Higher-dose upadacitinib outperforms adalimumab in DMARD-refractory PsA

Gary L. Crump, MD, FACR

Psoriatic arthritis is a challenging disease for rheumatologists for multiple reasons. First and foremost, unlike rheumatoid arthritis, which is clinically a purely single domain syndrome of inflammatory peripheral arthritis, psoriatic arthritis encompasses multiple domains that differ from patient to patient. These domains not only include inflammatory synovitis, but also enthesitis, dactylitis, inflammatory spine pain and of course the skin component.

Additionally – and largely because of these multiple disease domains – precise characterization of disease activity of PsA is much more difficult than with RA. There is no defined and validated objective measure of PsA disease activity that is easy to use in the clinic and applicable across all different types of disease and domains. There is certainly nothing as specific and well characterized as the multi biomarker disease activity panel that has been developed for RA. We are left with an amalgam of metrics adapted from RA, such as the ACR 20 score that only encompasses part of the disease, or other individual metrics of the specific domains, such as the LEI and PASI score.        

Furthermore, PsA is certainly still in need of new treatment modalities with different mechanisms of action. The availability of more oral options for this disease is certainly desirable. There is already one JAK inhibitor, tofacitinib, approved for PsA.

Enter upadacitinib, by way of this phase 3 trial, dubbed SELECT-PsA 1. In terms of ACR 20 response, both of the two doses of upadacitinib were effective compared to placebo; the 15 mg dose was noninferior and the 30 mg dose was superior to adalimumab, with the same trend noted at the ACR 50 and ACR 70 levels. Upadacitinib also was slightly better than adalimumab at many of the secondary clinical endpoints, such as enthesitis, dactylitis and skin measures. Most importantly, it was slightly better at percentage of patients attaining minimal disease activity (MDA) at week 24.

The practical question for rheumatologists is where will this drug fit in our treatment pathways for PsA? Based on this trial, there does not seem to be any one clinical subtype of PsA for which this agent appears to have distinct advantage over a TNF inhibitor, and it seems to generally be a slightly better anti-synovitis drug for this disease state than adalimumab.

If this drug is released at the 30 mg dose, clinicians will wrestle with the trade-off of a treatment that is, at best, slightly more effective yet has higher risks.

In Europe, only the 15 mg dose was approved. At that dose, it has minimal measurable advantage, and has minimally higher adverse event rates, with of course the advantage of being an oral agent, and the disadvantage of the need for regular lab monitoring. As always, more trial data and real-world experience will determine upadacitinib’s place in PsA treatment.

David A. McLain, MD, MACR, FACP, FRCP

Rheumatologists find their “tool box” loaded with tools for rheumatoid arthritis and psoriatic arthritis. For PsA, we have FDA-approved TNF inhibitors (infliximab, etanercept, adalimumab, golimumab, certolizumab), a PDE4 inhibitor (apremilast), a T-cell activation blocker (abatacept), IL-17A blockers (secukinumab, ixekizumab), an IL-12/IL-23 blocker (ustekinumab), an IL-23 blocker (guselkumab) and a JAK inhibitor (tofacitinib).

To date, we have 12 medications FDA-approved for PsA. If the pending application for upadacitinib is approved, we would have 13. This doesn’t include the non-FDA approved methotrexate, which is approved for psoriasis, but not PsA — although often a step in step-therapy.

What we need is guidance on which medication to use for a particular patient. When enthesitis is a major component, we think of apremilast. A laboratory test that would guide therapy to a particular agent would be very helpful. For rheumatoid arthritis, we now have the Scipher Medicine and Ambry Genetics introduced PrismRA molecular signature test to identify those patients who will not respond to TNF inhibitors and would not be candidates for TNF inhibitor cycling.

We realize how inefficient the present treatment paradigm is for our patients. If we “hit a home run” on the first couple of drugs, that makes our day. But for many patients, the trial and error method is all we have and we understand that for some patients, the disease progresses under our care.