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Tofacitinib Demonstrates Sustained Improvement in RA

In an article published in a recent edition of Arthritis Research & Therapy, Jurgen Wollenhaupt and colleagues from multiple international centers have discovered that tofacitinib 5mg and 10mg twice a day remained effective and safe even after 8 and 9.5 years respectively.

In an article published in a recent edition of Arthritis Research & Therapy, Jurgen Wollenhaupt and colleagues from multiple international centers have discovered that tofacitinib 5mg and 10mg twice a day remained effective and safe even after 8 and 9.5 years respectively.

Studies looking at the janus kinase inhibitor tofacitinib for the treatment of moderate to severe rheumatoid arthritis (RA) have proven it’s efficacy and safety up to 24 months. Typically tofacitinib is prescribed either as monotherapy or in combination with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for the treatment of RA.

While short term phase II and III trials have proven it’s safety and efficacy, tofacitinib has not been studied over the long term leaving it’s impact on quality of life and long term outcomes unknown. Data from long-term extension studies (LTE) are ongoing with data emerging regularly and providing insight into the impact of treatment over time.

The authors used data from the LTE ORAL Sequel study in an effort to describe the safety and efficacy of treatment with tofacitinib 5mg and 10mg twice daily for up to 9.5 years in RA patients.

The Study

The ORAL Sequel study is an open-label follow-up LTE study conducted in 414 centers in 43 countries and included patients completing a prior index study looking at tofacitinib safety and efficacy in RA. Subjects were allowed to continue or add stable background arthritis therapy such as NSAIDS, low dose morphine, select csDMARDs, injectable gold preparations and corticosteroids.

The primary objective of this study was to establish long-term safety and tolerability of 5mg and 10mg twice-daily tofacitinib by looking at adverse event reporting and clinical data. The secondary outcome measured was the persistence of long-term efficacy at the same doses as measured by the ACR20/50/70 response rates, the HAQ-0DI, the DAS28-ESR. Of the 4481 patients enrolled in the main study 49% of them remained in the study after 5 years.

The Results

Adverse events occurred in 90.4% and 90.0% of tofacitinib 5mg and 10mg groups respectively and were generally mild. This was comparable to the results of the index study. Serious adverse events occurred in 30.8% and 29.7% of 5mg and 10mg group participants respectively and led to dose reduction or temporary discontinuation in 46.1% and 39.6% of the 5mg and 10mg group participants respectively. With respect to all-cause adverse events leading to discontinuation, the most common were infections and infestations and abnormal lab values.

With regards to laboratory values, small changes were seen in blood counts with mild to severe neutropenia being rare (6.0% and 0.2% respectively). Similarly, lymphopenia was rare and of patients with mild, moderate, and severe lymphopenia, 0.9%, 0.3%, and 0.3%, respectively, developed serious infections.

With regards to efficacy, ACR20, ACR50, and ACR70 response rates were maintained from month 1 to 96 and were generally similar with tofacitinib 5 mg and 10mg twice daily. Improvements in overall HAQ-DI scores were seen in both groups with over 70% of subjects in the 10mg group seeing significant gains. Disease activity scores decreased at one month and remained consistent over time in both groups with remission occurring in 25% of subjects regardless of dose.

Take-Home Points for Clinicians and Final Thoughts

The ORAL Sequel LTE study represents the largest clinical development program for any RA treatment so far. The regularly reported data coming from the study continues to prove that tofacitinib is safe, effective, and well tolerated even over the long term up to 9.5 years and counting.
While 52% of patients discontinued the study by the 114th month, the incidence of AEs leading to drop out remained stable for the rest of the study and the safety profile remained consistent with prior phase II and III studies.

Serious malignancy, cardiovascular, mortality, and infection-related events were very rare with the exception of herpes zoster. Herpes zoster was more common in the 10mg group. Finally, serious events were rare even with very low lymphocyte counts.

This report introduces some clinicians, who aren’t familiar with them, to LTE studies. These continuation studies are very useful due to their rigorous safety reporting and controlled settings and can give us valuable information on what happens after the primary investigation is complete.

It is tempting to read a study, make a conclusion and then move on. However, quite often we see that, in the long term, the information, outcomes, and even the original conclusions can change significantly. That fact only gives more weight to these encouraging data proving the continued safety and efficacy of tofacitinib for RA in the long term.


Jurgen Wollenhaupt, Eun-Bong Lee, Jeffrey R. Curtis, 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 Research & Therapy (2019) 21:89 https://doi.org/10.1186/s13075-019-1866-2