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Getting to the Bottom of Lupus Biology

Bret S. Stetka, MD

November 07, 2017

Mary K. Crow, MD, is physician-in-chief and chair of the Department of Medicine at Hospital for Special Surgery (HSS). She is also chief
of the Division of Rheumatology at HSS and a leading researcher into the molecular mechanisms associated with rheumatologic disease.
Medscape recently spoke with Dr Crow about her work exploring the pathologic basis for systemic lupus erythematosus and also about
how untangling the pathologic contributors to lupus is pointing researchers toward new therapeutic targets.

Medscape:Your research involves studying the biology behind autoimmune disorders, including lupus. How did you get
involved in this line of work?

Dr Crow: I think it is the case that for many lupus investigators who are physician scientists, their first encounter with a lupus patient
influenced their careers. That was the case with me. The very first patient I saw as a medical student in which I was the primary person
evaluating the patient was a lupus patient—a teenage girl. It's just very compelling when you think about how severe the disease can be,
how debilitating and life-changing it can be, and then also how interesting it is from an immunologic point of view.

I was always very interested in autoimmune self-reactivity. Why would the immune system target one's own self and one's own cells? My
interest really comes from curiosity and trying to understand why a disease would develop in that kind of way—targeting the self.

Medscape: How do you define lupus?

Dr Crow: Lupus is a systemic autoimmune disease, meaning that it affects many different organ systems—maybe most organ systems.
It's based on impaired regulation of the immune system, with the immune system becoming generally activated in a sustained way over
many years and with the result being production of autoantibodies, production of many immune mediators, cytokines, and other factors
that then drive inflammation and, ultimately, organ damage. The disease is very fascinating and is focused on reactivity to components of
our own cells, particularly nucleic acids and particles that contain nucleic acids and proteins.

One of our main areas of interest over about 15 years has been based on the observation that type I interferon, which typically is
produced in the setting of a virus infection, is activated in most lupus patients in a sustained way. Our suspicion is that that overproduction
of type I interferon is a very fundamental problem in lupus that contributes to all of this autoimmunity and inflammation.

Medscape: Part of your work shows that interferon triggers certain gene expression profiles in lupus patients, correct?

Dr Crow: Right. As you might see in the course of a viral infection, the interferon is produced by a number of different cell types and then
acts on other cells through the interferon receptor. Through this mechanism, it then turns on or induces the expression of many different
genes—hundreds of different genes that are all meant in a healthy individual to orchestrate the control of a virus infection.

But when that response is sustained over time, it causes problems. The way we typically detect activation of the type I interferon pathway
is to look at cells from patients and actually measure in one way or another the activation of the hundreds of genes that are induced by
type I interferon. That said, we really focus on measuring three or four specific genes to get what we call the interferon gene expression
"signature." This interferon signature is a characteristic of most patients with lupus.

The End Goal

Medscape: Is the ultimate goal to identify biomarkers and eventually therapies for lupus?

Dr Crow: The end goal in pursuing characterization of this interferon signature is really to understand where it's coming from; what's
driving it. Our idea is that the disease, through the effects of interferon, is driven by our own DNA or RNA. We think the [interferon gene
expression signature] is a good biomarker of this important mechanism, but there are probably other better ways of measuring disease
activity.

It certainly could be a biomarker for potential responsiveness to some of the therapeutics that are being developed to target the interferon
pathway. I think this is still a question that needs to be supported by more data. But at least one study[1] has shown that patients with a
high interferon signature do demonstrate a more robust response to an antibody that blocks the type I interferon receptor. Measuring the
interferon signature ultimately might be a good way to identify the patients who are more likely to respond to particular therapeutics.

Medscape: And by identifying these particular profiles associated with lupus, will we see new therapies anytime soon?

Dr Crow: I think there are a number of potential ways that this pathway could be targeted therapeutically. I try to logically think through
the whole scenario that leads to this interferon signature. We need to identify what are the drivers of production of interferon and what are
the molecular pathways that are involved in this production. And then, once it's being produced by various cells, you can think about
targeting the cells that are the major producers of interferon. You can also think about the approach currently being tested in therapeutic
trials: blocking the receptor for interferon.

Targeting components of the signaling pathways downstream from the receptor is another potential approach. An example of one of those
might be a Janus kinase (Jak) inhibitor. There are inhibitors of Jak-STAT pathways that are currently available and others in development.
I think there are many different steps in the entire pathway that contribute to this interferon signature and could potentially be targeted.
One of the goals of understanding more about the underlying mechanisms of disease is to get a sense of what might be the most
productive way to interrupt this pathway.

Medscape: To what degree is lupus thought to be genetic?

Dr Crow: We typically talk about lupus as being affected by genetic factors as well as environmental triggers—and also just chance
factors. By chance factors, what I mean is that there are many different opportunities for cells to become activated—or not. With regard to
genetics, in recent years there's been more and more investigation and data available to identify the areas of the genome that are
associated with the statistical risk of having a diagnosis of lupus. An interesting question is whether or not these regions of the genome
are actually involved in coding for proteins that might be directly involved in the disease; or, rather, are these variants in regulatory regions
that might control a nearby gene or even many distant genes or do something we don't yet understand? I think the current view is that
most areas of the genome associated with the disease are in regulatory regions. We have a lot to learn about the impact of genetics.

A number of the genetic risk variants have been tracked or mapped to parts of the interferon pathway, close to genes encoding proteins
involved with either induction of interferon or response to interferon. There is no doubt that genetic variation plays some role in the extent
to which an individual is going to activate that pathway. There are clearly additional genetic factors that influence other aspects of the
immune system that are likely to be very important in whether you make a particular autoantibody. Many genetic variants—probably over
a hundred—can come into play, and they'll certainly be a little bit different in every individual.

Medscape:Are there known environmental triggers for lupus?

Dr Crow: It's been difficult to pin down one or another specific factor. There probably are external triggers, such as ultraviolet light, and
also internal triggers that could be very important. One internal trigger—and I mentioned it before—is our own nucleic acid. There could
be situations in which our DNA or RNA may become available to the immune system and activate it, similar to the way a virus might
activate the immune system.

And then there's the whole concept of stress being a factor. I think there's support for thinking that oxidative modification of the cell's
proteins or other parts of our cells can play a role in activating the immune system in a way that generates autoimmunity. A lot more work
needs to be done, particularly in the area of environmental triggers.

Lupus Risk and the Future of Treatment

Medscape: Do you have any advice on how doctors can advise patients on lupus risk reduction?

Dr Crow: That's a tough one. Timely diagnosis is certainly important. One important point is that lupus is really a clinical diagnosis. I don't
think we have enough confidence in any one blood test alone, whether it's a traditional blood test like measuring anti-DNA antibodies or
complement levels or newer biomarkers like the interferon signature or other gene expression patterns. The disease has a complex
clinical picture, and I think what you need is an experienced physician, usually a rheumatologist, to put together both the clinical picture
and the laboratory data to make a diagnosis.

If the patient does have some of the clinical manifestations of lupus (and they can be varied, from a skin rash to kidney problems to
arthritis to fever), the patient and the physician need to be very alert that lupus is a possibility and order appropriate blood tests. Then if
the picture does seem to fit with lupus, I think the best approach is to refer to a rheumatologist with expertise in lupus to manage the
problem.

Medscape: You're also investigating how a patient's sex influences lupus, correct?

Dr Crow: Yes. This is a relatively new project for us and is led by my colleague Dr Mikhail Olferiev in the lab. We're looking at the impact
of sex on lupus. You probably know that lupus is very highly skewed toward women: Maybe eight or nine times more women than men
get lupus. We're analyzing data from male and female lupus patients and healthy donors to try to understand why women get lupus more
frequently than men. We're also thinking about it the other way around and asking: Are men protected from getting lupus based on
molecular mechanisms that come into play in men that are not active in women?

Medscape: Are hormones thought to be a contributor?

Dr Crow: In general, yes, and I think that hormones do play a role in immune system activity, including perhaps that seen in lupus. But
the extreme sex skewing that you see in lupus is out of proportion to what can be attributed to hormonal effects. One proposed
mechanism that researchers are thinking about now is the role of the X chromosome and its chromosome dosage.

Women have two X chromosomes and men have one. Is there something that might be linked to mechanisms in what's called X
chromosome inactivation? This is an important mechanism in women that equalizes the expression of X chromosome genes between
men and women. There are complex mechanisms that are involved in X chromosome inactivation. Could there be something that goes
awry in that process that could contribute to this sex skewing? We're looking at our RNA sequencing data to see if we can get some hints
about that.

Medscape: Where do you see your research heading, say, 10 years down the road? And can you speak to the future of lupus
therapy?

Dr Crow: I think that our own lab, together with many labs around the world, is just going deeper and deeper into understanding the
underlying mechanisms of lupus. As we get more detailed insight, I think we will have better ideas about how to develop therapies for the
disease. In my opinion, lupus therapeutics are moving toward developing a data-based rationale for combining therapies that would allow
use of lower doses of each agent to reduce toxicity while targeting different parts of the immune system.
Medscape: Do you think that personalized medicine will play a role in lupus therapy in the near future?

Dr Crow: Personalized medicine is an interesting concept. To some extent, it's a trendy term that I think is a little bit overblown. But
there's no doubt that we are all different from each other. If you look at a patient with any disease, or group of patients with any disease,
the disease is not going to be manifested in the identical way from one person to another.

With a disease like lupus, personalized medicine is particularly attractive because the disease can manifest in so many ways. So you can
ask: How do we get to the underlying biology in patients with arthritis? And how does this differ from a patient with nephritis? And maybe
one day we will be able to target medications in a biologic mechanism-specific manner.

But at the same time, I do think that lupus is a definable disease that will have some very definable biological underpinnings. I generally
think that sustained innate immune system activation—with the type I interferon response being a very important part of that—might
represent that common fundamental thread. Eventually lupus therapy could evolve toward an approach that uses a drug that targets a
common molecular mechanism in the majority of patients but then adds on a second therapy or third therapy that is more targeted to the
particular clinical features of the individual patient. We'll have to wait and see.

References

1. Furie R, Khamashta M, Merrill JT, et al; CD1013 Study Investigators. Anifrolumab, an anti-interferon-α receptor monoclonal
antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017;69:376-386. Abstract

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Cite this article: Bret S. Stetka. Getting to the Bottom of Lupus Biology - Medscape - Nov 07, 2017.

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