Department of Internal Medicine
University of Texas Southwestern Medical School
Division of Rheumatology
Metroplex Clinical Research Center
Stanley B. Cohen, MD, has disclosed that he has received consulting fees and funds for research support from AbbVie, Amgen, Gilead Sciences, Lilly, and Pfizer.
The 2019 meeting of the American College of Rheumatology (ACR) and the Association of Rheumatology Professionals (ARP) brought together clinicians and investigators from all over the world. This annual meeting continues to provide the latest updates on disease management and novel discoveries that may ultimately have an impact on patient care.
There were many presentations on the 3 approved Janus kinase (JAK) inhibitors—baricitinib, tofacitinib, upadacitinib—and the investigational JAK1 inhibitor filgotinib, which is now completing phase III clinical trials. As a practitioner interested in rheumatoid arthritis (RA), I believe that these were some of the most important data presented at the conference.
In fact, there may be a pause in the introduction of new therapies for RA after the potential approval of filgotinib in 2020, so these JAK inhibitors may be the last new therapies we see for the foreseeable future.
Efficacy and Sequencing of JAK Inhibitors
Although we really have no head-to-head trials that directly compare the effectiveness of different JAK inhibitors, in separate clinical trials presented at ACR, the JAK inhibitors all seemed to have similar efficacy. What is missing are data on sequencing JAK inhibitors—replacing one JAK inhibitor with another after treatment failure. No such information was presented at this meeting, although anecdotally I hear that this is being done in clinical practice. I look forward to data that will establish whether this an appropriate and effective strategy. We should begin to see data from observational registries soon, now that 2 JAK inhibitors have been available in the clinic for over a year.
Safety Data From JAK Clinical Trials
Key safety data were also reported for upadacitinib and filgotinib.
Safety presentations from the upadacitinib clinical trial program demonstrated safety issues that we are familiar with from other JAK inhibitors: Adverse events of special interest continue to be infections such as herpes zoster, opportunistic infections including tuberculosis, and serious bacterial infections. Similar laboratory abnormalities to those associated with the other JAK inhibitors—such as hyperlipidemia, neutropenia, leukopenia and transaminitis—were also reported.
Combined safety data from across the overall filgotinib clinical trial program reported a similar adverse event profile but lower incidence of herpes zoster infection than we have seen with other JAK inhibitors and fewer opportunistic infections reported.
If filgotinib truly has a safer profile, that would suggest a unique role for this drug and would be important information for clinicians. However, the difference in safety profile may reflect differences in patient demographics and geographic differences in the regions from which each JAK inhibitor’s clinical trial program recruited patients. Lacking head-to-head studies with other JAK inhibitors, it will be difficult to be absolutely conclusive about whether the differences observed are real.
JAK Inhibitors and Risk of Thromboembolism
Separate clinical trial safety databases of the JAK inhibitors have suggested that the rates of venous thromboembolism (VTE), pulmonary embolism (PE), and arterial thromboembolism are similar across all JAK inhibitors. These events were seen rarely, with incident rates similar to those previously reported with conventional synthetic DMARDs and biologics.
At this meeting, a meta-analysis of 33 randomized, placebo-controlled trials of 6 JAK inhibitors was presented, which did identified no significant short-term risk of major adverse cardiovascular (CV) events or VTE in patients with RA initiating JAK inhibitors.
A pooled analysis from the SELECT trials presented at the conference showed that treatment with upadacitinib caused no apparent increase in major adverse CV events (MACE) or VTE over 24 months, and the incidence rates were similar to those reported in patients with RA who are taking biologics or other JAK inhibitors. However, for upadacitinib and the adalimumab comparator, patients who did develop MACE or VTE had ≥ 1 CV risk factor or ≥ 1 VTE risk factor at baseline. No association with change in platelet count could be confirmed. As with all of the approved JAK inhibitors, upadacitinib was associated with an increase in LDL and HDL cholesterol levels, with no change in the ratio of HDL to LDL. No association was seen for the change in lipids and MACE events.
Of interest, while the 2019 ACR meeting was being held, the European Medicines Agency issued a warning that patients with CV risk factors or with a previous history of VTE/PE should not be treated with tofacitinib 5 mg or 10 mg BID, owing to increased risk of these events. Their review considered data from study A3921133, an ongoing, open-label phase IV clinical trial evaluating the safety of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily compared with a TNF inhibitor in patients with RA 50 years of age or older with 1 additional CV risk factor. The FDA had previously amended the package insert for tofacitinib with a similar warning for the 10-mg dose but not the 5-mg dose, based on their analysis of the same study.
In previously reported placebo-controlled clinical studies of baricitinib, there was also an increase of VTE/PE in patients with CV risk factors (6 events occurred in patients treated with baricitinib 4 mg vs 0 cases of DVT/PE reported in the placebo group), resulting in a boxed warning on the package insert. A recent retrospective analysis of long-term safety with 10,127 years of follow-up presented at this meeting documented the difference in incidence rates in the placebo-controlled, randomized trials for the 4 mg dose compared with placebo. Long-term incidence rates in the baricitinib-treated patients were similar to the reported rates with other biologics and JAK inhibitors.
Currently, the mechanism of action for this increased incidence rate for thromboembolic events in patients with CV risk or VTE risk factors is not understood. For now, use of JAK inhibitors in this population is relatively contraindicated if other treatment options are available. I hope that further data analysis will help us determine whether this is a class effect for JAK inhibitors or if it is limited to particular therapies.Your Thoughts?