Baricitinib for RA exhibits long-term efficacy, low discontinuation due to adverse events
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Key takeaways:
- One-fifth of baricitinib-treated patients discontinued due to adverse events or death over about 6.5 years.
- The most common reason was sponsor’s decision due to fulfillment of study objectives.
Daily baricitinib, either 4 mg or 2 mg, demonstrates up to 6.5 years of efficacy with low rates of discontinuation due to adverse events in patients with rheumatoid arthritis, according to data published in Rheumatology.
“The long-term safety of baricitinib has been demonstrated,” Roberto Caporali, MD, of the University of Milan, and colleagues wrote. “However, as RA is a chronic disease with some patients receiving therapy for decades, it is important to understand not only the safety profile of a particular treatment but also the discontinuation rates and efficacy over the longest duration possible.”
To evaluate the long-term efficacy and discontinuation rates of daily baricitinib (Olumiant, Eli Lilly & Co.), Caporali and colleagues analyzed up to 6.5 years of data from three completed phase 3 studies, as well as a long-term extension study that included patients from each study. Those studies — RA-BEAM, RA-BUILD and RA-BEACON, plus the long-term extension RA-BEYOND — had reported the efficacy and safety of baricitinib in patients with an inadequate response to methotrexate, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs.
Each group of patients underwent completer and non-responder imputation analyses up to either week 340 or 336 of the extension study — roughly 6.5 years — depending on which of the phase 3 studies they had originally been enrolled in.
Over that time, adverse events, death or lack of efficacy were the cause of fewer than one-fifth of baricitinib discontinuations in the extension study, according to the researchers. The most common reason for baricitinib discontinuation was the decision of a sponsor after a patient had fulfilled study objectives.
In addition, numerically greater proportions of patients treated with baricitinib from all groups achieved low disease activity at 6.5 years vs. those treated with placebo. Among patients with an inadequate response to methotrexate, 37%, 34% and 32% of those initially treated with baricitinib 4 mg, adalimumab or placebo, respectively, achieved low disease activity by week 340. In patients with an inadequate response to conventional synthetic DMARDs, 35%, 34% and 33% of those initially treated with baricitinib 4 mg, baricitinib 2 mg or placebo, respectively, achieved low disease activity at week 336.
In patients with an inadequate response to biologic DMARDs, 23%, 23% and 21% of those initially treated with baricitinib 4 mg, baricitinib 2 mg or placebo, respectively, achieved low disease activity at week 336.
During the extension study, the overall discontinuation rate was 72% among those with inadequate response to methotrexate, 61% among those with inadequate response to conventional synthetic DMARDs and 67% among those with inadequate response to biologic DMARDs.
“These results demonstrated the long-term efficacy of baricitinib 4 mg and 2mg in patients with RA for up to 6.5 years of treatment,” Caporali and colleagues wrote. “Low rates of discontinuation due to [adverse events], death and lack of efficacy indicated that baricitinib 4 mg treatment was both efficacious and well-tolerated over the long term.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
The present long-term data for baricitinib (Olumiant, Eli Lilly) shows continued efficacy and no new safety signals. Previous research on baricitinib and other Janus kinase inhibitors has highlighted the rare development of opportunistic infections, with the typical suspects being tuberculosis, histoplasmosis, esophageal candidiasis, pneumocystis, cryptococcus and cytomegalovirus. Two additional notable infections to consider are multi-dermatomal herpes zoster (HZ) and BK virus.
HZ is characterized by the presence of unilateral, localized vesicular rash in a dermatomal distribution. Also described is disseminated herpes zoster (DHZ), where the patient is often older, acutely ill, septic, obtunded, immunosuppressed and has fever, thrombocytopenia, and potentially a fatal outcome. Definitions vary but DHZ usually refers to more than 20 lesions outside the initial dermatome with more than two dermatomes involved.
Although DHZ represents a type of multi-dermatomal HZ, there have been documented instances of milder cases where lesions appear across multiple dermatomes, either contiguous or noncontiguous, bilateral, or involving atypical dermatomes. Patients have often been informed that their multi-dermatomal rash and symptoms cannot be attributed to HZ due to the unusual presentation. However, it's crucial to recognize that such atypical manifestations could occur, especially among individuals who are immunosuppressed.
The BK virus, a DNA virus classified within the human polyomavirus family, was initially identified in 1971 from the urine of a kidney transplant recipient with the initials B.K. Other polyomaviruses include JC virus (the causative agent of progressive multifocal leukoencephalopathy), Simian virus 40 (SV40) and Merckle cell virus. BK infection is prevalent within the general population, with over 90% seroprevalence observed by the age of 4 years. After primary infection, the virus persists and may reactivate upon immunosuppression.
BK virus infection poses a significant risk post-transplantation, particularly for kidney recipients, potentially leading to kidney dysfunction if not managed promptly. Severe cases of BK virus-associated nephropathy can culminate in the loss of the transplanted kidney. Serum and urine BK virus levels can be obtained, but a renal biopsy is mandatory for diagnosis. BK virus infection should be considered in an immunosuppressed rheumatology patient with decreasing renal function of unknown cause. There is no definitive treatment for BK virus at this time other than lowering immunosuppression.
Finally, I have seen a JAK-inhibited patient with RA who has had multiple nonmelanoma skin cancers and now oral leukoplakia. Oral hairy leukoplakia is a condition triggered by the Epstein-Barr virus. It causes white patches on the tongue or other parts of the mouth. There is a small risk for progressing to oral cancer.
As we gain more experience with JAK inhibitors, we will need to be aware of these and other adverse events that are rare. I have seen all of these in the past year.
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