0.1–0.5) for tofacitinib 5 mg, and 0.2 per 100 PYs (95% CI 0.1–0.4) for TNF inhibitors. To date, this study only has provided IR data for CV mortality and not for general CV events. Previous data from IR for CV mortality derive from ISS after 9.5 years (as adjudicated MACE, including CV death, of 0.4; 95% CI 0.3–0.5]) [
11] and 9.5 years of experience (IR: 0.1; 95% CI 0.1–0.2) [
12]. Compared to TNF inhibitors, the incident rate ratio was 2.1 (95% CI 0.8–6.2) with tofacitinib 10 mg and 1.1 (95% CI 0.4–3.7) with tofacitinib 5 mg in these patients who were at least 50 years of age and had one or more CV risk factors [
1].
Regarding real-world studies, data from a 3-year post-marketing study (Cohen et al. [
24]) revealed a decrease in IR for CV events from 1.6 per 100 patient-years at the first 6-month interval to 0.3 at the final 6-month interval. The most frequent events were: myocardial infarction (29 cases), cardiac failure/cardiac failure congestive (21), cardiac disorder (19), atrial fibrillation (17), cardiac arrest (5), coronary artery disease (4), pericardial effusion (4), and tachycardia (3 cases). Data from the prospective, observational 5-year study embedded in the ongoing US Corrona Registry showed that, in 1544 patients initiating tofacitinib (2138 PYs) and 7083 with bDMARD (9904 PYs), rates of MACE were similar in both groups, HR 0.6 (95% CI 0.3–1.18) [
22]. Kume et al. [
27], in a prospective cohort study in real-word settings, found a tendency to a possible beneficial effect on atherosclerosis in patients with active RA receiving tofacitinib (despite serum cholesterol increased) as measured by carotid intima-media thickness.
Deep Venous Thrombosis and Pulmonary Thromboembolism
Long-term extension studies and phase III studies have not shown an increased risk of VTE with tofacitinib. Final data for the ORAL Sequel LTE study for up to 9.5 years in patients with RA showed an IRs for deep venous thrombosis (DVT) of 0.1 (95% CI 0.1–0.3) for tofacitinib 5 mg BID and 0.1 (95% CI 0.1–0.2) for 10 mg BID [
12]. The IRs for pulmonary embolism (PE) was 0.1 (95% CI 0.1–0.3) for tofacitinib 5 mg BID and 0.1 (95% CI 0.1–0.2) for 10 mg BID. Data from the ISS up to 9.5 years showed that DVT was reported in 36 patients (0.5%; IR: 0.2 [95% CI 0.1–0.2]) and PE in 28 patients (0.4%; IR: 0.1 [95% CI 0.1–0.2]) [
11]. Mease et al. [
75], analyzing data from phase I, II, and III RCTs and LTE studies [including 12,410 tofacitinib-treated patients from the development programs (RA:
n = 7964; psoriasis, PsO:
n = 3663; PsA:
n = 783)], reported that IRs of venous thromboembolism and arterial thromboembolism are generally higher in patients with cardiovascular or VTE risk factors. In RA, PsO, and PsA programs, with 5 and 10 mg tofacitinib, the IR for DVT (0.17; 95% CI 0.09–0.27; 0.15, 95% CI 0.09–0.22), PE (0.12, 95% CI 0.06–0.22; 0.13; 95% CI 0.08–0.21), and arterial thromboembolism (ATE, 0.32, 95% CI 0.22–0.46; 0.38; 95% CI 0.28–0.49) were similar. These AEs, along with thromboembolic events, were lower in patients who did not show baseline cardiovascular or VTE risk factors. In LTE studies and ISS, including all patients ages [
70], a relationship between tofacitinib (5 mg BID) and VTEs, including DVT and PE, was not found.
The phase IV ORAL Surveillance study was performed as an FDA requirement to study the CV safety profile of tofacitinib in RA patients at least 50 years old and with at least one additional CV risk factor. EMA’s safety committee has informed on 17 cases of PE out of 3123 patient-years with the tofacitinib 10 mg twice daily dose and 9 cases of PE out of 3317 patient-years with the tofacitinib 5 mg twice daily dose compared with 3 cases out of 3319 patient-years with a TNF inhibitor [
76]. The IR for PE was 0.5 per 100 PYs (95% CI 0.3–0.9) for tofacitinib 10 mg, 0.3 per 100 PYs (95% CI 0.1–0.5) for tofacitinib 5 mg, and 0.09 per 100 PYs (95% CI 0.02–0.26) for TNF inhibitors [
1]. Compared with TNF inhibitors, the HR for PE was 6.0 (95% CI 1.8–20.3) for tofacitinib 10 mg and 3.0 (95% CI 0.8–11.1) for tofacitinib 5 mg. Regarding DVT, the IR was 0.4 per 100 PYs (95% CI 0.2–0.7) for tofacitinib 10 mg, 0.3 per 100 PYs (95% CI 0.1–0.6) for tofacitinib 5 mg, and 0.2 per 100 PYs (95% CI 0.1–0.4) for TNF inhibitors [
1]. Compared with TNF inhibitors, HR was 2.1 (95% CI 0.8–5.7) with tofacitinib 10 mg and 1.7 (95% CI 0.6–4.6) with tofacitinib 5 mg. The IR for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54; 95% CI 0.32–0.87) versus patients with baseline CV risk factors treated with tofacitinib 10 mg twice daily in the RA clinical program (0.24; 95% CI 0.13–0.41) [
75,
76]. According to these data, tofacitinib should be used with caution in patients with known risk factors for VTE [
1], such as those with heart failure, cancer, or any inherited blood coagulation disorder [
76,
77]. Verden et al. [
78] evaluated postmarketing reporting rates for related thromboembolic risks with three inhibitors of JAK (tofacitinib, tofacitinib extended-release, and ruxolitinib), and found no raised rates for DVT and PE. Nevertheless, they showed a trend toward higher-than-expected reporting rates.
Regarding real-world settings, IR for PE reported in the Corrona Registry [
22] (including tofacitinib-naive/bDMARD treated and tofacitinib treated) with baseline CV risk factors were similar to those observed among the corresponding patients in the tofacitinib development program. No signals of disproportionate reporting of DVT, PE, or ATE with tofacitinib were identified in the DA Adverse Event Reporting System (FAERS) database [
75]. Yun et al. [
19], in a retrospective study using data from 2010–2015 US MarketScan claims, compared the risk of VTEs between patients with RA who initiated treatment with tofacitinib and ADA. The authors identified a total of 6022 initiators for ADA (4798 PYs) and 2155 for tofacitinib (1523 PYs). The authors detected 60 VTEs (20 in tofacitinib users and 40 in ADA users) and concluded that the risk was comparable between the two treatments (IR with tofacitinib: 1.3; 95% CI 0.8–2.0 versus IR with ADA: 0.83; 95% CI 0.6–1.1; HR of VTE for tofacitinib: 1.07; 95% CI 0.5–2.1). Desai et al. [
20], in a recent observational cohort study using administrative claims data from the Truven Marketscan (2012–2016) and Medicare (and data from 50,865 patients with RA who started treatment with tofacitinib or TNFi), concluded that the incidence of DVT in these patients is infrequent (< 1 per 100 person-years). The absolute rates of VTE in routine care RA patients were low and comparable to those observed in pre-marketing trials of baricitinib and tofacitinib. Moreover, patients from Medicare insurance had a mean age of 71 years and a rude incidence rate per 100 PYs of 1.12 with tofacitinib (95% CI 0.5–2.3 versus 0.9; 95% CI 0.8–1.1 with TNF inhibitors). Cohen et al. [
24], in the 3-year post-marketing study, reported 15 cases of pulmonary embolism and 9 of pulmonary thrombosis. Liang et al. [
79] evaluated the incidence of inpatient VTEs in treated patients with RA by using a US claims database. The age and sex standardized IR for VTE was 0.9 per 100 PYs (95% CI 0.7–1.0). Results from a pharmacovigilance analysis performed by the World Health Organization considering the ongoing clinical debate on the safety profile of tofacitinib and baricitinib showed that patients who switched to another bDMARD or tsDMARD had a higher risk than csDMARD and first bDMARD or tsDMARD users [
80]. Patients with a DVT or PT/PE were older and more frequently reported use of prothrombotic medications (e.g., contraceptives) or existing clinically relevant risk factors of TEV (e.g., treatment with antithrombotic agents). Further risk factors potentially associated with risk of blood clots in lungs are having heart failure, having inherited blood clotting disorders, having had blood clots in the veins, having cancer and planning to have or having recently had major surgery [
81]. They concluded that, to date, real-world evidence regarding the safety of JAK inhibitors is lacking, and with the inherent limitations of pharmacovigilance data, the results of the study suggest that the thromboembolic safety of JAK inhibitors requires ongoing real-world assessment to determine whether a class and dose relationship exists. Thus, real-world assessments are needed to determine the safety of JAK inhibitors.
Mortality
In patients who received tofacitinib in phase II, III, and LTE studies, the overall all-cause mortality rate was 0.3 per 100 PYs (95% CI 0.2–0.4) and 0.5 per 100 PYs (95% CI 0.4–0.7) if deaths occurring at any time after the last dose are included [
41]. Mortality rates were similar between phase III and LTE studies, and within phase III ones, among groups receiving tofacitinib (5 and 10 mg, BID), ADA, and placebo. Causes of death in phase III studies included: infection (6 cases), non-CV causes (3 cases, 1 of them receiving placebo), cardiac events (2 cases, 1 of them receiving ADA), cancer (1 case), trauma (1 case), or unknown cause (1 case). In the LTE studies causes were: infection (6 cases), cancer (6 cases), cardiac events (3 cases), non-CV causes (2 cases), suicide (2 cases), or unknown cause (1 case) [
41]. Wollenhaupt et al. [
12], in the LTE study of up to 9.5 years with tofacitinib, reported an IR for all-cause mortality of 0.3 (95% CI 0.2–0.4). In the interim results of the Oral Surveillance study, there were 28 deaths from all causes out of 3140 PYs in the tofacitinib 10 mg BID arm and 19 deaths from all causes out of 3324 PYs in the tofacitinib 5 mg BID arm compared with 9 cases out of 3323 PYs in the TNF inhibitor arm [
75]. The mortality within 28 days of the last treatment was higher in patients treated with tofacitinib than in those taking TNF inhibitors [
1]. The IRs were: 0.9 (95% CI 0.6–1.3) for tofacitinib 10 mg, 0.6 (95% CI 0.3–0.9) for tofacitinib 5 mg, and 0.3 (95% CI 0.1–0.5) for TNF inhibitors. Compared with TNF inhibitors, HR was 3.3 (95% CI 1.6–7.0) for tofacitinib 10 and 2.1 (95% CI 1.0–4.7) for tofacitinib 5 mg. The main causes of mortality were: CV events, infections, and malignancies [
1]. The IRs for fatal infections (within 28 days of treatment) were 0.18 (95% CI 0.07–0.39) with tofacitinib 5 mg BID, 0.22 (95% CI 0.09–0.46) with tofacitinib 10 mg BID, and 0.06 (95% CI 0.01–0.22) with TNF inhibitors [
45].
Regarding real-word data, in the US Corrona Registry, the IR for death was 1.0 (95% CI 0.6–1.6), which was also similar for patients initiating bDMARDs [
64]. Pope et al. [
36], when describing the 3-year experience with tofacitinib in Canada, indicated that 27 patients (out of 1226 of those who discontinued tofacitinib, 2.2%) passed away during the treatment. Cohen et al. [
25], in the 3-year post-marketing study, reported an overall mortality rate of 0.3 per 100 PYs. Causes of death were: infections (15 cases), CV events (8 cases), stroke (4 cases), pulmonary embolism (2 cases), ILD (2 cases), demyelination (1 case), Stevens-Johnson’s syndrome (1 case), and surgical complications (1 case).
Risk Characterization and Relative Safety
A relatively large number of patients followed up for an adequate period of time and involving special populations is necessary to establish consistent conclusions about the safety of uncommon AEs. Tofacitinib RCTs and LTE studies and safety studies in special populations provide reassurance about the possibility of detecting additional unexpected adverse events [
38]. The last ISS analysis included 7061 patients, representing 22,875 PY of tofacitinib exposure, with a median exposure of 3.1 years, and 30% of patients had > 5 years of exposure [
11]. Study A3921133 contributes > 10,000 patients/year of exposure to tofacitinib in patients with CV risk factors [
75]. Lee et al. [
82] evaluated the relative efficacy and safety of tocilizumab, rituximab, abatacept, and tofacitinib in 1796 patients with RA having inadequate response to TNFi. By using a Bayesian network meta-analysis of RCTs, the authors found no significant differences regarding the number of withdrawals due to AEs. They suggested a comparable safety profile between biologic agents and tofacitinib. None of the treatments were associated with a significant risk of withdrawals due to AEs. Vieira et al. [
83], in another Bayesian network meta-analysis of tofacitinib versus biologic agents, also concluded that the treatment with 5 mg tofacitinib BID has AE rates comparable to those of abatacept, golimumab, tocilizumab, and rituximab during the 24 first weeks.