Better Arthroplasty Outcomes, Hope in Scleroderma, and Other Rheumatology Advances

Bret S. Stetka, MD


January 03, 2018

Editorial Collaboration

Medscape &

Following the 2017 American College of Rheumatology (ACR) Annual Meeting—held in San Diego, California, November 3-8—Medscape spoke with Hospital for Special Surgery rheumatologists Dr Robert F. Spiera, MD, and Dr Susan M. Goodman, MD, about their research and highlights from the conference.

How Social Factors Influence Post-Arthroplasty Outcomes

Medscape: You gave several presentations at this year's ACR meeting on the ways disparities affect outcomes in knee and hip replacements. Can you share what you've found?

Dr Susan M. Goodman, MD

Dr Goodman: The focus of our research has been to better understand the interactions between social factors and healthcare outcomes. It turns out to be very complicated when you look at socioeconomic factors because there are always a lot of levels of interaction.

To try to piece out what's what, we've been using arthroplasty registry cases, which have an enormous amount of very rich data, including specific pain and function outcomes that are measured both preoperatively and at 2 years, as well a lot of information about the individual patients like age, sex, and education. Then we've worked with a census tract coding mechanism that allows us to geocode the individual patient addresses. That helps us look at the specific associations between individual level cases and census tract variables and then to look further to see which variables interact.

In the first paper[1] presented at the ACR meeting, we looked at the association of educational achievement and arthroplasty outcomes. We looked at all of our patients' individual level data. One of the first things we found in just putting the cohort together is that those patients who had college educations tended to come into this surgery earlier and to do better. The patients without education waited a lot longer and came in a far worse state. Even though they had significant improvement, they didn't quite catch up.

Then we looked to see if there was an interaction between education and poverty. To do that, we linked our cases to a census tract map showing the percent below poverty. What we found was that if you were highly educated, it didn't really matter where you lived; your outcome was the same. But those patients who weren't well-educated had worsening outcomes as the poverty level increased.

We've seen that relationship both with race and education as the individual factors that contribute to healthcare outcomes and interact with poverty. We also presented our study looking at education and poverty and the interaction there for knee replacement outcomes,[2] as well as the relationship of hip replacement outcomes for black patients and community poverty.[3]

Medscape: I wonder if there is a self-perpetuating cycle where people in impoverished communities with lower education have worse outcomes, which their peers witness, making them in turn less likely to want to have that procedure.

Dr Goodman: That's a well-described phenomenon. We know that there's a very strong volume/outcome relationship. If people are going to community hospitals that don't do a lot of procedures—and people tend to stay in their neighborhood for surgery—then the logical conclusion is that this isn't a good operation. So it is self-perpetuating.

Medscape: You presented one other study[4] on the impact of being from an immigrant community. What did you find?

Dr Goodman: We wanted to see if being from an immigrant community or other features like sex had any effect on arthroplasty outcomes. We found that immigrant communities really had no impact on health outcomes. Coming from communities with a high proportion of foreign-born residents had no effect on their outcomes. That was an interesting negative association.

A New Cannabinoid Treatment for Scleroderma

Medscape: Dr Spiera, you presented some interesting data on the new cannabinoid compound for scleroderma. Can you tell us about that?

Dr Robert F. Spiera, MD

Dr Spiera: Yes. To first set the backdrop, though, this is a multicenter, industry-sponsored trial for which I served as the lead investigator.

Scleroderma is one of our most challenging rheumatic diseases to treat. There hasn't yet been what we would consider a proven "disease-modifying" drug, meaning a drug that you can introduce that actually changes the clinical course of the disease. We have hints that there are things out there that may be effective, some of which are fairly substantial therapies, including immunosuppressive or immunomodulatory therapies. However, there's been a major unmet need for a relatively safe drug that may have promise in terms of preventing progression of the disease or even lead to regression of the disease in systemic sclerosis.

A number of presentations at the meeting related to the phase 2 trial with this compound called lenabasum. It's a cannabinoid receptor agonist that is preferentially selective for cannabinoid-2 (CB-2) receptors. The endocannabinoid system is intimately involved in the innate immune response. CB-2 engagement helps lead to resolution of the innate immune response, which is of relevance in scleroderma because a perpetuated innate immune response leads to inflammation and fibrosis, that "scarring" process that's so integral to what we observe in scleroderma clinically.

As a selective CB-2 receptor agonist compound with limited central nervous system penetration, it doesn't really have the significant neuropsychiatric effects associated with cannabinoid-1 receptor activation. Engagement of CB-2 receptors in in-vitro systems has suggested potential antifibrotic effects, and these have been demonstrated in animal models of fibrosis and scleroderma. This suggests that this could be a promising strategy in human disease.

Promising Phase 2 Results

Dr Spiera: The primary paper[5] we presented at the meeting was the results of a phase 2, double-blind, randomized, controlled trial looking at this drug in early diffuse systemic sclerosis. Patients with scleroderma were randomly assigned to active drug or placebo using a 2:1 randomization scheme (meaning for every two patients randomly assigned to active drug, one patient was randomly assigned to placebo). It was a relatively short trial lasting about 16 weeks, 12 of which they were on therapy. Background therapy with treatments often used in diffuse systemic sclerosis such as mycophenolate or methotrexate was allowed to be continued in both groups.

We assessed and compared outcomes between groups. For our primary outcome measure, we used the ACR Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS), which includes measurements in five domains felt to be important in assessing patients with this disease. One of the most important measures included in the CRISS is the Modified Rodnan Skin Score, which assesses quantitatively skin thickening in these patients. Other components of the CRISS are forced vital capacity (a measure of lung function), the Physician Global Assessment, the Patient Global Assessment, and the Health Assessment Questionnaire-Disability Index, a patient-reported outcome assessing their function.

We showed that over the course of the trial, patients treated with active drug had significant improvement in the median CRISS, whereas it was flat for those treated with placebo. This was exciting in terms of a drug showing potential efficacy in a relatively short trial where often we are mostly looking for safety and hoping for a signal suggesting efficacy, possibly even just in our translational outcomes. In this trial, we actually showed a statistically significant benefit with regard to our primary efficacy outcome.

The question was whether this benefit was actually "real." One of the more impressive things that really supported this was that we did skin biopsies[6] on patients before and after treatment, whether they were on active drug or placebo. We then had a very experienced scleroderma investigator examine these biopsies and apply a scoring system evaluating the degree of fibrosis and inflammation in these specimens. He was, of course, blinded to treatment assignment. He found that paired specimens from lenabasum-treated patients were clearly more likely to show improvement in inflammation. Of note, and perhaps surprising, they also were much more likely to show improvement and stabilization in fibrosis, which we did not traditionally think would likely change impressively in such a short period of time.

Analysis of gene expression in the biopsies similarly showed that genes related to pathways involved in extracellular matrix organization, collagen catabolism, and inflammation and cytokine response, which are all relevant in scleroderma, were all downregulated in specimens from patients on active therapy and stayed flat in those from placebo-treated patients.

These were enormously encouraging results. The sponsor, Corbus, is about to launch a large international phase 3 trial of the drug to treat scleroderma.

We also presented the open-label extension data for this trial.[7] After the completion of the blinded phase of the trial, all patients were allowed access to treatment with lenabasum in an open-label fashion. There was a window in which patients were off active therapy. Within 28 weeks of therapy with active drug, there was again an impressive improvement in CRISS and skin score. Although patients with scleroderma can improve spontaneously over such an extended period of time, the degree of improvement observed was further supportive of the possibility of this being an effective therapy.

Seeking Other Scleroderma Treatments

Medscape: That's very encouraging for this condition. Are there any other promising treatments out there that you know of?

Dr Spiera: There's a lot out there being looked at. We all have our favorite immunomodulatory drugs that we use in practice. Mycophenolate has been shown to have some promise in scleroderma lung disease.

I should mention that in this trial, patients were all allowed to be on background therapy, and about 90% were in both groups, very often with mycophenolate. So whatever benefit we were seeing here was in addition to that.

There have also been trials with aggressive therapies including high-dose immunoablative chemotherapy and stem cell transplant to salvage the patients' immune system.

Medscape: That's great that there's encouraging news out there for these patients. There were other things you presented at the meeting as well, right?

Dr Spiera: This is sort of switching gears a little bit. Our Scleroderma, Vasculitis, and Myositis Center produces a patient education newsletter every month, and we had an Association of Rheumatology Health Professionals presentation about that at the meetings.[8]

Our center manager, Elizabeth Soto-Cardona, MPH, presented an analysis of what we did and how we define content in these electronically distributed patient education materials. Basically, previously their content had been determined by the center physicians just deciding what we thought patients thought was important. We assumed that psychosocial and support issues were most important to them.

But then we surveyed patients about the content we had sent out and in parallel surveyed physicians in our department about that content. It turns out that, yes, physicians' perception was that patients think the support and psychosocial issues are more important, whereas the patients clearly felt that the hardcore facts and underlying science of the diseases and their therapies were more important. That oral presentation was interesting in terms of helping us be better at providing educational resources for our patients.

Reflections on ACR

Medscape: Before we go, I'd like to get both of your general thoughts on this year's ACR meeting. It seemed like this year was a particularly big meeting with lots of data. Were there any big topics or presentations that drew your attention?

Dr Goodman: Well, there have always been sort of incremental gains in a lot of areas, so I don't think there've been any huge breakthroughs. There are a lot of incremental gains and interesting work in that regard.

Dr Spiera: I would sort of echo that. Last year, there was a tremendously important study presented on the role of tocilizumab in giant-cell arteritis.[9] But in the disease areas that I really focused on at this year's meeting, scleroderma and vasculitis, we didn't have any huge studies that came to roost.

There was one vasculitis study,[10] which we weren't part of, that looked at tailoring a rituximab remission maintenance strategy in antineutrophil cytoplasmic antibody-associated vasculitis to the patient, as opposed to just a routine use of rituximab on a predefined schedule. That study showed that there are probably advantages to tailoring it to a patient. I didn't think that was shocking, but to a lot of the world it's important to show that that can be done.

But in my two areas of interest, there was nothing otherwise that I'd highlight in a major way, though I hope I'm not offending or missing something!

Medscape: It seems like biosimilars are always a big topic. Are either of you involved at all with biosimilar trials or have any interest in that area?

Dr Goodman: Those really aren't that interesting. They're an economic reality, but they don't really have any intrinsic interest. If they actually make drugs more accessible to more people, that'll be a positive.

Medscape: I guess the controversy around them is that they're not all that much cheaper than the branded compounds?

Dr Goodman: So far there have not been huge differences.

Medscape: Thank you both so much for your time and sharing your thoughts on the meeting.

Dr Goodman reports no relevant conflicts of interest; Dr Spiera reports receiving research funding from Corbus Pharmaceuticals Holdings, Inc.


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