Abstract
Objectives: Baricitinib is a selective oral inhibitor of JAK1/JAK2 for patients with moderately-to-severely active rheumatoid arthritis (RA). Baricitinib’s safety profile in Japanese patients was evaluated using six studies (five Ph2/Ph3 trials, one long-term extension study through 01 September 2016) from an integrated database (nine RA studies).
Methods: Incidence rates (IRs) or exposure-adjusted IRs (EAIRs) of adverse events (AEs) per 100 patient-years (PY) were calculated using data which included RA patients exposed to any baricitinib dose.
Results: Five hundred and fourteen Japanese patients received baricitinib for 851.5 total PY of exposure (median 1.7 years, maximum 3.2). The EAIR of treatment-emergent AEs was 57.4/100PY. There were no deaths; 31 patients had serious infections (IR: 3.6/100PY), 55 herpes zoster (6.5), 0 tuberculosis, 10 malignancies (1.1) including two lymphomas, two major cardiovascular AEs (0.3), one gastrointestinal perforation (0.1), and four deep vein thrombosis (0.5). In Japanese patients, herpes zoster was more frequent than that of patients overall in the integrated database, but the events were considered manageable.
Conclusion: In this analysis, baricitinib had acceptable safety profile in Japanese RA patients in the context of demonstrated efficacy. Aside from herpes zoster, baricitinib safety was not notably different between Japanese RA patients and those RA patients in the integrated database.
Trial registration: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at https://clinicaltrials.gov/
Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammatory synovitis and progressive destruction of cartilage and bone. It is associated with joint swelling and tenderness, fatigue, and physical disability, as well as elevation of acute-phase reactants such as C-reactive protein (CRP). Treatment for RA focuses on controlling synovitis, improving physical function, and preventing joint damage [Citation1].
Conventional synthetic (cs) disease modifying antirheumatoid drugs (DMARDs), including methotrexate (MTX), have been used for RA treatment in Japan for the last few decades. Biological (b) DMARDs have been approved since 2003 in Japan. Both csDMARDs and bDMARDs provide clinical effectiveness and acceptable safety profiles, although there are some safety concerns including an increased risk of infections [Citation2,Citation3].
JAK inhibitors have been recently added as a new treatment option for RA. JAK-mediated signaling pathways are known to play an important role in RA pathogenesis [Citation4–6]. Baricitinib, a selective oral inhibitor of Janus kinase (JAK) 1 and JAK2, demonstrated significant clinical efficacy and acceptable safety in Phase 3 RA clinical trials [Citation7–10]. The efficacy and safety results from Japanese patients who participated in these Phase 3 clinical trials were similar to those from the overall trial patients [Citation11]. Baricitinib improved the signs and symptoms of RA, improved physical functioning, and inhibited the progression of joint destruction. Baricitinib also improved patient-reported outcomes early in the treatment of these patients. In September 2017, baricitinib was approved in Japan for the treatment of patients with RA.
Double-blind, randomised controlled trials are the standard approach to determine the short-term safety of therapy. Agents used to treat chronic conditions, such as RA, also need to demonstrate long-term safety. Furthermore, for low IR events, an integrated analysis using total exposure of treatment is more valuable.
In this report, we direct our attention to these needs by developing a comprehensive safety profile of baricitinib in Japanese RA patients which integrates available data from a Japan clinical trial and several multi-regional clinical trials including a long-term extension (LTE) study.
Materials and methods
Study designs and patients: Patient-level data from nine RA studies (seven double-blind randomized clinical trials (four Phase 3, three Phase 2), one open-label Phase 1b study, and one ongoing LTE study (through 01 September 2016)) were initially integrated for assessment of safety in the overall RA patients (trial descriptions, ) [Citation12]. Japanese patients joined six of these trials (four Phase 3, one Phase 2, and the ongoing LTE study); data from these patients were then extracted to assess safety for the Japanese RA patients.
Table 1. Patient populations.
Patients in Phase 2/Phase 3 trials were aged ≥18 years with moderately-to-severely active RA. Patients were excluded who had recent serious infections (including active or untreated latent tuberculosis (TB)) and/or selected laboratory abnormalities. Baricitinib doses were evaluated in a range from 1 to 15 mg daily. Doses of 1–8 mg daily were evaluated in two Phase 2 dose-ranging studies; higher doses (up to 15 mg daily) were administered in earlier phase studies. The Phase 3 and LTE studies included only the 2 and 4 mg doses. Trials were conducted in accordance with ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines, and were approved by each center’s institutional review board or ethics committee. Written informed consent was provided by all patients.
Patients who completed the Phase 3 or Phase 2 NCT01185353 [Citation13] trials were eligible for the LTE study; those who enrolled in the Japan Phase 2 study NCT01469013 [Citation14] were not eligible for the LTE study. Patients who were randomized to 2 mg and not rescued in the originating study continued on 2 mg in the LTE study; all other patients received 4 mg independent of originating study treatment. Patients who received 4 mg for at least 15 months without rescue and maintained low disease activity or remission were blindly re-randomized to 4 mg or to a step-down dose of 2 mg.
The integrated analysis set (All-bari-RA) included all available data on patients (Japanese and non-Japanese) who received at least one dose of baricitinib [Citation12]. For the Japanese patients, the dose ranged from 1 to 8 mg daily. Although uncontrolled, this analysis set provides the largest number of PY of exposure to date in Japanese patients with RA, and is sufficient to assess uncommon events.
Assessments: Evaluation of safety included treatment-emergent AEs (TEAEs), AEs leading to temporary interruption or permanent discontinuation of study drug, serious AEs (SAEs), AEs of special interest (including serious infection, herpes zoster, TB, malignancy, major cardiovascular adverse event (MACE), deep vein thrombosis (DVT)/pulmonary embolism (PE)), and death. Herpes zoster was reported as a MedDRA preferred term and as a cluster by counting several MedDRA preferred terms which Eli Lilly and Company defined. SAEs were defined as any event that met the International Conference on Harmonisation E2A seriousness criteria [Citation15].
For TEAEs and AEs leading to temporary interruption, exposure-adjusted incidence rates (EAIRs) were calculated as the number of unique patients with an event per 100 patient-years (PY) of overall exposure time. For AEs leading to permanent discontinuation and SAEs, EAIRs were calculated as the number of unique patients with an event per 100 PY of overall exposure time, which included any post-drug follow-up time. For AEs of pre-specified special interest including deaths, incident rates (IRs) were calculated as the number of unique patients with an event per 100 PY of observation time, which included any post-drug follow-up time, censored at event.
Results
Patients: In the All-bari-RA analysis set, 514 Japanese patients with RA were treated with baricitinib. At baseline (i.e. patients entered the originating study), a majority of the Japanese patients were female (76%), with a mean age of 54 years and a mean of 5.6 years since diagnosis of RA. Most (80%) were on concomitant MTX. The mean number of swollen joints (66 joints assessed) and Clinical Disease Activity Index (CDAI) score were 11 and 26, respectively, which indicated moderately-to-severely active disease ().
Table 2. Baseline demographics and measures of disease activity.
Five hundred and fourteen Japanese patients received at least one dose of baricitinib for a total of 851.5 PY of exposure. Among them, 407 patients continuously received baricitinib 4 mg. Over 82% of patients had ≥1 year and 42% had ≥2 years of treatment, with a maximum exposure of 3.2 years and a median of 1.7 years ().
Table 3. Safety measures of special interest.
AEs including SAEs: The TEAE EAIR of the Japanese patients was 57.4 per 100 PY (). Most commonly reported TEAEs were nasopharyngitis (n = 184, EAIR 21.6), increased blood creatine phosphokinase (n = 56, EAIR 6.6), abnormal hepatic function (n = 55, EAIR 6.5), and herpes zoster (reported as a preferred term) (n = 54, EAIR 6.3) (Supplementary Table 1). Most TEAEs (92%) were mild or moderate in severity. The system organ classes (SOCs) in which TEAEs were most commonly reported were Infections and infestations (hereafter, named by infections) (EAIR 41.8), Gastrointestinal disorders (EAIR 23.4), and Investigations (EAIR 19.4).
The SAE EAIR was 9.3 (). The most commonly reported SAEs were herpes zoster (preferred term) (n = 13, EAIR 1.5), pneumonia (n = 6, EAIR 0.7), and interstitial lung disease (ILD) (n = 4, EAIR 0.5). The most frequently reported SAEs were infections. Through 01 September 2016, there were no deaths in the Japanese RA patients treated with baricitinib.
Table 4. Serious adverse events (SAEs) detail.
The most frequently reported AEs leading to temporary interruption or permanent discontinuation were infections (Supplementary Table 1). The most common infection leading to discontinuation was herpes zoster (preferred term) for which discontinuation was required in all Phase 3 protocols (but not LTE).
AEs of special interest
Infection: The serious infection (reported as SAE) IR was 3.6 (95% confidence interval [CI]: 2.5, 5.2) (). The most common serious infections were herpes zoster (preferred term) (n = 13, EAIR 1.5), pneumonia (n = 6, EAIR 0.7), Pneumocystis jirovecii pneumonia (n = 3, EAIR 0.3), enteritis infectious (n = 2, EAIR 0.2), and pyelonephritis (n = 2, EAIR 0.2); there were no infections leading to death.
The infection EAIR was 41.8, and the vast majority of infections (97%) were mild or moderate. The IR of herpes zoster (reported as a cluster) was 6.5 (95%CI: 4.9, 8.4), with most cases (93% [51/55]) being mild to moderate. About 16% (9/55) had multidermatomal distribution (≥3 contiguous or ≥2 non-contiguous dermatomes), and none had visceral involvement. After discontinuation of baricitinib and use of antiviral therapy, most of the herpes zoster (cluster) cases (40/55) recovered or resolved during the respective studies. The other 15 patients had not recovered by the end of follow-up time. There were three cases of post herpetic neuralgia reported. Three cases of Pneumocystis jirovecii pneumonia were reported in three patients (EAIR 0.3). These were all SAEs. All three patients had risk factors; three received concomitant MTX, and two had baseline lymphopenia. There were no cases of sepsis, no cases of new onset TB or reactivation of latent TB.
Malignancies: Ten malignancies (excluding non-melanoma skin cancer (NMSC)) were diagnosed in 10 patients (IR 1.1 (95%CI: 0.6, 2.1)): breast cancer (n = 2, including one case with metastasis); and one case each of cervix carcinoma, chondrosarcoma, diffuse large B-cell lymphoma, gastric mucosa-associated lymphoid tissue (MALT) B-cell lesion lymphoma, gastric cancer, malignant fibrous histiocytoma, rectal cancer, and renal cell carcinoma (). To further quantify malignancy risk, we assessed patients who were initiated and maintained on 4 mg (n = 407, 653.8 PY) in the All-bari-RA analysis set. In this All-bari-RA 4 mg sub-cohort, the malignancy (excluding NMSC) IR was 1.1. In the All-bari-RA analysis set, no lymphoma cases were reported in the control periods; two cases were reported during the LTE study (IR 0.2, ). These two patients initially received placebo and were rescued to 4 mg. Lymphoma types were B-cell and gastric MALT B-cell lesion. The patient with B-cell lymphoma had background MTX treatment as a risk factor; the patient with MALT lymphoma, concomitant use of tacrolimus. The MALT lymphoma was successfully treated with H. pylori eradication alone. There were no other cases of lymphoproliferative disorder. There was one NMSC case reported (IR 0.11 (95%CI: 0.0, 0.6), ). The patient developed a scab with erythema more than 20 years ago. This was treated with cryotherapy approximately 7 years before the study, however, a black scar remained and continued to grow. No change in size was noted after entry into the study. During the LTE study, biopsy revealed this to be Bowen’s disease and a tumorectomy was performed.
Table 5. Case summary of malignancies (excluding NMSC) for all the cases in the All-bari-RA analysis set.
Gastrointestinal (GI) perforation: One GI perforation case (perforated diverticulum) was reported (EAIR 0.12 (95%CI: 0.0, 0.7), ). The patient was on MTX background treatment and taking NSAIDs and prednisone.
MACE: Two MACE cases were reported (IR 0.3 (95%CI: 0.0, 1.0), ): basal ganglia haemorrhage and cerebral infarction. The basal ganglia haemorrhage resolved without interruption of baricitinib. The patient with the basal ganglia haemorrhage had hypertension and hyperlipidemia. In the cerebral infarction case, the patient was reported as recovering without interruption of baricitinib. The patient was taking concomitant prednisolone, a low level risk factor.
DVT/PE: A total of four patients experienced DVT (IR 0.5 (95%CI: 0.1, 1.2), ). All patients had one or more risk factors which included obesity and prior history of DVT. One of the four DVTs was serious. Anticoagulants were administered and baricitinib was stopped, and the patient recovered. No patients experienced PE at the cut-off date of 01 Sep 2016. After the cut-off date, one patient experienced PE.
Interstitial lung disease/pulmonary fibrosis (PF): Four patients experienced ILD (EAIR 0.5 (95%CI: 0.1, 1.2), ). Four patients had serious ILD; all patients stopped baricitinib and the three patients receiving MTX stopped MTX. The three patients with serious ILD recovered, and the other one was recovering at the end of follow-up time. The patients with serious ILD had one or more risk factors such as concomitant use of MTX, prior treatment for breast cancer, or history of smoking; one patient had a medical history of MTX-induced interstitial pneumonia.
Discussion
A safety assessment of baricitinib in Japanese RA patients was conducted using an integrated analysis of clinical studies with up to 3.2 years of exposure. Our data suggest that the safety profile of Japanese RA patients was generally similar to the profile seen in the RA patients overall in the integrated database (overall patients) aside from herpes zoster, the risk of which was higher in Japanese patients treated with baricitinib [Citation12]. The safety profile of Japanese patients treated with baricitinib was also generally similar to the profiles observed for Japanese patients in other RA therapeutic trials [Citation16–20].
In the Japanese patients, over 82% had ≥1 year and 42% had ≥2 years of baricitinib treatment, while in the overall patients nearly 78% had ≥1 year and 54% had ≥2 years of treatment (). The exposure duration was generally similar in both patient populations.
In the Japanese patients, the TEAE EAIR was 57.4; TEAEs were most frequently reported in the SOC of Infections. Although the TEAE EAIR was higher for the Japanese patients (57.4) than that of the overall patients (44.3, ), the types of AEs with high EAIRs in the Japanese patients were generally similar to those observed in the overall patients (in both patient populations, TEAEs were most commonly reported in the SOC of Infections (EAIR: Japanese 41.8; overall 29.9), and Gastrointestinal disorders (Japanese 23.4; overall 14.6)). Nasopharyngitis was the most common TEAE observed in the Japanese patients (EAIR 21.6) as well as in the overall patients (EAIR 6.5). The higher nasopharyngitis incidences observed for the Japanese patients were also seen in all arms of the RA-BEAM study (the baricitinib 4-mg arm (Japanese 17.2%; overall 7.6%), the adalimumab arm (Japanese 22.2%; overall 10.3%), and the placebo arm (Japanese 15.1%; overall 7.2%)) [Citation7,Citation11]. Similar results were also observed for the Japanese and overall patients in the tofacitinib LTE studies [Citation16]. Therefore, the higher TEAE EAIR observed in the Japanese patients as compared with that of the RA patients overall in the integrated database was considered largely due to the higher rates of nasopharyngitis in the Japanese patients.
The SAE EAIR of the Japanese patients (9.3) was similar to that of the overall patients (9.0), the tofacitinib Japanese LTE study patients (10.7) [Citation16], and within the range of those of the golimumab Japanese trial patients (7.9–14.5) [Citation17,Citation18]. No deaths were reported in the Japanese patients treated with baricitinib.
The EAIR of permanent discontinuation due to AEs in the Japanese patients (9.6) was higher than that of the overall patients (5.8), presumably due to the high IR of herpes zoster (cluster) observed in the Japanese patients (6.5 in the Japanese, 3.2 in the overall). Discontinuation for herpes zoster was required in all Phase 3 protocols (but not in the LTE study).
Regarding AEs of special interest, the serious infection IR in the Japanese patients (3.6) was numerically higher than that of the overall patients (2.9); 95%CI for the Japanese patients (2.5–5.2) overlapped that of the overall patients (2.5–3.4). The serious infection IR in the Japanese patients was similar to that observed in the tofacitinib Japanese LTE study patients (3.3) [Citation16], and within the range of those of the golimumab Japanese trials (3.0–3.8) [Citation17,Citation18].
The IR of herpes zoster (cluster) in the baricitinib-treated Japanese patients (6.5) was higher than that of the overall baricitinib-treated RA patients (3.2); 95%CI for the Japanese patients (4.9–8.4) did not overlap that of the overall patients (2.8–3.7). Specifically, in RA-BEGIN study, the incidence of herpes zoster during 52 weeks was 10% (3/29) of the Japanese patients in the baricitinib 4-mg arm, 8% (3/39) in the baricitinib + MTX arm, and 6% (2/36) in the MTX monotherapy arm, compared to 3, 2 and <1%, respectively, in the overall study population [Citation11]. In RA-BEAM study, the incidence of herpes zoster during 24 weeks was 4% of the Japanese patients in the baricitinib 4-mg arm, 2% in the adalimumab arm, and 0% in the placebo arm, compared to 1, 1 and <1%, respectively, in the overall study population [Citation11]. In the integrated database, the IR of herpes zoster (cluster) in the Asian patients was also higher than that of the overall RA patients (data not shown). Similar results were also seen in the integrated analysis of the tofacitinib trials (IR: 8.0 in Japanese, 6.1 in Asian, 4.0 in overall) [Citation21]. These IRs of herpes zoster in the JAK inhibitor-treated Japanese patients were higher than that observed in the Japanese patients with RA in a large observational cohort study with the Japanese RA patients (0.9) [Citation22].
It was reported in 2015 that genetic polymorphisms possibly influenced susceptibility to herpes zoster in RA patients treated with JAK inhibitors [Citation23]. Two polymorphisms were suggested to be relevant to a higher risk of herpes zoster in tofacitinib-treated patients, although these polymorphisms were relatively uncommon and explained only a fraction of the increased risk observed in the tofacitinib-treated Japanese patients. In some part, similar genetic polymorphisms relevant to risk of herpes zoster might account for the observed differences with the baricitinib treatment.
Recently, recombinant VZV vaccines have been launched in the U.S and also approved in Japan and Europe [Citation24]. Currently little evidence on the efficacy and safety of these vaccines in RA patients is available; future studies are warranted in this respect. In any case, the close monitoring of herpes zoster infections in Japanese baricitinib-treated patients should be required.
There were 10 cases of malignancies excluding NMSC reported in the Japanese patients. As a result of review on the individual cases, two patients with rectal cancer or MALT lymphoma very likely had symptoms of malignancy prior to receiving the first dose of baricitinib, and malignant fibrous histiocytoma in another patient was reported very early (within 60 days) after starting baricitinib (). These three cases are likely not related to baricitinib treatment. The malignancy (excluding NMSC) IR in the Japanese patients (1.1) was numerically higher than that of the overall patients (0.8); 95%CI for the Japanese patients (0.6–2.1) overlapped that of the overall patients (0.6–1.0). The malignancy (excluding NMSC) IR in the Japanese patients was similar to that of the tofacitinib Japanese LTE study patients (1.2) [Citation16]. There was one case of NMSC reported in the Japanese patients, however, the patient most likely had NMSC prior to treatment with baricitinib. In the overall patients including the Japanese patients, there was no signal suggesting an increased risk of malignancy at this clinical development stage [Citation12]. However, since our trial exposure time is still relatively limited in evaluating risks of both the Japanese patients and the overall patients, further studies including the post-marketing period are scheduled to evaluate the potential risk of malignancy.
The MACE IR in the Japanese patients (0.3) was numerically lower than that of the overall patients (0.5); 95%CI for the Japanese patients (0.0–1.0) overlapped that of the overall patients (0.4–0.7). The MACE IR in the Japanese patients was similar to that observed in the tofacitinib Japanese LTE study patients (0.4) [Citation16]. It is known that patients with RA are at an increased risk of VTE [Citation25,Citation26]. The DVT/PE IR in the Japanese patients (0.5) was comparable to that of the overall patients (0.5), and within the range of background rates (0.3–0.8) in cohort studies of the RA population [Citation25–27]. The ILD EAIR in the Japanese patients (0.5) was numerically higher than that of the overall patients (0.2); 95%CI for the Japanese patients (0.1–1.2) overlapped that of the overall patients (0.1–0.3). The ILD incidence in the Japanese patients (0.8% (4/514)) was within the range of that reported from Japanese clinical trials of adalimumab (0.6%) [Citation19] and certolizumab pegol (3.1%) [Citation20]. However, there were differences in the overall exposure time of those clinical trials (baricitinib, 851.5 PY; adalimumab, mean duration of exposure of 168.7 days for 171 patients; certolizumab pegol, 136.2 PY), making any comparison difficult without further analysis of the ILD incidence and the overall exposure time.
The analysis of laboratory variables using an integrated database of all doses was not conducted since the large variability in laboratory values with different doses made interpretation of the results difficult. Long-term treatment results of 4-mg, the recommended clinical dose, in the Japan Phase 2 study had already been published [Citation28]. Laboratory variables results in these Japanese patients were generally similar to those in the 4 mg long-term cohort of the overall patients [Citation12].
Although we feel that more than 500 patients with up to 3.2 years of exposure appeared to be sufficient to evaluate Japanese safety at this clinical development stage, the Japanese data need to be interpreted with some caution when comparing the Japanese data with data of the overall patients because the number of the Japanese patients (n = 514) is much smaller than that of the overall patients (n = 3492). Other limitations include ones that can be attributed to the LTE study: changes in background therapies in the study were made according to clinician discretion and baricitinib dosing such as rescue or step-down dosing were allowed.
The safety profile of baricitinib in Japanese with RA was evaluated in over 500 patients treated for up to 3 years. Baricitinib was well-tolerated in these patients throughout its development. However, the risk of herpes zoster in Japanese RA patients treated with baricitinib was higher than that of the overall patients. Although currently there is no signal suggesting an increased risk of malignancy in the Japanese RA patients compared with the overall patients, further studies are needed to provide more insight into the long-term risks of JAK inhibitors. Overall, in the context of its efficacy demonstrated in several studies in active RA patients [Citation7–11], baricitinib has shown an acceptable safety profile in Japanese patients up to 3 years of long-term exposure.
Conflict of interest
Masayoshi Harigai has received research grants from AbbVie Japan, AYUMI Pharmaceutical Corporation, Chugai Pharmaceutical Company, Eisai Company, Takeda Pharmaceutical Company, Mitsubishi Tanabe Pharma Co., Taisho Toyama Pharmaceutical Co., Ltd., and Teijin Pharma, participated in consultancies and advisory panels for Bristol-Myers Squibb K.K., Chugai Pharmaceutical Company, Ono Pharmaceuticals, Teijin Pharma, and Eli Lilly and Company, and is the baricitinib advisor for Eli Lilly Japan K.K.
Yoshiya Tanaka has received research grants from Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Company, Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Company, Bristol-Myers Squibb K.K., MSD, Astellas Pharma Inc, AbbVie Japan, and Eisai Company, and has received speaking fees and/or honoraria from AbbVie Japan, Chugai Pharmaceutical Company, Daiichi Sankyo Co., Ltd., Bristol-Myers Squibb K.K., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc, Takeda Pharmaceutical Company, Pfizer Japan Inc., Teijin Pharma, Asahikasei Pharma Corp., YL Biologics, Sanofi, Janssen Pharmaceutical K.K., Eli Lilly and Company, and GlaxoSmithKline.
Tsutomu Takeuchi has received grants from Astellas Pharma Inc, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Company, Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Company, Teijin Pharma, AbbVie Japan, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Taisho Toyama Pharmaceutical Co., Ltd., Eisai Company, AYUMI Pharmaceutical Corporation.; speaking fees from AbbVie Japan., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Company, Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Astellas Pharma Inc, and Daiichi Sankyo Co., Ltd.; and consultant fees Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., AbbVie Japan, Nipponkayaku Co. Ltd., Janssen Pharmaceutical K.K., Astellas Pharma Inc,. Taiho Pharmaceutical Co., Ltd.
Smolen S. Josef has received grants for his institution from AbbVie, Janssen, Eli Lilly and Company, MSD, Pfizer Inc., and Roche and has provided expert advice to and/or had speaking engagements for AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai Pharmaceutical Company, Gilead, GlaxoSmithKline, ILTOO Pharma, Janssen, Eli Lilly and Company, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc., Roche, Samsung, Sanofi and UCB.
Kevin L. Winthrop has received consulting and investigator fees from AbbVie, Eli Lilly and Company, Galapagos, Gilead, and Pfizer Inc.
Atsushi Nishikawa, Chadi G. Saifan, Taeko Ishii, Terence P Rooney, and Yoshitaka Isaka are employees of and own stock in Eli Lilly and Company.
Maher Issa and Naotsugu Akashi are employees of Eli Lilly and Company.
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The authors wish to thank the patients, investigators, and study staff who were involved in these studies. The authors also thank Yasushi Takita in Eli Lilly Japan K.K for consultation on interpretation of data, Gregory Smith in Eli Lilly Japan K.K for medical writing assistance, and Hangtao Xu in Eli Lilly and Company for table preparation.
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References
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