Infections in Baricitinib Clinical Trials for Patients with Active Rheumatoid Arthritis

Winthrop KL, Harigai M, Genovese MC, Lindsey S, Takeuchi T, Fleischmann R, Bradley JD, Byers NL, Hyslop DL, Issa M, Nishikawa A, Rooney TP, Witt S, Dickson CL, Smolen JS, Dougados M.
Annals of the Rheumatic Diseases, May 2020

Baricitinib, an oral selective JAK1 and JAK2 inhibitor,8 demonstrated significant clinical efficacy in phase 3 RA trials. Pooled data from these trials, including a long-term extension (LTE), inform the safety profile for baricitinib, mainly to evaluate the incidence of infection in patients with active rheumatoid arthritis (RA), with a focus on serious infection, tuberculosis (TB), herpes zoster (HZ) and opportunistic infection (OI). The data collected were from eight double-blind randomised ...

Perfil de Seguridad de Baricitinib en el Tratamiento de Artritis Reumatoide a lo largo de una mediana de 3 años de tratamiento: Un análisis actualizado integrado de seguridad

Genovese MC, Smolen JS, Takeuchi T, Burmester G, Brinker D, Rooney TP, Zhong J, Daojun M, Saifan C, Cardoso A, Issa M, Wu W-S, Winthrop KL.
Lancet Rheumatol 2020;2:e347–57

RA is a chronic, life-long disease requiring long-term treatment. As such, it is important to understand the long-term safety profile of DMARDs. In this analysis, baricitinib maintained a stable safety profile during long-term exposure. This baricitinib safety analysis included integrated data from nine Phase 3, 2, and 1b clinical trials, and one long-term extension, with data up to 360 weeks. 3700 patients were included, with maximum follow-up of almost 7 years – representing an additio...

Keywords: JAK, Baricitinib, Clinical, Safety

Translated by: Igor Kos

Análisis Integrado de Seguridad de Tofacitinib en Artritis Psoriásica en Estudios de Fase 3 y de Extensión a Largo Plazo y Comparación con Datos Observacionales de Mundo Real

Burmester GR, Curtis JR, Yun H, FitzGerald O, Winthrop KL, Azevedo VF, Rigby WFC, Kanik KS, Wang C, Biswas P, Jones T, Palmetto N, Hendrikx T, Menon S, Rojo R.
Drug Saf. 2020;43:379-392

Patients with psoriatic arthritis (PsA) had similar safety profile with TOF to that of other systemic therapies in real-world settings, except for the known risk of HZ. Treatment recommendations from EULAR and GRAPPA for patients with PsA vary according to adverse prognostic risk factors, disease manifestations and responsiveness to prior treatment. Safety concerns for most PsA therapies include gastrointestinal AEs, hepatotoxicity, opportunistic infections (OIs) including TB, and SIEs. This s...

Keywords: JAK, Tofacitinib, Real World, Safety

Translated by: Igor Koz

Efectividad a Largo Plazo de la Vacuna Viva Herpes Zoster en Pacientes con Artritis Reumatoide Tratados Posteriormente con Tofacitinib

Winthrop KL, Wouters A, Choy EH, Chen C, Biswas P, Wang L, Soma K, Needle E, Valdez H, Rigby WFC.
Ann Rheum Dis. 2020 DOI: 10.1136/annrheumdis-2019-216566

The results of ORAL Sequel suggest that the live zoster vaccine (LZV) may not provide adequate long-term protection in patients with RA receiving TOF. This LTE study enrolled 100 patients with RA, 14 weeks post LZV vaccination. Patients received either TOF 5 mg BID, or TOF 10 mg BID in addition to any background csDMARDs. Incidence rates and 95% CIs for HZ post-vaccination were calculated based on time to first event. Short-term varicella zoster vaccine (VZV) specific immunity was evaluated a...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor Koz

A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis

Bechman K, Subesinghe S, Norton S, Atzeni F, Galli M, Cope AP, Winthrop KL, Galloway JB.
Rheumatology (Oxford) 2019;58(10):1755–66

Absolute serious infection rates were low. However, across the JAKinibs, the incidence of HZ is higher than expected for the population. While the risk was numerically greatest with BARI, indirect comparisons between the drugs did not demonstrate any significant difference in risk. How JAKinibs increase the risk of HZ reactivation is unclear, but how different JAKs interact in the immune response suggest that there may be differences in safety profiles between JAKinib drugs, underpinned by the...

Una Revisión Sistemática y Metaanálisis del Riesgo de Infecciones con Moléculas Pequeñas Inhibidoras de JAK en Artritis Reumatoide

Bechman K, Subesinghe S, Norton S, Atzeni F, Galli M, Cope AP, Winthrop KL, Galloway JB.
Rheumatology (Oxford). DOI: 10.1093/rheumatology/kez087

How JAKinibs increase the risk of HZ reactivation is unclear. Roles of different JAKs in the immune response may suggest differences in safety profiles between drugs, underpinned by their differential JAK selectivity profiles. The authors undertook a systematic review and meta-analysis to evaluate SI and opportunistic indicator infections including HZ in RA Phase II/III clinic trials with JAKinibs. A literature review of RCT of TOF (5 mg BID), BARI (4 mg OD) and UPA (15 mg OD) was conducted. A...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor

Evaluación de las Respuestas Vacunales Neumocócica y Antitetánica en Pacientes con Artritis Reumatoide recibiendo Baricitinib: Resultados de un Subestudiode Extensión

Winthrop KL, Bingham CO III, Komocsar WJ, Bradley J, Issa M, Klar R, Kartman CE.
Arthritis Res Ther. 2019 Apr 18;21(1):102

Approximately two thirds of long-term BARI treated patients achieved satisfactory humoral and functional responses to 13-serotype pneumococcal conjugate vaccine (PCV-13), whereas tetanus toxoid vaccine (TTV) responses were less robust. Both RA management guidelines and recommendations suggest vaccinating patients with RA against pneumococcal disease with PCV-13 and PPSV-23. The inhibition of the JAK mediated signal transduction pathways in RA treatment could diminish vaccine responses. Given t...

Keywords: JAK, Baricitinib, Clinical, Safety

Translated by: Igor

Perfil de Seguridad de Baricitinib en Pacientes Japoneses con Artritis Reumatoide Activa con más de 1.6 años de Tiempo Medio de Tratamiento: Un análisis integrado de Estudios Fase 2 y 3

Harigai M, Takeuchi T, Smolen JS, Winthrop KL, Nishikawa A, Rooney TP, Saifan CG, Issa M, Isaka Y, Akashi N, Ishii T, Tanaka Y.
Mod Rheumatol. 2019 Feb 20:1-23. DOI: 10.1080/14397595.2019.1583711

In this integrated analysis, BARI showed an acceptable safety profile in Japanese patients with up to 3.2 years of exposure. Other than incidences of herpes zoster (HZ), no major differences were noted with BARI safety in Japanese patients with RA, compared to the patients in the integrated database. BARI has previously demonstrated significant clinical efficacy and acceptable safety. Japanese patients who participated in the BARI clinical development programme, were comparable to those from th...

Keywords: JAK, Baricitinib, Clinical, Safety

Translated by: Igor

Herpes Zoster y Tofacitinib: Resultados Clínicos y Riesgo de Terapia Concomitante

Winthrop KL, Curtis JR, Lindsey S, Tanaka Y, Yamaoka K, Valdez H, Hirose T, Nduaka CI, Wang L, Mendelsohn AM, Fan H, Chen C, Bananis E.
Arthritis Rheumatol 2017;69(10):1960–68

The results of this analysis of patients with herpes zoster (HZ) within the global tofacitinib (TOF) RA programme suggest that there is likely to be a greater HZ risk in patients receiving TOF and glucocorticoids compared with patients receiving TOF monotherapy. The global TOF RA development programme comprised 2 Phase 1, 9 Phase 2, 6 Phase 3 and 2 long-term extension studies. These studies included 6192 patients; data were reviewed to identify cases of HZ. Crude incidence rates of number of pa...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor Kos

Seguridad E Inmunogenicidad de la Vacunación Para Herpes Zoster en Pacientes con Artritis Reumatoide Antes de Empezar Tofacitinib: Un Ensayo Aleatorizado Fase II

Winthrop KL, Wouters A, Choy E, Soma K, Hodge J, Nduaka C, Biswas P, Needle E, Passador MS, Mojcik C, Rigby W.
Arthritis Rheumatol. 2017 Oct;69(10):1969-1977. doi: 10.1002/art.40187

Patients with RA who started treatment with tofacitinib 2–3 weeks after being vaccinated against herpes zoster had similar varicella zoster virus (VZV)-specific humoral and cell-mediated responses to the live vaccine compared to patients who received placebo. In this Phase 2 study, humoral and cell-mediated immune responses were evaluated before receipt of live zoster vaccine (LZV) and at 2, 6 and 14 weeks after vaccination, having been randomised to tofacitinib 5 mg BID or placebo, 2&nda...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor Kos

Herpes Zoster y Tofacitinib en Pacientes con Artritis Reumatoide

Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, Kawabata T, Riese R.
Arthritis Rheumatol 2014;66:2675–84

Patients who were treated with tofacitinib in the RA clinical development programme were more likely to develop herpes zoster than were those who received placebo. Cases of herpes zoster reported by investigators in the Phase 2, Phase 3 and long-term extension studies of tofacitinib were evaluated. Herpes zoster was noted in 5% of tofacitinib-treated patients; only 7% of these cases were serious, no patients with herpes zoster died and only 10% permanently discontinued tofacitinib treatment. T...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor Kos

Seguridad a largo plazo de Tofacitinib para el Tratamiento de la Artritis Reumatoide hasta 8.5 años. Análisis integrado de datos de los Ensayos Clínicos Mundiales

Cohen BS, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, Winthrop KL, Charles-Shoeman C, Thirunavukkarasu K, DeMasi R, Geier J, Kwok K, Wang L, Riese R, Wollenhaupt J.
Ann Rheum Dis 2017;76:1253-1262. DOI 10.1136/annrheumdis-2016-210457

This analysis of exposure to tofacitinib, an oral JAKi for the treatment of RA, for up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. Adverse events were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports. Data were collated into an integrated safety summary of tofacitinib in adult patients with active RA, and included data spanning the tofacitinib clinical programme: from 2 P...

Keywords: JAK, Tofacitinib, Clinical, Safety

Translated by: Igor Kos

The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis

Winthrop KL, Silverfield J, Racewicz A, Neal J, Lee EB, Hrycaj P, Gomez-Reino J, Soma K, Mebus C, Wilkinson B, Hodge J, Fan H, Wang T, Bingham CO 3rd.
Ann Rheum Dis. 2015 Mar 20. pii: annrheumdis-2014-207191. doi: 10.1136/annrheumdis-2014-207191. [Epub ahead of print]

The increased risk of serious infection among RA patients means vaccinations against pneumococcus and influenza are recommended in this group of patients. Studies evaluating immune response to these vaccines in conjunction with DMARD therapy can provide clinicians with important information relating to things such as timing of vaccination. This study aimed to assess the effect of tofacitinib on vaccine responses to PPSV-23 and the trivalent seasonal influenza vaccine in those whom tofacitinib...

Herpes Zoster and Tofacitinib Therapy in Patients with Rheumatoid Arthritis

Winthrop KL, Yamanaka H, Valdez H, et al.
Arthritis Rheumatol. 2014 Jun 18. [Epub ahead of print]

It is well established that patients with RA are at an increased risk of herpes zoster (HZ). What is less well known is whether some of the newer therapies available for treatment of RA increase this risk. Tofacitinib has been reported to be associated with an increased risk of HZ and this study quantifies that risk and reviews potential factors that represent an increased risk. Using data from the tofacitinib RA development programme; phase 2, 3, and long-term extension clinical trials, over 20...