Professor of Medicine and Population and Quantitative Health Sciences
Timothy S. and Elaine L. Peterson Chair in Rheumatology
Division of Rheumatology
Department of Medicine
University of Massachusetts Medical School
Division of Rheumatology
Department of Medicine
UMass Memorial Medical Center
Jonathan Kay, MD, has disclosed that he has received consulting fees and funds for research support from AbbVie, Alvotech Suisse, Boehringer Ingelheim, Celltrion Healthcare, Gilead Sciences, Horizon Therapeutics, Kolon TissueGene, Merck Sharp & Dohme, Novartis, Pfizer, Samsung Bioepis, Sandoz, and UCB.
Although the major theme about rheumatoid arthritis (RA) therapy that emerged during the 2019 ACR Annual Scientific Meeting was the efficacy and safety issues surrounding JAK inhibitors, numerous exciting new approaches for the treatment of RA were also presented. Some of the studies may prompt me to consider changes to my practice, whereas others will not. However, each has led me to re-examine my approach to treating patients with RA.
Rituximab is an effective IV therapy for RA. A study presented by Verhoef and colleagues suggested that rituximab can be given effectively and more conveniently as a single lower dose to patients with active RA who are seropositive for rheumatoid factor or anti-CCP antibodies. In a comparison of efficacy and safety of treatment, a 500-mg dose of rituximab was noninferior to a 1000-mg dose at 3 months, but not at 6 months, after treatment. In the intention-to-treat analysis, both 500-mg and 200-mg doses of rituximab were noninferior to the 1000-mg dose at both 3 and 6 months.
Will these findings change my practice? I would consider using these lower doses of rituximab instead of the higher dose. With the availability of rituximab biosimilars, I might use this rituximab regimen, rather than other biologic agents, in a larger proportion of patients with RA to provide effective therapy at a lower cost.
Novel Small Molecule: IRAK-4 Inhibitor
Although we now have 3 FDA-approved JAK inhibitors for RA, IL-1 signal transduction is not mediated by JAKs. IRAK-4 is a signaling kinase for toll-like receptors and IL-1 receptors. Thus, IRAK-4 inhibition interferes with IL-1 signaling.
I was intrigued by the results of a phase IIb study of the small molecule IRAK-4 inhibitor PF-06650833 in patients with RA inadequately responsive to methotrexate. This dose-ranging study compared 4 different doses of this novel IRAK-4 inhibitor to the JAK inhibitor tofacitinib or placebo in patients with high RA disease activity, many of whom had received previous corticosteroids and some of whom had been treated previously with a tumor necrosis factor (TNF) inhibitor.
Treatment with the IRAK-4 inhibitor brought about greater reductions in SDAI (the primary endpoint) for all doses tested vs placebo. It also resulted in statistically superior reductions in DAS28-CRP and ACR50 responses vs placebo. Infections were the most frequently observed adverse events; no deaths occurred.
The combination of a novel mechanism of action, with both early efficacy and reasonable safety justifies bringing this IRAK-4 inhibitor into phase III clinical development.
Vagus Nerve Stimulation
Another proof-of-concept study was of a novel approach to treatment: vagus nerve stimulation for patients with active RA who had not responded to a number of different drug treatments. Tracey and colleagues had previously shown that vagus nerve stimulation inhibits TNF release in patients with RA.
At ACR 2019, Gaylis and colleagues presented results of a study examining the ability of a small implantable vagus nerve stimulator to decrease cytokine production in patients with active RA. Patients received 2 different doses (either 1 minute daily or 1 minute 4 times daily) of active vagal nerve stimulation or sham treatment, in which the device was not turned on.
At Week 12, active stimulation resulted in decreased levels of the proinflammatory cytokines IL- 1, IL-6, and TNF and only minimal changes in the sham group. Five of the 10 patients treated with active vagal stimulation exhibited meaningful, clinically important reductions in disease activity scores (DAS28-CRP and CDAI).
Device implantation to treat RA is a completely novel approach. I await the results of larger follow-up studies.
There is an unmet need for treatment among patients with RA in whom multiple therapies have failed; the unique mechanism of action of vagus nerve stimulation to decrease levels of proinflammatory cytokine levels may be an effective approach to treat these patients.
Patients with RA who are in sustained remission prompt consideration of de-escalating treatment to see if disease control can be maintained with less medication at a lower cost. Since TNF inhibitors are usually more expensive than conventional synthetic disease-modifying antirheumatic drugs (DMARDs), it would be preferable to taper the TNF inhibitor first.
However, Emery and colleagues found that withdrawing the TNF inhibitor from patients with early RA who had achieved remission resulted in loss of remission. Thus, in my practice, I first taper conventional synthetic DMARDs before reducing the TNF inhibitor dosing frequency. The study presented at ACR by van Mulligen and colleagues supports this approach.
In adults with early RA and sustained very low disease activity, van Mulligen and colleagues compared tapering either the conventional synthetic DMARD or the TNF inhibitor during Year 1 and then tapering the remaining medication during Year 2.
They found that twice as many patients reached DMARD-free remission by Year 2 after tapering the conventional synthetic DMARD first compared with tapering the TNF inhibitor first. This suggests that one should first taper the conventional synthetic DMARD rather than the TNF inhibitor.
This study supports the strategy of reducing the methotrexate dose before reducing the biologic dose in patients with early RA. In my practice, I typically attempt to reduce the methotrexate dose in patients who have achieved excellent control of their disease activity on the combination of methotrexate and a TNF inhibitor. However, I have been reluctant to discontinue methotrexate completely. This study suggests that, at least in patients with early RA, methotrexate may be tapered and discontinued with continued control of disease activity and that the TNF inhibitor might even be discontinued subsequently to achieve DMARD-free remission.
However, the conclusions of this study do not necessarily apply to patients with RA of longer duration. It will be interesting to see if similar results can be achieved using the same study design in patients with established RA.
I’d like to hear from you: Will the results of these studies influence how you treat patients with RA in your practice? I encourage you to post your thoughts and questions in the comments section below.