The face of therapy is changing in SLE. There is a need to allow a higher proportion of patients to get to low disease activity and into remission, and there continues to be a need for cure. In concert with these goals, we are increasingly considering the possibility of adding to our standard therapy for LN. We have 2 recent arrivals to the LN space: voclosporin and belimumab.

If we are starting patients on steroids and mycophenolate or cyclophosphamide, then the following question arises: How should we time the introduction of a newer agent such as voclosporin? Voclosporin, in combination with mycophenolate and low-dose steroids, appears to have an excellent early renal response rate at 24 weeks, but we do not yet know enough about long-term toxicity. I would think that voclosporin-based combination therapy would only be used in patients who have a close-to-normal glomerular filtration rate. Further, the duration of therapy would likely need to be limited to 6 to 12 months, owing to the risk of renal toxicity.

We are all used to adding belimumab for patients who do not have LN, so we are familiar with the agent and we already know how to use it. Another advantage is that it does not appear to add to the risk for infections. The major disadvantage is that it does not have an oral form.

Regarding both voclosporin and belimumab, I was interested in the timing of the introduction of these therapies in the combination paradigm for LN (ie, were all agents started at once, as it appeared from the publications, or were they added in succession to see if any adverse events emerged with each new agent?). So, I contacted some individuals involved in the clinical trials, and it appears that there is usually an addition of the treatments in sequence rather than all at the same time. As with many newly arriving treatments, there might be a gap between how the literature reads and how one practices. At this juncture, I plan to use more of an add-on paradigm, albeit a rather quick add-on.

Lupus is extremely heterogeneous, and we are all coming to realize that there is a kind of balance in immunity, allowing for healthy sways from one end of the scale to the other end. In lupus, the challenge may be related to getting to a smaller tipping balance (ie, the balance that is observed in healthy individuals). For instance, with a viral infection, a healthy person can generally handle the illness and get back to equilibrium in fairly short order. With lupus, the balance is, in a sense, tipping one direction and then tipping too far the other direction—either way, the unbalanced state results in lupus. Different patients have different tipping points and mechanisms by which they react, which is why you get the heterogeneity (ie, all of the patients share some things, and groups of patients share a few more specific things).

At this point, we are working toward precision medicine for lupus, but we will need to be satisfied with just a bit more precise medicine. As such, I am happy to have different options. I think that any drug might be the best drug for some individual at some point. I would like to have a lot of different drugs to work with, and I would like to have a lot of tests available to help me determine how to best apply them.

As Dr Hahn mentioned, voclosporin has just been approved for LN, and so we can also hope that it may have a role in the rest of lupus. We shall see. And we had already been familiar with belimumab, but now we know from the most recent reporting from a dedicated LN study that belimumab showed improvements in renal response when added on to other treatments. Previously, there had been a signal in exploratory analysis, but now we have a study that was designed to answer that question. Some of the other agents that are of investigational interest or are in development for SLE include the type I interferon receptor blocker anifrolumab; the intracellular activation inhibitors baricitinib, iberdomide, and deucravacitinib; and agents that inhibit numerous B-cell and T-cell activation pathways. There are interesting data from trials of B-cell and T-cell co-stimulation inhibitors atacicept and telitacicept. And there are others.

I am perhaps more of a skeptic, possibly in concert with my strong focus on understanding factors and pathways that are involved in the development of SLE. I have been thinking about lupus for decades, going back to 1979, when I first came to this country. In fact, Dr Hahn was one of the first names that I learned at that time. She and Dr Merrill have noted the clinical heterogeneity of the disease, and I think that all of us would agree that SLE is equally heterogeneous in terms of the pathways, molecules, and cells that are involved in the expression of the disease.

The question of why very successful phase 2 trials fail in the third phase is important. Let us say that you have, conservatively, 50 pathways involved in SLE, and you target one of them. It would be naive to expect that such an approach would be likely to succeed in clinical trials. Until we reach our goal of truly classifying patients with SLE up front into more homogeneous groups and treating patient subsets more specifically to their disease expression, a viable approach is to try to treat patients with 2 or 3 drugs in combination. Another reason why phase 3 trials may fail is because we start out with the wrong premise. For instance, ustekinumab binds to the p40 subunit of interleukin 12 and interleukin 23, and there was the premise that this target is particularly significant or is a main driver of SLE, and this does not appear to be true. The same type of faulty premise may apply to the B-cell–depleting agents; we assume that B cells drive disease in all patients with SLE when, in fact, they do not.

Belimumab and voclosporin were both shown to deliver clinical improvement in large clinical trials, which is satisfying, but we need to do more. While there is no consensus on how to time multiple therapies, I agree with Dr Hahn’s thoughts on add-on therapy, or a slightly staggered initiation of drugs.