Discontinuation of tofacitinib after achieving low disease activity in patients with rheumatoid arthritis: a multicentre, observational study

Kubo, Shunsuke; Yamaoka, Kunihiro; Amano, Koichi; Nagano, Shuji; Tohma, Shigeto; Suematsu, Eiichi; Nagasawa, Hayato; Iwata, Kazuyuki; Tanaka, Yoshiya

doi:10.1093/rheumatology/kex068

Cited by 22 publications

(19 citation statements)

References 37 publications

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“…A recent report analyzed the effects of discontinuation of tofacitinib therapy in a small group of RA patients who achieved low disease activity. About one third of patients remained without a disease flare . The FDA approved tofacitinib for the treatment of RA in 2013, but only at a lower (10 mg daily) therapeutic dose, citing safety concerns at the higher (20 mg daily) dose.…”

Section: A Brief Survey Of Approved and Late Phase Jakinibsmentioning

confidence: 99%

“…Changes in laboratory parameters for patients treated with jakinibs also include a decrease in the number of lymphocytes, NK cells, neutrophils, and platelets. The clinical consequences of the decrease in NK cells, which appears to reverse in the long‐term, remain unclear and do not include serious infections or malignancy . It is of note that most jakinibs are competitive inhibitors and, in theory, their actions might be overcome by pharmacological doses of the relevant cytokine, without necessarily inhibiting their immunosuppressive action.…”

Section: Side Effects Of First Generation Jakinibsmentioning

confidence: 99%

“…This is the arena in which jakinibs have been most intensively studied. Tofacitinib, a JAK3, JAK1, and JAK2 inhibitor, has been studied in a large number of patients with RA in six phase 3 clinical trials testing its efficacy and safety, [54][55][56][57][58][59][60][61][62][63][64] (NCT01039688, NCT00814307, NCT00847613, NCT00853385, NCT00856544, and NCT00960440) and is approved for this indication in many countries around the world ( 67 The FDA approved tofacitinib for the treatment of RA in 2013, but only at a lower (10 mg daily) therapeutic dose, citing safety concerns at the higher (20 mg daily) dose.…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

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Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

129

100

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In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.

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Section: A Brief Survey Of Approved and Late Phase Jakinibsmentioning

confidence: 99%

Section: Side Effects Of First Generation Jakinibsmentioning

confidence: 99%

Section: Rheumatoid Arthritismentioning

confidence: 99%

See 1 more Smart Citation

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

129

100

View full text Add to dashboard Cite

show abstract

“…The only data available were obtained from RA patients who had stopped tofacitinib after completing clinical trials and long-term extension studies. These patients had been on tofacitinib treatment for long periods of time before immediate discontinuation, and none of them received a dose-reduction strategy [21,22].…”

Section: Introductionmentioning

confidence: 99%

Outcomes of dose reduction, withdrawal, and restart of tofacitinib in patients with rheumatoid arthritis: a prospective observational study

Mori¹,

Ueki

2019

Clin Rheumatol

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Objective This study was designed to compare outcomes of dose reduction, withdrawal, and continuation of tofacitinib in patients with rheumatoid arthritis (RA) and to examine effectiveness of rescue with an original treatment regimen for disease flare. Methods We prospectively enrolled 100 patients who had high or moderate disease activity and treated them with tofacitinib at 5 mg twice daily for 1 year. All patients achieving remission or low disease activity (LDA) were assigned to a withdrawal, dosereduction, or continuation group, then followed until disease flare or end of the study. For flare cases, the original treatment regimen was reintroduced. Results During the first year, 68 patients achieved remission or LDA (median sustained time 49.0 weeks). Subsequently, disease flare occurred at the following crude incidence rates per person-year (95% confidence interval [CI]): 0.73 (0.43-1.22) after withdrawal, 0.44 (0.25-0.77) after dose reduction, and 0.04 (0.01-0.27) during continuation. Kaplan-Meier estimates of median flare-free time (95% CI) were 7.0 months (2.8-11.2) for withdrawal and 21.0 months (4.1-37.9) for dose reduction. In the Cox regression analysis, adjusted hazard ratios (95% CIs) were 18.11 (2.38-138) for withdrawal and 9.13 (1.19-70.4) for dose reduction compared with continuation. Restart of the original treatment regimen led to rapid remission in flare cases (93% for withdrawal and 100% for dose reduction). Conclusion After achievement of remission or LDA, the dose-reduction strategy seems preferable to immediate withdrawal of tofacitinib. Restart of the original regimen can reinduce RA control in flare cases. Key Points • During the 1-year tofacitinib therapy, two-thirds of RA patients with high or moderate disease activity achieved rapid and sustained remission or low disease activity. • During subsequent years, the incidence rate and adjusted hazard ratio for disease flare were significantly higher following tofacitinib immediate withdrawal than following dose reduction. • Half of the patients were estimated to remain flare-free for 21 months after dose reduction and for 7 months after withdrawal of tofacitinib. • Restart of the original treatment regimen rapidly restored disease control in almost all flare cases.

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“…If no treatment choice exists, the sponsor should provide access until the intervention becomes available to the population. Studies evaluating the outcomes that occur in study participants after the end of the pre-specified follow-up period of the research study are almost nonexistent 21 .…”

Section: Fair Access To Post Study Benefitsmentioning

confidence: 99%

III. The role of the Research Ethics Committees in the regulation of Pharma-Sponsored studies

Aguilar-Salinas

Pascual‐Ramos

Sierra‐Madero

et al. 2020

RIC

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Participants of Pharma-sponsored research are exposed to risks, benefits, and uncertainties that do not occur in other forms of clinical studies. Ethics committees represent the subjects' first line of protection. This responsibility begins with the study review and ends after all study subjects finish the intervention. The objective of this paper is to review the most common controversial issues found in Pharma-sponsored studies. Potential solutions are proposed to prevent or resolve the polemical aspects. However, different challenges will be faced in the near future (e.g., when new therapies reach their late stage of development). All parties involved in research should work together to guarantee the protection of participants, the paramount principle on which clinical investigation is based. Pharma-sponsored research is a crucial driver to develop and implement innovative approaches to improve the informed consent process and the execution of the studies. (REV INVEST

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Discontinuation of tofacitinib after achieving low disease activity in patients with rheumatoid arthritis: a multicentre, observational study

Abstract: It is possible to discontinue tofacitinib without flare in about a third of patients with RA. A low RF predicts maintenance of LDA after discontinuation of tofacitinib.

Cited by 22 publications

References 37 publications

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Outcomes of dose reduction, withdrawal, and restart of tofacitinib in patients with rheumatoid arthritis: a prospective observational study

III. The role of the Research Ethics Committees in the regulation of Pharma-Sponsored studies

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