COMMENTARY

From Washington, an Update on Arthritis and Arteritis

Jonathan Kay, MD

Disclosures

November 22, 2016

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Hello. I am Dr Jonathan Kay, the Timothy S. and Elaine L. Peterson Chair in Rheumatology and professor of medicine at the University of Massachusetts Medical School. I am reporting for Medscape from the 2016 American College of Rheumatology annual scientific meeting in Washington, DC.

Today I would like to cover just a few of the many highlights from this year's meeting, starting with the new phase 3 clinical trial of tocilizumab, an interleukin (IL)-6 receptor inhibitor in giant cell arteritis.[1] This study was an efficacy and safety study looking at tocilizumab in patients with documented giant cell arteritis to see whether tocilizumab improved the remission of patients after tapering from glucocorticoid therapy. The patients were studied for 52 weeks, and patients who were at least 50 years of age who had giant cell arteritis confirmed by temporal artery biopsy or cross-sectional imaging with elevation of acute-phase reactants that was attributable to giant cell arteritis were randomly assigned 1:1:2:1 into four groups.

The first group was treated with a short course of prednisone over 26 weeks, which was tapered, and they were given a weekly subcutaneous placebo. The second group received a long course of prednisone tapered over 52 weeks, again, with a weekly subcutaneous placebo. The third group received weekly subcutaneous tocilizumab at the usual dose of 162 mg and a 26-week short-course prednisone taper. The fourth group received an every-other-week dose of tocilizumab subcutaneously at 162 mg and a short-course prednisone taper over 26 weeks. The randomization allowed twice as many patients to be entered into the weekly subcutaneous tocilizumab arm as into the other three arms.

Patients who flared or could not adhere to the protocol-defined tapering schedule received open-label prednisone as an escape therapy but continued on their double-blinded tocilizumab or placebo. Sustained remission was the primary outcome, and it was defined at week 52 as the absence of flare and normalization of the C-reactive protein after week 12, combined with adherence to the protocol-defined prednisone taper. The patients who were the proportion of patients in sustained remission, comparing the combined groups on tocilizumab with the short-course prednisone group and the long-course prednisone group, respectively, were considered primary and key secondary endpoints of this study.

The study was a positive study. It showed that the addition of tocilizumab to a 26-week prednisone taper was superior to both short- and long-course tapers without concomitant tocilizumab therapy in achieving sustained remission at 52 weeks. This addition of tocilizumab also allowed a reduction in the total cumulative prednisone dose. From this study, it looks as if tocilizumab will be an effective adjunct to prednisone in the treatment of giant cell arteritis, sparing prednisone and also leading to a larger proportion of patients achieving remission without flares and with normalization of their acute-phase reactants.

This certainly is going to change therapy. However, the cost of tocilizumab compared with the cost of prednisone alone is something that will have to be considered in the treatment of these patients. The potential adverse outcomes of inadequately treated giant cell arteritis, however, certainly justify the use of an effective medication regardless of its cost.

Cardiovascular Safety

The next study that I would like to allude to is the PRECISION trial, which is a cardiovascular study that is comparing celecoxib vs naproxen therapy. A large study, enrolling over 20,000 patients, is looking at the occurrence of cardiovascular adverse outcomes. This study will be presented as a late-breaking abstract by Elaine Husni, from the Cleveland Clinic.[2] The abstract included no data, so the outcome of this study will certainly be a surprise. This is clearly a very important study because the potential for selective cyclo-oxygenase 2 (COX-2) inhibitors to increase cardiovascular risk is significant. This study certainly should provide us with interesting information about cardiovascular outcomes of selective COX-2 inhibitor therapy.

There is another comparative cardiovascular safety study that was conducted looking at etanercept compared with tocilizumab in patients with rheumatoid arthritis (RA).[3] Tocilizumab is an IL-6 inhibitor that is known to increase low-density lipoprotein (LDL) cholesterol levels. This increase in cholesterol levels, although not increasing the cardiac risk ratio, was thought perhaps to increase the cardiovascular risk of therapy. This 5-year, randomized, open-label, parallel-group, multicenter, noninferiority clinical trial was embarked upon to look at the occurrence of cardiovascular adverse outcomes and adjudicated outcomes in patients treated with either tocilizumab or etanercept. The researchers found that there was no clear difference between tocilizumab and etanercept in terms of adverse outcomes and, in terms of the statistical design, excluded more than a 43% relative increase in the hazard of major cardiac adverse events. However, tocilizumab did increase LDL cholesterol levels compared with etanercept. All of the overall safety issues should be considered for both of these medications.

More Biosimilar Data

The final study that I would like to mention is a newsworthy study called the NOR-SWITCH trial.[4] This is a study that looked at the biosimilar infliximab CT-P13, the Celltrion product, compared with the reference product produced by Janssen. In this study, patients in Norway were randomly assigned in a double-blinded fashion to receive either continued originator infliximab or the biosimilar over 52 weeks. Patients who were on infliximab for any of the indications and who were doing well were randomly assigned to either continue using their drug or to switch to the biosimilar. The primary outcome measure of this study was a worsening of disease activity, either by a predefined outcome measure for each of the different diseases—including RA, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn disease, and ulcerative colitis—or agreement on the part of patient and physician that the disease was worsening.

The study enrolled nearly 500 patients at 40 Norwegian study centers. It was a tremendous effort coordinated by Professor Tore Kvien at the University of Oslo. Professor Kvien and his group are presenting data at this meeting that were also recently presented at the European Gastroenterology meeting in Vienna, which showed that looking at the entire population, combining all of the diseases together, there was no difference in terms of disease worsening between the biosimilar and the reference product. The study was not powered to look at differences in individual diseases. In Crohn disease, there were slightly more patients on the biosimilar who had disease worsening, but the study was underpowered to be able to detect significant differences between the biosimilar and the reference product in terms of individual diseases.

This study, which is called NOR-SWITCH, is really NOR-transition in that it shows the safety and reliability of transitioning patients once from the reference product, infliximab, to the biosimilar. In terms of the safety of switching, which might occur if there is nonmedical switching dictated by third-party payers, which would require multiple switches, the study design has not yet been carried out and reported in terms of long enough term switches to justify the safety and efficacy of repeated switches back and forth. I anticipate, however, that that information will be gathered in clinical practice when third-party payers require transitioning from a reference product to a biosimilar and then to another biosimilar and back and forth over time, based upon economic considerations.

Conclusions

At this meeting in Washington, we talked about a study that looks at tocilizumab as a steroid-sparing agent in giant cell arteritis, suggesting that tocilizumab is effective in improving outcomes in giant cell arteritis compared with prednisone alone. Next, another study showed that tocilizumab is noninferior to etanercept in terms of risk for cardiovascular outcomes in RA. Next, data were promised that will be presented comparing celecoxib vs naproxen in terms of cardiovascular outcomes in patients treated with a selective COX-2 inhibitor compared with a traditional nonsteroidal anti-inflammatory drug. Finally, a very interesting and certainly newsworthy study looked at transitioning between a reference product and a biosimilar in multiple indications for which both are indicated. This is just a small sampling of the many papers that were presented at this meeting. Certainly, more information will come over time.

Thank you very much for your attention, and I look forward to seeing you again on Medscape. I am Dr Jonathan Kay.

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