TNF-a Inhibition and the Treatment of Hidradenitis Suppurativa

Bruce Strober, MD, PhD

In this presentation, Dr Strober provides us with new data on TNF alpha inhibition in the treatment of hidradenitis suppurativa (HS). HS is sometimes referred to as acne inversa; however, Dr Strober feels it is a different disease based upon a lot of lines of evidence.

Based on recent insights into the pathogenesis of this disease, TNF inhibition has found to be an effective treatment. Essentially, it’s phenomenological, because if you look at lesional skin, there is more TNF alpha as compared to peri-lesional as compared to control skin. This isn’t to say that TNF is the only relevant cytokine; in fact, it may be the first of many which will be targeted over the next decade. Just like in psoriasis, TNF will be the first cytokine studied for targeting in HS.

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Etanercept

Overall, etanercept (ETN), at the doses that have been studied, does not appear to be effective treatment for HS. The prospective, double-blind, placebo-controlled trial of 20 subjects were randomized 1:1 for ETN 50mg BIW versus placebo for 24 weeks. The primary efficacy endpoint assessed the Physician Global Assessment (clear or mild). Secondary endpoints included change in Patient Global Assessment and quality of life (DLQI). The results demonstrated that there was no statistically significant difference in benefit between ETN and placebo. There are some case reports that also verify this phenomenon.

Infliximab

The case reports for infliximab, which were published several years ago, showed efficacy in the treatment of HS; however, many patients had concomitant IBD, which is not uncommon among patients with HS.

A prospective, double-blind, placebo-controlled trial of infliximab IFX) included 38 subjects randomized to either IFX or placebo. The study’s primary endpoint was a 50 percent reduction in HS Severity Index (HSSI) at week 8 and secondary endpoints included change in Visual Analog Scale (VAS) and DLQI.

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As noted in the table above, the HSSI score takes into account a variety of features, including dressing changes and pain—which are aspects of the HS experience that should be queried with each patient.

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As we can see, about 25%-30% of patients on IFX have a reduction in HSSI score versus the placebo group. If you look at the 25%-50% reduction range, you can still see a bias towards IFX. Dr Strober feels that these are good data substantiating the value of IFX for the treatment of HS.

The VAS score as well as DLQI also show that IFX did better than placebo.

Dr Strober has used IFX on at least forty patients and feels that it really is the best drug out there, if you can access it. He also recommends using it with methotrexate to sustain the effect of IFX.

Adalimumab

Adalimumab (ADA) represents the best set of studies done to date for the treatment of HS. The PIONEER II study looked at the safety and efficacy of ADA versus placebo in patients with moderate-to-severe HS after treatment for the first 12 weeks. The endpoint involved counting abscesses and inflammatory nodules. The HiSCR score, which Dr Strober feels is a valid score, is not dissimilar from other endpoints, in that it measures relevant issues in HS.

The study design was rigorous, in that they did a randomized, placebo-controlled approach. They key point here is that ADA will be dosed weekly, not every other week as it is when treating psoriasis. The phase II studies showed that ADA every other week did not perform as well.

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Interestingly, many more women were enrolled in this study than men. Also of note, is that two thirds of the patients in the study were smokers. Remember that HS is a systemic, inflammatory disease. Much like psoriasis, we should think of it as a systemic syndrome of inflammation.

When we look at the data (below), we can see the numerical improvement in the rating scale of skin pain is biased towards ADA versus placebo and we can see more people achieving a HiSCR on ADA versus patients on placebo.

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The ADA group also does better with regard to inflammatory lesion count reduction as well as the Sartorius Score reduction.

The safety data are remarkably clean in these studies, particularly focusing on infection, serious infection and malignancy. If anything, there were more events in the placebo group.

Clinical Pearls

What do we need to remember about HS?

  • HS is a chronic, negatively life-impacting disease.
    • Associated with metabolic syndrome (obesity, DM, HTN, dyslipidemia)
  • Pathogenesis multifactorial; primarily inflammatory and not infectious, and our understanding is evolving
  • Phase II/III studies with adalimumab are the best studies, to date, and convincing of efficacy and good safety
  • Infliximab also is very effective

 

MauiDerm News Editor-Judy L. Seraphine, MSc

 

Antibiotic Stewardship and Isotretinoin

Presented by Guy Webster, MD, PhD

Written by Judy Seraphine, MSc

In this presentation at Maui Derm 2015, Dr Webster discusses the proper use of antibiotics, i.e., “antibiotic stewardship” and how the use of isotretinoin can help us avoid the use of antibiotics.

Dr Webster states that the philosophy of antibiotic use used to be “bacteria are bad, kill them all.” The yang of that philosophy, which we are beginning to appreciate more, is that bacteria are really a part of our personal ecosystem, whether on the skin or in the gut, and that if we mess with our own personal ecosystem, we may cause problems. There’s reasonable data showing that antibiotic use among children at a young age can lead to increased weight gain as they get older due to changes in their flora that become stable.

Remember that antimicrobials are in many soaps and personal products. In fact, 75% of adults have detectable levels of antimicrobials. Topical antibiotics are available over-the-counter and are not regulated (e.g., polymyxin, neomycin, bacitracin). Dr Webster feels that the big problem with antibiotic usage is in farming. The concept here is that antibiotics promote animal growth. The United States uses 29 tons of agricultural antibiotics per year. Resistant strains, as well as antibiotics themselves, can get into wastewater from livestock and poultry farms leading to a potentially altered microbial ecosystem as well as causing disease.

MRSA has also been seen in animals. Strain ST398 was a sensitive Euro human strain that crossed into animals. The use of tetracycline to increase hog weight gave birth to resistant ST398 variants, including MRSA. This strain is now recovered from human infection as well as supermarket beef and pork (30%) and shopping cart handles (10%). There is a clear crossover from the farm to the community. (Nature 499:398, 2013) Data suggest that 30% of farm workers using tetracycline feed have tetracycline-resistant MRSA nasal colonization. On the contrary, only 2% of workers from antibiotic-free farms carry nasal MRSA.

Dr Webster asks us to think about this question—in the face of ongoing agricultural abuses, will what we do with the use of antibiotics make a difference?

The dermatology specialty has a long history of profligate antibiotic usage and until recently, most dermatologists were not study-driven as many diseases are too rare to easily study. We also know that many diseases are said to respond to antibiotics; however, they are not infections (e.g. acne, rosacea, eczema, hidradinitis, bullous pemphigoid).

How do we decide how/when to use a long-term antibiotic?

Long-term antibiotic use is defensible when you are treating a real disease that could harm the patient and clearly responds to antibiotics, and there is nothing more sensible, safe, and/or affordable.

Granuloma annulare (GA) is a great example. There are case reports published in several journals supporting the long-term use of antibiotics for GA; however, recent studies have shown little benefit and this is probably something that we, as dermatologists, should stop doing.

Doxycycline is clearly effective for the treatment of mild-to-moderate bullous pemphigoid. It has demonstrated superior safety as compared to prednisone and may be given for years.

Reasonable evidence and randomized controlled trials support the use of doxycycline and minocycline for the treatment of acne. The use of cephalexin, azithromycin, penicillin, ampicillin, ciprofloxacin, and TMP/SXT is only supported by anecdote or smaller studies. While many dermatologists prefer personal experience over data, Dr Webster believes that we need to shift away from this and use what has shown to be effective in studies.

The duration of oral antibiotics for the treatment of acne has not been widely studied. Recent guidelines suggest that it should be limited to three to six months. A retrospective cohort study, published in 2014, found that the mean duration of use was 129 days and among the 31,634 courses, 57.8% did not use concomitant retinoid therapy. Although the duration of antibiotic usage is decreasing compared with previous data, some patients are still receiving them for longer periods than they probably need; thus increasing exposure and cost.

Data show that the use of topical retinoid plus an antibiotic is effective for the treatment of acne and after three months, if patients are on the topical retinoid alone, they tend to do as well as those patients who are on combination therapy or an antibiotic alone. The key is to utilize the retinoid from the beginning.

One concern for all clinicians is the development of resistant strains with the use of long-term antibiotics. Unlike the current beliefs about the long-term use of antimicrobial agents, one study found that the prolonged use of tetracycline antibiotics commonly used for acne treatment lowered the prevalence of colonization by S aureus and did not increase resistance to the tetracycline antibiotics. (Antibiotics, Acne, and Staphylococcus aureus Colonization Matthew Fanelli, MD, Eli Kupperman, BA, Ebbing Lautenbach, MD, MPH, Paul H. Edelstein, MD, and David J. Margolis, MD, PhD)

Minimizing Antibiotic Use

Besides giving an antibiotic with a retinoid, you need to consider patient fears, common sense, cost and adverse events. The UK is very concerned about resistance and they tend to use isotretinoin much faster.

Clinical Pearls

  • No topical monotherapy
    • Add benzoyl peroxide to minimize resistance
  • Oral antibiotics should be given with a topical retinoid
    • Allows for discontinuation of antibiotic after three months in most
  • Earlier switch to isotretinoin or spironolactone when antibiotic + retinoid fails

Isotretinoin Issues

Isotretinoin has been used for many years and, in fact, the longer we use it, the safer we have deemed it to be. Isotretinoin resistance can develop from inadequate dosing, virilization, being taken on an empty stomach, young patients with bad disease, and competing medications. Data show that a meal high in fat increases the absorption of isotretinoin.

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Common adverse events (AEs) among patients taking isotretinoin include dry skin, dry lips, high triglycerides and acne flares. Uncommon AEs include elevated CK and elevated AST and ALT. Patients may also experience dry eyes, decreased night vision, depression, and acne fulminans, i.e., an eruption of bad acne in a patient who may have had relatively trivial acne.

Isotretinoin-induced acne fulminans is uncommon, but devastating. It is most often seen early in the treatment of patients, usually on too high of a dose, with moderate-to-severe chest acne. If someone presents with a few nodules on their chest, Dr Webster will often start them at 20mg/day of isotretinoin along with one month of prednisone 20mg/day.

Isotretinoin and bowel disease has become a worry. There have been scattered reports of patients flaring as well as scattered reports of safe usage. Retrospective studies have shown no link or a very weak link between IBD flares and isotretinoin usage. There may; however, be a link between acne and IBD and antibiotics and IBD. (J. Invest Derm 2012, doi:10.1038/jid.2012.387)

 Many small studies, although not all adequate, have been conducted looking at the association between isotretinoin and bone mineral density (BMD). A recent study using DEXA found that there was no change from the beginning to the end of isotretinoin treatment in patients’ BMD.

Regarding depression, studies have shown that there are no differences in depression among teens taking isotretinoin versus antibiotics and that there is no greater risk of suicide in isotretinoin versus non-isotretinoin. But, there are always case reports where someone is on the drug and gets depressed, goes off the drug and gets better, then goes back on and gets depressed again. Those outliers probably have something real going on. Studies have been conducted looking at patients with bipolar disease. If you have a known bipolar teen whom you are looking to put on isotretinoin, you may want to consult with the psychiatrist.

 

 

 

 

 

 

 

Social Media

Jeff Benabio, MD

In this presentation at Maui Derm 2015, Dr Benabio reviews some important issues around social media and medicine. Dr Benabio reminds us that there’s a general feeling of malaise among physicians. Why do we suppose there is such angst in healthcare? One reason to consider is that doctors are uncomfortable with the idea that they are being rated on the Internet.

There are several factors that have contributed to the changes we see in healthcare; these include the digitalization of healthcare, consumerism and healthcare reform. Social media is one of the main digital aspects of medicine. When we think about social media, try not to think just “FaceBook.” Social media a lot more—it is all of the tools that allow us to connect and share with other people.

It is important to remember is that it’s not just about the numbers. What we need to understand is why the numbers [of views/hits] can be so astronomically high and why that can be important in healthcare. The numbers are high because a. the information has essentially become free; b. we are wired to connect; and c. smartphones are ubiquitous. When we put all of this together, we see very different behaviors. We can see this in business and in healthcare. Consumers/Patients are acting differently because information is free and everyone can connect to everyone.

Economists have discussed the idea that we are reaching a state whereby consumers, i.e., patients have what’s referred to as “perfect information.” Patients now have almost “perfect information” about their disease, their hospital, their health plan, their doctor, etc. They can choose what they do about it. For us, as healthcare providers, we need to understand that this is where our patients are going to get their information. We need to know the information that’s out there, particularly the information about our practices and ourselves.

There are whole fields of study around what’s called ‘behavioral economics.’ Studies are looking at how consumers behave in certain situations. This is the same thing in healthcare, i.e., how patients behave when they have information that they didn’t have before. Consumers used to choose products based on a. prior information; b. other opinions; and c. marketing. Today, things are fundamentally different. Prior experience is no longer perfect; in fact, consumers are nowhere near as loyal to brands as they used to be. Your prior experience is not nearly as informative as other people’s opinions. We can begin to question whether we know what’s right or whether the crowd knows what’s right. We, as consumers, truly believe that other people have good information. Marketing, today, is much easier to ignore.

If we consider healthcare, a recent study showed that 62% of consumers/patients have used online reviews to learn about doctors and this number is continuing to grow. There are websites, such as healthgrades, that provide very good information. The whole purpose of healthgrades is to provide accurate information to consumers about their healthcare choices. Healthgrades retrieves their information from quality metrics and national service metrics. In a few years, your data may be publicly reported as they are already doing that now with hospitals and consumers love it.

While consumers like healthgrades, they trust Yelp more than any other review site. As physicians, that may be a hard pill to swallow. Consumers use Yelp for other decisions with very good accuracy. A 2014 paper by Hanauer and colleagues surveyed patients regarding physician-rating sites. They found that 40% of patients say online reviews are very important and 35% of patients selected a physician based on a positive review. Additionally, 37% of patients avoided a physician with negative reviews.

Doctors are very concerned with how these reviews are filtered. Do you have to pay for advertising in order to obtain positive reviews? Dr Benabio has done some research on this question. A recent study, using regression analyses, looked at correlations between whether physicians had paid for advertising or not and whether that had any impact on if Yelp filtered the review. It turns out that the factors that were significant were having either a one-star or five-star review. Whether or not you were a Yelp advertiser or not did not make a difference.

For the most part, our patients love us. The average score for a doctor is 9.3 out of 10. Patients are interested in wait times, billing/payment, staff friendliness, ease of scheduling, and office environment/cleanliness.

Consumers of all types use Google. Eighty-six percent of patients Google their symptoms before they see a doctor. Google is running “pilot” physician consultations with patients when they search for healthcare-related topics. Consumers are realizing that they can get point-of-question care live from platforms like Google. HealthTap is another site that is aggressively recruiting physicians to participate in point-of-question care. HealthTap is connecting these questions with patients to enable them to do live video visits with a doctor. Doctors are now doing house calls again…they are meeting patients wherever they are. This is a normal expectation for consumers.

Another site, Iodine, allows patients to input their medications and then provides them with perfect information from other patients’ ratings on that prescription/product. Real Self is a similar platform for cosmetics. Today’s patients want transparency. A Deloitte study found three out of four consumers believe providers should publish quality of care information on the Internet. Two out of three patients believe that providers should publish their prices online.

Other Social Media Sites

Twitter is technically a microblog. It’s a way to say “what are you doing?” It’s a powerful tool to share information and report news. About one in four physicians use social media daily, mostly for keeping up with healthcare news. Plastic surgeons tend to lead with 50% of them using Twitter. Virtually all surveys of physicians who use social media say that it has a positive effect, i.e., it increases patient engagement, improves care delivery and patients are more satisfied. Doctors also feel more connected to patients and peers and it is a great tool for education.

Doximity is a social networking site for doctors. It allows you to take topics from a journal and engage in a conversation with your colleagues. Doximity also has very interesting crowd-source data.

What about Instagram? Instagram is a photo application that tends to be very much in the moment. There are 150 million active users and it’s the most popular social media site for teenagers.

How does social media affect healthcare usage? The American Academy of Facial Plastic and Reconstructive Surgery conducted a poll and found that one in three respondents in a survey pool of 2700 of its members said that they had seen an increase of procedure requests as a result of patients’ social media awareness.

In the last few years, FaceBook has gone public and as a result, they are now filtering posts. This is trying to drive you towards paying for advertising. As it turns out, people respond better to ads than they do random posts.

Summary

In conclusion, we need to recognize that the future of dermatology and healthcare is digital. As physicians, we needn’t use all of the existing social media sites but we must understand social media as it is changing what it means to be a patient. Sincerity and commitment to our patients is “always in.”

 

MauiDerm News Editor-Judy L. Seraphine, MSc

 

 

 

 

 

 

 

 

 

Botulinum Toxin: Science and Evidence Data, Dose, Duration, Dogma

Joel L. Cohen, MD

In this presentation, Dr. Cohen discusses the neuromodulators that we commonly use and how to best apply the science and evidence into clinical practice. Dr. Cohen spends about 40 percent of time in practice doing Mohs surgery and the other 60 percent is dedicated to aesthetics.

It’s important to remember that we typically don’t focus in one area but rather treat assess patient’s full face and multiple regions, and we tend to use a combination of therapies/treatments (neuromodulators, fillers, lasers, and other energy-based devices such as radiofrequency and ultrasound). Clinical research is important to us, as clinicians, for a number a reasons — not only does it allow us to see what products are coming up on the horizon, but it affords us the opportunity to experience these therapies first-hand in clinical practice.

Currently, we have three neuromodulators approved for aesthetic use; onabotulinumtoxinA ((Botox), abobotulinumtoxinA (Dysport) and incobotulinumtoxinA (Xeomin). The important concept here is that these products are probably more similar than they are different.

 

BTX-A On-label Aesthetic Uses

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Of note, when you go to other countries, especially in Europe, you will see a different spectrum and wider-spectrum of approved aesthetic indications for these products.

We know, from clinical data, that botulinumtoxin can make patients feel better about themselves and can help them outwardly convey their inner emotions more appropriately. Many patients want to delay the outward appearance of aging as well as simply “look their best”. (Finn, Cox, Earl. Social Implications of Hyperfunctional Facial Lines. Dermatol Surg 2003;29:450-455.)

A double-blind, randomized, placebo-controlled health outcomes survey conducted by Dayan and colleagues analyzed the effect of botulinumtoxin type A injections on quality of life and self-esteem. The researchers found that the injections result in improvements in quality of life (QOL) and self-esteem. Additionally, botulinumtoxin-naïve patients demonstrated greater improvements in QOL and self-esteem than participants previously exposed to botulinumtoxin. Moreover, botulinumtoxin-familiar patients demonstrated sustained improvement in QOL and self-esteem as compared to botulinumtoxin-naïve patients, even when injected with placebo.

All of the approved botulinumtoxin type A products have a 150 kD botulinumtoxinA core neurotoxin protein. Incobotulinumtoxin (Xeomin) lacks the accessory proteins that are naturally produced by clostridial bacteria, which Botox and Dysport maintain.

When you look at the clinical studies, remember that there are different comparisons and different endpoints. Non-inferiority studies tend to compare two products at very specific time points. One noninferiority study compared incobotulinumtoxinA to onobotulinumtoxinA at four weeks and 12 weeks, as assessed by investigators, a panel of independent raters, and patients. This study demonstrated that incobotulinumtoxinA is equally as effective as onabotulinumtoxinA in the treatment of glabellar frown lines and both products were well tolerated — at the specific timepoints studied. There are; however, issues with non-inferiority studies. Because there are two time-points, there may be a missed evaluation of the duration of efficacy and a “waning effect.”

If you look at different demographics of your study cohort in some clinical trials, you’ll see that in some studies it’s really reflective of what we do in clinical practice; however, in other studies, it may not be – such as a disproportionate number of patients being quite young. These are issues that need to be considered when we’re looking at overall responses and comparisons among different products.

We also need to think about “low-powered” comparisons. In a comparison of two botulinum toxin type A preparations for the treatment of crow’s feet (Prager, et al), there were only 21 patients in this study. This may not be enough to tease out any major differences between the products in terms of the number of patients studied.

So, in short, there are 3 botulinum toxin products available in the US. It’s very difficult to make direct comparisons. These are different products and we need to consider the fact that the dosing can be different and the studies can be designed differently in terms of non-inferiority, demographics and power as well as an evolution of different study endpoints (2-grade improvement versus 1-grade).

We are beginning to see a shift towards more stringent primary endpoints. A randomized, double-blind, placebo-controlled phase III trial, conducted by Hanke and colleagues, investigated the efficacy and safety of incobotulinumtoxinA in the treatment of glabellar frown lines using Composite Endpoint Treatment Success (CETS), i.e., looking at a two-grade improvement. If you look at how often physicians saw a two-grade improvement versus patients, you will see about 48 percent.

 

Composite Endpoint Treatment Success

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Remember that it’s difficult to compare data as previous studies often used a one-grade improvement; therefore, demonstrating a larger responder rate and a longer duration of treatment.

The pivotal trial with Botox for the lateral canthal lines required at least a two grade improvement from baseline on both the investigator’s and subject’s assessment of CFL severity at maximum smile using the 4 facial wrinkle scale. At day 30, we see a responder rate of 25.7%. Dr Cohen states that we know we have seen higher responder rates than this; however, because there has been a chance in the way in which the FDA wants this to be assessed, i.e., patient and physician composite scores, the numbers are lower.

What about conversion ratios?

Again, remember that these are different products and we need to look at them as such. Various studies have looked at the concept conversion ratios, but that may be difficult to compute in clinical practice. Regulatory agencies worldwide have recognized that these products are not interchangeable.

 Some Other Things to Consider…

When we look at patients, specifically speaking about the lateral canthus, not everyone needs the exact injections that were used in clinical trials. There have been studies, dating back to 2003, looking at different patterns of injections and the way that different people look. It’s important to identify these features in your patients and individualize therapy. When Dr Cohen looks at a patient and he/she is superior dominant, he may give more of the neuromodulator up high, and a little bit less in the middle or below. Keep in mind that on that same horizontal is the bunny line and the contraction of the nasalis. Also along this horizontal is the pharmacologic brow lift.

If we understand the anatomy that the orbicularis oculi pushes our brows down and the frontalis lifts them up, then if we inject the one site where you’re getting the maximum pull down below the lateral, you may see better improvement in the lateral brow lift we can sometimes see when we treat the lateral orbicularis oculi.

Drs Cohen and Dayan conducted an open-label, randomized, dose-comparison study of botulinum Toxin Type A in the treatment of dermatochalasis. They found that a single-site injection of botulinum toxin type A in the lateral infrabrow can offer effective treatment for mild to moderate upper eyelid dermatochalasis—with perhaps a couple of millimeter lateral brow lift at best.

We know that when we look at patient’s brow positioning, there are some that should not be injected with a neuromodulator in the off-label area of the forehead. There was an important article that was published in JAMA Dermatology last year that looked at not only a grading scale for dermatochalasis, but it also discussed the factors associated with dermatochalasis. (Jacobs L, et al, 2014) From a grading scale, there are four categories for sagging eyelids (mild, moderate, severe, very severe). Specific risk factors associated with sagging eyelids include, age, male sex, lighter skin color, smoking status and higher BMI. In many cases, people “blame” genetics for sagging eyelids; however, we can see that there are things that we can do to intervene to help reduce the risk.

Combination Delivery

After the approval of Radiesse with in-office adding of anesthesia in the same syringe, some physicians began to use the same adaptor to combine fillers and neuromodulators. Dr Cohen doesn’t feel that this is a good idea; in fact, he believes that it probably does not save time, leads to an unstandardized mixture, and likely leads to less precise injections – as there are simply some areas where you don’t want toxin but you do want filler. So combination in the same syringe of toxin and filler in Cohen’s view is not a good idea, but combination of toxin and filler in their respecitive different syringes is still a good concept.

When it comes to the lower face and the area around the mouth, a study conducted by Carruthers et al indicated that both physicians and patients saw a greater improvement when the patient was injected with both the hyaluronic acid dermal filler and a neuromodulator. (Carruthers A, et al. Dermatol Surg. 2010;36:Suppl4:2121-2134.

And other studies have shown synergy with the combination treatment of different regions with toxin and filler. A 2003 study of Botox plus Restylane demonstrated that if you inject patients with Botox and then have them come back for Restylane, it has a longer tissue residence time in terms of filler and correction than if you injected Restylane alone (18 weeks versus 32 weeks.)

Dosing

Many of us have seen an overall change in practice patterns when it comes to dosing. In some areas, like especially the forehead, we have shifted from higher doses of toxin to lower doses in order to achieve a more natural, relaxed look for our patients. In the forehead, for example, Dr Cohen and other colleagues who participated in the more recent PRS journal consensus, now inject about half of the dose they previously used in the forehead — thus creating often a more natural look, simply softening the musculature, and maintaining brow shape and positioning better. There’s a lot to consider with regards to neuromodulators. We have seen where NOT to inject, but it’s important to maintain brow positioning and shape as well as symmetry.

There are very specific grading scales that can be useful in clinical practice and Dr Cohen recommends incorporating them into your regimen. This is helpful when discussing the goals of therapy with patients—for instance, for the forehead “softening of the musculature”.

 

 

 

 

 

 

Growth Factors in Photodamaged Skin: Clinical Pearls

Zoe Diana Draelos, MD

Dr Draelos provides us with her clinical pearls on growth factors (GF):

  • GF are multifunctional peptides active in the picogram range
  • GF act as signaling molecules between cells by binding to cell surface receptors
  • GF modes of targeting:
    • GF release into the blood stream to reach distant targets (endocrine mode)
    • GF diffuse over short distances to affect other cells (juxtacrine mode)
    • GF influence neighboring cells (paracrine)
    • GF act on the cells in which they are produced (autocrine mode)
  • GF relevant to cosmeceuticals are epidermal growth factor, keratinocyte growth factor, fibroblast growth factor, platelet-derived growth factor
  • Epidermal growth factor is produced from macrophages and monocytes, it affects epithelium and endothelial cells stimulating the proliferation of keratinocytes, fibroblasts, and endothelial cells
  • Keratinocyte growth factor is a small signaling molecule that binds to fibroblast growth factor receptor 2b found in the epithelialization-phase of wound healing
  • Fibroblast growth factor is a very potent angiogenic factor derived from monocytes, macrophages, and endothelial cells (22 human FGFs identified) that induces proliferation of endothelial cells, keratinocytes, and fibroblasts
  • Platelet derived growth factor is produced by platelets, macrophages, neutrophils, smooth muscle cells and induces proliferation of smooth muscle cells and fibroblasts
  • Current controversy exists as to whether growth factors are drugs or cosmetics

Immunotherapy Update

Keith T. Flaherty, MD

At Maui Derm 2015, Dr Flaherty, a medical oncologist at Massachusetts General Hospital, reviewed updates in melanoma therapy for advanced disease and how these drugs have impacted clinical care. As we try to build on targeted therapy based on our current knowledge of pathways, we ask ourselves what will be the role of combinations and/or precision medicine-type immune therapy matching strategies. Of note, the therapies discussed are investigated in the metastatic setting first, and as dermatologists, we are considering their use in the adjuvant setting.

Ipilimumab

Ipilimumab was the first entry into the field in terms of a positive phase III trial. Ipilimimab at 3mg/kg, with or without gp100, was given every three weeks for four treatments. Based on the data, there’s no question that ipilimumab outperformed the gp100 vaccine alone. This outcome, at the level of overall survival, demonstrated the efficacy needed to warrant the approval of ipilimumab.

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Ipilimumab was already a ten-year old therapy for which metastatic melonama patients were taking the drug for a few months course of treatment and who are still alive and well. Dr Flaherty states that we knew, when these results emerged, that there may be a truly, durable, lasting effect.

There is a cost to this type of treatment in terms of adverse events (AEs). All of the toxicities associated with this drug come from autoimmune attack(s) affecting the skin, large intestine, endocrine glands, or hepatic autoimmune injury. Why these tissues and not others? There are several theories, but not a firm understanding. If you focus on the ipilimumab monotherapy group, you can look at those who had severe autoimmune toxicity, i.e., you have to stop giving the drug and/or give high-dose corticosteroids to stop the autoimmune reaction. This occurs about 10 percent of the time. Everything short of this autoimmune toxicity appears, in short, in mild or moderate form and basically goes away without any immunologic intervention.

Phase III MDX010-20 Study: Most Common irAEs (Grades 3-5) Over Entire Study

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The idea is that we think we’re unmasking normal tissue tolerance, but in a largely reversible way. About two thirds of patients who receive ipilimumab have some form of autoimmune toxicity, only about 10 percent have enough of it that it creates a truly life-threatening scenario for which we need to intervene. Not all of the toxicities manifest at the same time. Dr Flaherty feels that in major melanoma programs, we have become quite comfortable with regards to counseling patients as far as what to look out for and when to call with suspected reaction(s). Dr Flaherty believes that ipilimumab is a therapy that can absolutely be safely administered.

The other phase III trial that corroborated the effects of ipilimumab looked at patients taking ipilimumab (10mg/kg) plus decarbazine (850 mg/m2) or dacarbazine (850 mg/m2) plus placebo at weeks one, four, seven, and ten, followed by dacarbazine alone every three weeks through week 22. This trial was similarly positive with the addition of ipilimumab. The difference, as shown below, was really not very different from that of the ipilimumab versus vaccine trial.

First-line Ipilimumamb/DTIC vs DTIC: OS

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The toxicities of the two-drug approach were modestly worse. When the FDA looked across the two data sets, they didn’t feel that the addition of chemotherapy was synergistic; therefore, they went with the previous study and approved ipilimumab as a monotherapy for metastatic melanoma.

In clinical practice, you can look at the pooled data set (below) and feel comfortable counseling patients that they have about a 20 percent chance of walking away with the diagnosis of metastatic melanoma by receiving this treatment (four doses over three months) with time-limited risk of toxicity.

Ipilimumab Analysis: Pooled OS Analysis

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We have learned that if you “cherry-pick” patients and only treat those with lower disease burden, the rate may be as high as 30 percent.

The PD-1 Pathway

What is the role of the PD-1 pathway in suppressing anti-tumor immunity? How might we think about deploying antibodies that try to intercept this negative immune regulator? We can target on either the PD-1 side or the PD-L1 side [with antibodies]. Scientifically, we would anticipate that this would alleviate the negative influence that the expression of this immune marker on tumor cells can produce in terms of silencing T-cells directly. There was a belief that PD-L1 target is actually safer than PD-1 targeting because you don’t disrupt PD-L2/PD-L1 interactions that a PD-1-blocking antibody would and there is some clinical evidence that this may be true.

Pembrolizumab

Pembrolizumab was FDA-approved in the late summer of 2014. In the pivotal, randomized study, patients who had received ipilimumab and/or a BRAF inhibitor, if they were BRAF mutant, were randomized to receive pembrolizumab 2mg/kg IV every three weeks (ongoing), pembrolizumab 10mg/kg IV every three weeks (ongoing) or chemotherapy. This was a trial that was aiming to show that patients who had exhausted the available therapies could benefit from treatment with pembrolizumab. This data set addresses the unmet need of patients who don’t get a benefit from ipilimumab.

Primary End Point: PFS (RECIST v1.1 Central Review)

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The data (above) is impressive when looking at pembrolizumab compared to chemotherapy at the level of progression-free survival. This is clearly a positive study and very important data for patients who had exhausted all of the other treatment options. It is true; however, that this therapy does not work for all patients and about half of patients will still experience disease progression. The number of patients who have objective responses, again these are patients who have not exhausted all other options, appears to be about 20-25 percent.

Two different doses were investigated in this study (2 mg/kg Q3W and 10mg/kg Q3W). Because there was no difference in efficacy, the lower dose, which is modestly safer, was the regimen that was approved. The toxicity is identical in type with ipilimumab. This type of immune therapy produces the same autoimmune reactions in terms of the affected organs and tissues. The issue is that the severity is clearly lower than that of iplimumab.

AEs of Clinical Interest for Pembrolizumab

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If you look at the Grade 3 and Grade 4 AEs (above), notice how there are only a few autoimmune toxicities in the approved pembrolizumab group (2mg/kg).

For our patients, this is a drug that can be effective and a bit less dangerous in terms of autoimmune toxicities.

Nivolumab

Nivolumab, another PD-1 antibody that was approved in December 2014, was studied in patients who had not received prior therapy. Patients were randomized to nivolumab (3 mg/kg IV every two weeks) plus placebo or placebo plus dacarbazine (1000 mg/m2 IV every three weeks). The thought here was that if you were going to conduct a clinical trial that was chemotherapy controlled, you couldn’t include BRAF-mutant patients because you wouldn’t offer them decarbazine as a front-line “cytotoxic” therapy. Patients in this study were stratified based on PD-L1 status.

This drug has a huge impact in terms of overall survival.

Primary Endpoint: Overall Survival

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The data demonstrate a one-year overall survival rate of 73 percent. Many practitioners look at the evidence and would like to get PD-1 antibodies in the front-line. Currently, these drugs are approved for second- or third-line.

Progression-free survival clearly improved as well with nivolumab. These are immune therapies, but they have a clear impact on tumor burden as well. About sixty percent of patients have some demonstrable tumor effect.

When you see a response, the likelihood that the response is going to be durable through six and twelve months of follow-up is very likely.

PD-L1 status is an interesting biomarker to which we should pay attention. The overall survival outcome for patients whose tumors express PD-L1 on their surface does better than the control group and the overall population. (see below)

OS by PD-L1 Status*

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It is fairly clear that we can do some enrichment by using PD-L1 on the tumor as a biomarker.

Combination Therapy

In the medical oncology metastatic melanoma field, there is a lot of research around the concept of combining PD-1 and CTLA-4-blocking antibodies. Tumor responses in patients receiving nivolumab plus ipilimumab demonstrated that approximately 90 percent of patients responded after a follow-up of about 13 months.

Cli

There is still a group of patients who remain refractory, even to two-drug therapy. This phase I data ultimately launched a large phase III trial and we expect to see the data in June of this year (2015). The combination regimen cannot be given at the full dose of each drug; at least one of the therapies has to be attenuated. The data in the phase III trial is not quite as robust; however, we look forward to hearing the results in June.

When you look at the best available data with PD-1 monotherapy (pembrolizumab), this is actually not bad (below). Dr Flaherty feels that it is still unclear as to whether combination therapy is lifting us to a new plateau. We need more evidence to support that. Regarding safety, in patients who were taking combination therapy at the doses that were taken into the phase III trial, there was a sixty percent rate of severe (Grades 3 and 4) autoimmune toxicity. The results from the phase III data will help us to determine whether or not this combination therapy can be clinically useful.

Pembrolizumab Change in Tumor Size

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Adjuvant Therapy

There is some preliminary evidence on adjuvant therapy as we only have an interim result from a trial looking at ipilimumab monotherapy versus placebo in 951 patients with high-risk, stage III, completely resected melanoma. The primary endpoint was recurrence-free survival. If you focus on hazard ratio, there is about a 25 percent improvement. The question is whether or not this drug is really doing something more effective in the adjuvant setting than it would otherwise do in the overt metastatic setting. This is not clear—we need to see more data, more follow-up, and more overall survival evidence to know if this is a therapy that should be moved to the high-risk, resected setting. This therapy can have significant toxicity consequences, so we do have reason to be concerned.

Toxicities are substantial in the adjuvant setting. Notice the rate of Grade 3 and 4 toxicities. (below) This is the same drug that has a ten to twelve percent toxicity rate in the overt metastatic setting, but more in the adjuvant setting—partly because of the higher dose.

Safety: Immune-related Adverse Events

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There were treatment-related deaths in this trial. This is not something that we can take lightly.

Vaccines

From 2010 to 2015, in the metastatic melanoma field, we have run about twelve phase III trials and they have all been positive, except for the most recent of the vaccine trials, a MAGE-3 peptide. Prior to this, we have had three peptide vaccine trials suggesting a detriment in overall survival. We still have not found a way to deploy these therapies. Dr Flaherty states that many of us are hopeful that either by using some biomarker selection strategy or, more likely, using these agents with immune checkpoint antibodies, we may be able to find utility in steering immune responses towards specific epitopes. Currently, there are no ongoing phase III trials.

Conclusions

Ipilimumab was the first-in-class immune checkpoint inhibitor and has demonstrated survival advantage. Long-term follow-up clearly supports survival impact with only three months of therapy. PD-1/PD-L1 is considered “best-in-class” based on higher response rates and better disease control; however, the percentage rate of long-term survivors is unknown. The combination of ipilimumab/nivolumab suggests synergistic toxicity and the question remains regarding synergistic efficacy. The adjuvant role of therapy is still not defined as we only have interim data for ipilimumab at the higher dose.

 

 

 

 

Systemic Treatment of Psoriasis: What’s New?

Written by Judy Seraphine, MSc–Maui Derm News Editor

The field of psoriasis, especially with regards to systemic therapy, is ever evolving. In this presentation, Dr Craig Leonardi discusses what’s new as far as treatment for psoriasis and what we need to know for this first quarter of 2015.

Inventory of Biologics with Utility in Psoriasis

As we all know, the T-cell inhibitors, alefacept and efalizumab, once both approved for the treatment of psoriasis, were withdrawn from the market due to lack of use and serious infections (PML), respectively. Our attention has shifted to managing cytokines rather than affecting T-cells directly. This approach has led us to more successful research.

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Our second-generation biologics (adalimumab, etanercept, infliximab, and certolizumab) all target TNF-alpha. Ustekinumab, an IL-12/23 antagonist is a third generation biologic with which most of us are familiar.

There are a growing number of new and emerging biologics for the treatment of psoriasis. Guselkumab, tildrakizumab, and another therapy under development by Boehringer-Ingelheim all target IL-23. Secukinumab (approved February 2015), ixekizumab, and brodalumab target IL-17.

New Development Efforts

Certolizumab-Pegol (CZP)

CZP is a pegylated Fab fragment that was initially approved for the treatment of Crohn’s disease in 2008. In 2009, it was approved for the treatment of rheumatoid arthritis and in 2013, CZP received approval for both active psoriatic arthritis and ankylosing spondylitis. The phase II psoriasis trial of 176 patients demonstrated positive efficacy results with no unexpected safety issues. Patients were randomized to CZP 200 mg queow, CZP 400 mg qmonth, or placebo.

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(Ortonne JP, et al. J.Am.Acad.Dermatol. 56[Suppl 2], AB6. 2007; Reich K, Ortonne JP, Gottlieb AB, et al. Br J Dermatol. 2012:167:180-190.).

Several years later, the company started a phase III program in psoriasis. Dr Leonardi feels that if you have patients with significant psoriatic arthritis and you are running out of TNF antagonists, you may want to consider CZP.

IL-23

Remember that ustekinumab is an antibody that targets the p40 subunit. When it does that, it hits both IL-12 and IL-23 because the p40 subunit is shared. Targeting IL-12 and IL-23, causes a rich set of downstream effects, including down-regulation of Th1, Th17, and Th22 immunocytes. We will also see a decrease in the production of cytokines in the skin, especially IL-17a, IL-17f, and TNFα.

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These features are suggestive of the psoriasis phenotype, so this is a good approach to targeted therapy.

Ustekinumab

In the phase III studies, PHOENIX 1 and PHOENIX 2, ustekinumab 45 mg and 90 mg, at 28 weeks, achieves a PASI 75 in 71%, 79%, 70% and 79% of patients, respectively. (Leonardi CL, Kimball AB, et. Al.. Lancet. 2008; 371:1665-74.)

What about the newer drugs, guselkumab, tildrakizumab, and BI-655066 that selectively block IL-23? These drugs selectively target the IL-23 p19 subunit, which is not shared with IL-12, thereby allowing them to function as IL-23 selective monoclonal antibodies.

Guselkumab

The phase II trial demonstrates that this novel anti-IL-23 p19 subunit monoclonal antibodiy is a significant drug. Several doses were used and compared not only to placebo, but also to adalimumab. At week 12, four of the doses showed a PASI 75 between 75% and 81% indicating that this is a high performance drug. Regarding adverse events, three serious infections, one malignancy and three MACE events were reported. There were no anaphylactic reactions or serum sickness-like reactions. (Callis Duffin K., et al. AAD 2014. P8353)

Tildrakizumab

Tildrakizumab is a novel anti-IL23p19 monoclonal antibody. Unlike usetekinumab, it blocks IL23 and not IL12. In phase 2 trials, at week 16, 76.2% of patients achieved a PASI-75 and 52.2% of patients achieved a PASI-90. All doses (5 mg, 25 mg, 100 mg, 200 mg) were statistically significant at PASI-75 compared to placebo. Common adverse events included nasopharyngitis and URTI. Overall, the drug appears to be generally safe and well tolerated. (Thaci D P1537 EADV 2013)

Boehringer-Ingelheim 655066

BI 655066 is a novel anti-IL23p19 monoclonal antibody given as a single subcutaneous injection. The phase 2 study results demonstrated a PASI-75 in 87% of patients and PASI-90 in 58% of patients at week 12. Thirty-three percent of patients remained clear after 66 weeks. (Krueger J. EADV 2014). This is a very early phase 2 study, and lot more work will likely be done.

IL-17

Secukinumab

Secukinumab was approved in the United States for the treatment of psoriasis on January 21, 2015. Langely and colleagues published what Dr Leonardi refers to as “masterful” manuscript in the New England Journal of Medicine in 2014. As a clinician, if you would like to completely understand secukinumab, this publication may be extremely beneficial to you. (Langley R, et al. N Engl J Med. 2014;371:326-338.)

Secukinumab (300 mg and 150 mg) demonstrates a much faster response rate in achieving a (PASI-50), in 3 weeks and 4 weeks respectively, when compared to that achieved by etanercept in 7 weeks. Like many physicians, Dr Leonardi sees his patients at one-month into the experience. With a drug like secukinumab, you will understand at that visit whether or not it is going to achieve the results that we expect. We can see a PASI-75 in over 80% of patients at week 12 and continuing through week 52 with this drug.

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There are no significant safety issues associated with secukinumab. One of the fascinating things that we have seen is the FDA’s independent analysis of this drug.

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FDA Briefing Document. Dermatologic and Ophthalmic Drugs Advisory Committee Meeting October 20, 2014 Background Package for BLA 125504 Cosentyx (Secukinumab)

Figure 1 (above) is plotting clear/almost-clear response versus serum concentration of drug. The FDA is modeling where they expect/what percent of patients will achieve clear/almost-clear based on concentrations of the drug. They have four real data points on the graph and the rest is a dosing model. This is the first time that Dr Leonardi has seen the FDA predict a response based on serum concentration. This gives us a more informed way of using the medicines that we prescribe, especially the more expensive ones. In figure 2 (above), the FDA was looking at the dosing on the left side and suggested that patients would be better served, the heavier weighted patients, if they went with the 450 mg dose—a dose that had never been tested. The FDA was so unconcerned with the safety profile of secukinumab that they urged the company to run the drug harder than they already have. This reflects a dramatic shift in the FDA as far as the approach to this drug, psoriasis, and the severity of the disease.

The labeling for secukinumab is also interesting. Remember, they are not so much concerned with safety with this drug. “Recommended dose is 300 mg by subcutaneous injection at Weeks 0, 1,2,3, and 4 followed by 300 mg every 4 Weeks. For some patients, a dose of 150 mg may be acceptable.” Some feel that the insurance industry may challenge the 300 mg dosing. With these therapies, maybe they are saying for whatever reason you have, you may want to alter the dose. Dr Leonardi feels that this is good because we should be able to use expensive resources in ways that are creative and best for our patients, our specialty, and for society.

Ixekizumab

Phase 3 data for this drug will likely be available in March 2015. Phase 2 data have shown that this is a very high-performance drug with a high percentage of patients achieving PASI-90. The drug is exceedingly well tolerated with no serious adverse events reported. (N Engl J Med 2012;366:1190-9) The scientists at Eli Lilly looked at the predictive value of PASI-50 for predicting PASI-75 response. This analysis showed that there was good overall sensitivity (83%), specificity (87%), PPV (90%), and NPV (77%). This is showing that if your patient, treated with ixekizumab, achieved PASI-50 response they would go on to achieve PASI-75 by week 12. This is important—think about when you might be seeing your patient for the first time.

This class of drugs shows significant clearing and increased patient and physician satisfaction.

Brodalumab

Phase 2 data for brodalumab shows positive efficacy results.

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This drug was again well tolerated and demonstrates a favorable safety profile.

One study looked at long-term maintenance of clinical response with brodalumab therapy and found that the vast majority of patients did quite well over a 96-week period. (N Engl J Med. 2012 Mar 29;366(13):1181-1189)

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Psoriatic Arthritis (PsA)

Based on Dr Leonardi’s understanding of the literature, the TNF antagonists are the standard drugs of choice for the treatment of psoriatic arthritis. When looking at adalimumab, etanercept, and infliximab, the ACR 50 responses were 39, 37, and 41, respectively. (Mease P, et al. Presented at: ACR; October 14-19, 2004; San Antonio, Tex. (Abstract L6-521);Enbrel package insert. Amgen;Antoni C, et al. Ann Rheum Dis. Published Online First January 27, 2005. doi: 10.1136/ard.2004.032268.) Looking at ustekinumab 45 mg and 90 mg, we see a significantly less response rate with an ACR 50 of 24.9 and 27.9, respectively. (Kavanaugh A, et al. ACR2012. Abstract 2562.)

Secukinumab released its phase 3 PsA results at the American College of Rheumatology in November 2014. In this study, the patients received IV secukinumab for the first three doses and then changed over to subcutaneous secukinumab. Using this scheme, we can see ACR 50 response rates similar to those of the TNF antagonists. (See graph below)

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Again, the IL-17 antagonists are finding their way in rheumatology as well.

Choosing Highly Effective Drugs

Number Needed to Treat (NNT)

The NNT is the average number of patients who need to be treated to achieve one additional good outcome (e.g. the number of patients that need to be treated for one to benefit compared with a control in a clinical trial). It is defined as the inverse of the absolute risk reduction.

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You can see that we’re starting to cluster as we get to the bottom, whether you’re thinking about PASI numbers or NNT numbers. It really is quite remarkable. According to Dr. Leonardi, in the case of ixekizumab, the NNT is 1.1 meaning that if you treat 11 patients with Ixekizumab, 10 will achieve a PASI-75.

Do we really need biomarkers when clinical response is profound and fast?

We have been talking about biomarkers for years, but it’s quite likely that when a patient comes back after four weeks, we will have a good understanding of how he/she is going to respond to the various classes of therapy.

Small Molecules

Tofacitinib, an inhibitor of JAK 1 and 3, was recently approved at 5 mg BID for the treatment of rheumatoid arthritis. The data for psoriasis is positive, in that it is highly efficacious and is relative well tolerated. (Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol (2012) 167, pp 668–677)  Serious adverse events included atrial fibrillation, pyelonephritis, and urosepsis. Mild decreases in HgB levels were greater in the 15 mg BID group and transient decreases in PMNs were seen in the 5 mg and 15 mg BID groups. There were also dose-related increases in HDL and LDL. (Harness J, et al. EADV 2010: P558)

There were issues in the rheumatoid arthritis program that will be brought to attention despite the fact that RA and psoriasis are two completely different immunologic disorders. The FDA commented that the risk of malignancy appeared to increase in a dose and time dependent fashion and the data also suggest tofacitinib treatment is associated with an increased risk of serious infections, including opportunistic infection.

A Few Final Comments

The traditional psoriasis treatment paradigm was that of a stepwise progression, i.e., patients must fail the previous “step” of therapy before initiating more “aggressive” therapy. In today’s dermatology setting, psoriasis treatment is not stepwise. Choice of therapy depends on individual patient characteristics. We have a rich set of biologic agents and five more coming down the pipeline. As dermatologists, it’s time that we “rethink our goals.”

 

 

 

 

 

 

 

Update on Psoriasis Comorbidities

Joel M. Gelfand, MD, MSCE

Dr Joel Gelfand provides us with an update on the comorbidities often associated with psoriasis. Over the last decade, we have been able to identify factors that may contribute to comorbidities in psoriasis. Environmental risk factors include smoking and obesity. Scientists have also identified genes and loci associated with psoriasis, diabetes, and cardiovascular disease including PSORS2/3/4, CDKAL1, ApoE4, and TNFAIP32. We should also consider mediating factors such as pathophysiology, effects of treatment, and the psychosocial impact of psoriasis. (Azfar RS, Gelfand JM. Curr Opin Rheum 2008;20:416–422)

Currently, data suggest that we do have well-established comorbidities of psoriasis. These include:

  • Heart attack, stroke, cardiovascular death
  • Metabolic syndrome
  • Diabetes
  • Psoriatic arthritis
  • Mood disorders (anxiety, depression, suicide)
  • Crohn’s disease
  • T cell lymphoma (rare)

The risk of cardiometabolic disease in patients appears to increase with more severe disease. What does this mean clinically? As previously noted, patients with more severe psoriasis experience an increased risk of MI, stroke, cardiovascular death, and diabetes. There is an average of five years of life lost. The ten-year risk of a major CV event attributable to psoriasis is six percent. Literature suggests that the risk of cardiovascular disease in patients with severe psoriasis is comparable to the risk conferred by diabetes. Additionally, patients treated for severe psoriasis are 30 times more likely to experience MACE (attributable to psoriasis) than to develop a melanoma.

Research has also been conducted using UK-based data comparing cardiometabolic events in psoriasis versus rheumatoid arthritis (RA). We can see that patients with psoriasis have a higher rate of diabetes, but this is not seen with RA patients. There is something specific about psoriatic disease making one more prone to developing diabetes over time. (See Figure 1) These data also demonstrate that psoriasis patients treated with systemic or phototherapy have a similar increased risk of CV and all cause mortality compared to RA treated with disease modifying treatments.

 FIGURE 1

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Clinicians should recognize that metabolic problems start early and there is emerging pediatric data. The prevalence of the metabolic syndrome in pediatric psoriasis is 30 percent versus 7.4 percent in the control population.

The skin of patients with psoriasis has increased regulation/expression of cardiometabolic genes, more so than the up-regulation of inflammatory genes. This tells us that the skin itself may be the source of the abnormalities that we’re seeing.

We should also remember that psoriasis is more than just skin deep. Psoriasis is associated with increased vascular inflammation independent of traditional risk factors and equivalent to ten years of aging. Advanced FDG-PET/CT imaging demonstrated subclinical inflammation in the liver and joints.

How are we doing as healthcare providers?

Overall, cardiovascular risk factors are under-screened and under-managed in patients with psoriasis. CDC US population data indicates poor screening rates for hypertension—only four percent of severe psoriasis patients receive screening for hypertension in the dermatology office versus 61 percent patients in the non-dermatology setting.

Should we treat psoriasis aggressively to lower the risk of CV disease?

The answer is that we really don’t know for certain. Observational data suggest that methotrexate and TNF inhibitors lower the risk of cardiovascular events. Data do not yet exist to determine a protective effect of phototherapy, apremilast, and ustekinumab on CV events. (Micha R et al. Am J Cardiol 2011;108:1362–1370; Barnabe C et al. Arthritis Care Res (Hoboken) 2011;63:522–529; Prodanovich S et al. J Am Acad Dermatol 2005;52:262–267; Wu JJ et al. Arch Dermatol 2012;148:1244–1250; Ahlehoff O et al. J Int Med 2013;273:197–204)

Emerging Comorbidities

Newer data suggest that following are also comorbid conditions associated with psoriasis:

  • Sleep apnea
  • Nonalcoholic steatohepatitis (NASH)
  • Chronic obstructive pulmonary disease (COPD)
  • Adverse infectious disease outcomes
  • Chronic and end-stage renal disease
  • Peptic ulcer disease

Moderate to severe psoriasis is also a risk factor for chronic kidney disease (CKD). Data suggest that there is nearly a two-fold risk of moderate to advanced CKD among psoriasis patients and a greater than four-fold risk of end stage renal disease requiring dialysis. Risks are independent of diabetes, hypertension, and nephrotoxic medication. The risk of CKD associated psoriasis is greater than the risk of CKD associated with diabetes and hypertension. (Wan J, Wang S, Denburg MR, Shin DB, Gelfand JM. Risk of moderate to advanced kidney disease in patients with psoriasis. BMJ 2013;15;347:f5961)

There are clear clinical implications that comprehensive care is required for patients with psoriasis as we shift from the old paradigm of “just a skin disease” to the new paradigm of “a systemic disease.”

Clinical Implications

Standard Screening Recommendations (US Preventative Services Task Force (HTN) 2007; American Diabetes Association Guidelines 2014 (Diabetes Care 2014;37:S5-S13); ACC/AHA 2013 Guideline on the assessment of CV risk)

  • Hypertension
    • Every 2 year if BP <120/80 mm Hg
    • Every year if BP 120 to 139/80 to 89 mm Hg.
  • Diabetes (Fasting plasma glucose, HbA1c, or OGTT)
    • Adults ≥ 45
    • Adults BMI ≥25kg/m2 who have one or more additional RFs
    • Repeat every 3 years
  • Cardiovascular risk assessment:
    • Traditional risk factors every 4-6 years in patients 20-79
    • Estimate 10 year risk in those 40 -79

Psoriasis and Cancer

We should remember to encourage patients to stay up-to-date on age appropriate cancer screenings, including cervical cancer, colon cancer, breast cancer, and lung cancer. (CDC guidance accessed 1/21/14Note: Earlier Screening recommended in those at high risk; Moyer VA et al Screening for lung cancer: US Preventative Services Task Force recommendation statement. Ann Internal Med.  doi:10.7326/M13-2771)

  • Cervical cancer: Pap smear (q 2-3 yrs ages 21-65)
  • Breast cancer: mammography (50-74, q 2 yrs)
  • Colon cancer: (50-75) fecal occult blood q year, flex sig q5 yrs, colonoscopy q10 yrs)
  • Lung cancer: Annual low dose CT screening for 55-80 with ≥30 pack year history and current smoker or quit within 15 years

Large, long-term follow-up studies are necessary to determine the risk of cancer with psoriasis treatments.

Psoriasis and Infection

It is important that we screen psoriasis patients for streptococcal infection with guttate flares. In severe psoriasis, it’s also important to test for HIV. Psoriasis patients who are undergoing immune suppressive treatments should stay up-to-date with all recommended vaccinations as well, including influenza, pneumonia, zoster, hepatitis B, and HPV. (http://www.cdc.gov/vaccines/schedules/downloads/adult/adult-combined-schedule.pdf)

Psoriasis and Mood Disorders

Healthcare providers should ask patients about depression and anxiety symptoms and monitor the impact of treatment on psychiatric symptoms as well as refer for treatment when appropriate. Some data suggest that cognitive behavioral therapies and meditation may modestly enhance the response to psoriasis treatment.

Psoriasis and PsA

Remember the importance of identifying the signs and symptoms of psoriatic arthritis, including:

  • Morning joint stiffness
  • Joint pain that improves with activity
  • Swollen, tender joints, dactylitis, enthesitis
  • Check X rays of affected joints and CRP
  • Co-manage with rheumatology, DMARDs

In conclusion, we have to look beyond the skin for our psoriasis patients. A comprehensive care approach is essential for our patients. Patients should be educated about the disease, treatment, and associated risk factors.

Maui Derm News Editor-Judy L. Seraphine, MSc

Psoriasis Update: Current Therapies

Bruce Strober, MD, PhD

At Maui Derm 2015, Dr Strober led the psoriasis panel with a discussion on current therapies.

Apremilast

Apremilast, an oral phosphodiesterase type 4 inhibitor, was approved for psoriatic arthritis in March, 2014 and subsequently approved for the treatment of moderate-to-severe psoriasis in September, 2014. The data for apremilast rests on two major Phase III studies, ESTEEM 1 and ESTEEM 2. Patients with moderate to severe plaque psoriasis (PASI = 12, BSA =10%, sPGA =3) were randomized 2 to 1 to apremilast 30 mg twice daily or placebo. At week 16, all placebo patients switched to apremilast 30 mg through week 32. At week 32, all patients who achieved PASI-75 were randomized (1:1, blinded) to continue apremilast or receive placebo. Upon PASI-75 loss, patients who were re-randomized to placebo resumed apremilast treatment.

The efficacy (PASI 75 achievement at 16 weeks) of apremilast in either study (ESTEEM 1/ESTEEM 2) is somewhere around 29% to 33% and placebo is around the 5% to 6% range. Apremilast demonstrated an acceptable safety profile and appeared to be well tolerated for up to 52 weeks.

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Within these studies, subanalyses were performed looking at nail, scalp and palmoplantar psoriasis based on the NAPSI, ScPGA, and PPPGA. Apremilast demonstrated significantly greater response rates versus placebo for psoriasis affecting the nails, scalp, and palmoplantar areas among patients with NAPSI ≥1 (n=266), ScPGA ≥3 (n=269), or PPPGA ≥3 (n=42) at baseline, respectively. This data demonstrates reduced severity in nail, scalp, and palmoplantar psoriasis at week 16, and observed improvements up to week 32. Keep in mind that the patients in this study with palmoplantar psoriasis were seen in the context of also having moderate-to-severe psoriasis; these are not patients with bona fide, stand-alone palmoplantar psoriasis.

Overall, the drug appears to do well on various parts of the body, much like our other good psoriasis medications.

When you’re discussing apremilast with your patients, there are two side effects that seem to appear to be most troublesome—diarrhea and nausea. Over the course of the study, approximately one in six patients experienced diarrhea or nausea; however, probably fewer than five percent of patients found it intolerable and very few patients discontinued this drug due to either side effect.

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Most commonly, these side effects occur during the first one to two months of therapy. There are no real “studied” approaches to minimizing these side effects; however, after the first of couple of months, the side effects did tend to wain.

Apremilast: Effects on Itch

Psoriasis patients have reported itching as the most bothersome symptom of psoriasis. (Lebwohl MG, JAAD. 2014) A pooled analysis of VAS of itch from ESTEEM 1 and 2 demonstrated improvements in pruritus with apremilast as early as week 2 and maintained through week 32. The reduction of itch in many patients precedes the clearing of their skin.

Additional Considerations with Apremilast

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As previously noted, apremilast demonstrated an acceptable safety profile and was generally well tolerated for up to 52 weeks with no new or unexpected safety findings. In Dr Strober’s opinion, you should perform baseline labs prior to starting any medicine for moderate-to-severe psoriasis. This is, in part, due to the fact that you may have to switch drugs if they do not respond to the initial therapy. Current data show no indication for a need for laboratory monitoring with apremilast, as no organ- or system-specific toxicities have been detected.

One of the two warnings on the label for this drug is the risk for depression or thoughts of suicide. Another pooled analysis of the ESTEEM 1 and 2 trials studied psychiatric disorders and depression with the use of apremilast. There is a slight increase in frequency of depression with the patients on apremilast versus placebo (1.2 % to 0.5%). Based on an analysis of clinical trials of apremilast and the published literature on psoriasis, there is no evidence of an increased risk of psychiatric events, including suicide, with the use of apremilast. The rate of depression was comparable to the background rate in the psoriasis population. People often ask about this issue, but Dr Strober feels that depression and mood effects of apremilast are possible, but are relatively rare. This should be discussed with the patient at the baseline visit, and followed prospectively.

One important way of looking at the data is to consider how the drug affects the population overall with regards to symptoms of depression. The PHQ-9, a patient-reported questionnaire, has been very well accepted, according to the medical community, as a very reliable, subjective means to detect depression. Using the PHQ-8, a similar study lacking one question found in the PHQ-9, invesigators found that psoriasis patients receiving apremilast achieved significant improvements in the PHQ-8 total score compared to those receiving placebo—indicating that their depressive symptoms may improve over the course of therapy.

Weight loss is another warning in the apremilast label. While weight loss has been observed in the ESTEEM trial (approximately one in five to six patients), there were no significant clinical consequences observed from the weight loss. The average weight loss over one year of therapy across all study subjects receiving apremilast is about four pounds. When discussing this drug with your patients, this is an issue that should be mentioned. Weight loss did appear to level off over time and it was not correlated with diarrhea/nausea. One cannot predict who will experience weight loss, and this side effect affects patients of both high and low BMI. Of note, only two patients in the clinical studies discontinued apremilast because of weight loss.

Drug Survival

Dr Strober concluded his presentation by discussing a few posters that have been presented over the past year regarding drug survival. According to Dr Strober, “one of the biggest failings of the medicines that we use for psoriasis is that they don’t always keep working.”

Which drugs do the best when looking at analyses?

There are three different analyses out there and they’re all corroborating one another. The first study (van den Reek and colleagues) aimed to describe one-year drug survival for adalimumab, etanercept, and ustekinumab in a daily practice psoriasis cohort. The other objective was to introduce the concept of ‘happy’ drug survival defined as DLQI≤5 combined with being ‘on-drug’ at a specific time-point. 249 patients were included in the study. The patients were asked how ‘happy’ they were over a course of time, i.e., 1. remained on the drug and; 2. DLQI was reduced to less than or equal to five.

Of note, your average patient, when he/she enters a clinical study for moderate to severe psoriasis, has a DLQI in the 10 to 13 range. If you are able to bring those patients to less than or equal to five, then you are achieving a measurable and clinically significant improvement in quality of life.

In this study, at baseline, the majority (n=115, 73%) was considered ‘unhappy’ and the minority ‘happy’ (n=42, 27%). The percentage of ‘happy’ on-drug patients increased to 79% after 1 year. In summary, ustekinumab showed better overall drug survival compared to etanercept and a trend towards better overall drug survival compared to adalimumab. Why do we suppose we may see these results? We must keep in mind that in these studies there is no randomization. Secondly, does the frequency, setting and method of administration make a difference? With ustekinumab, a subcutaneous medication commonly is administered in the office every 3 months. This set of features may allow patients to stay on drug longer. We should also consider whether or not the DLQI is a valid means to measure happiness and drug survival.

A multicenter, longitudinal, observational study, PSOLAR, evaluated persistency, i.e., treatment longevity, of biologics for psoriasis. While this study was funded by Janssen Biotech as part of the post-marketing surveillance for ustekinumab, it is important to note that over seven hundred patients were on drugs other than ustekinumab.

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Again, this was not a randomized study, and patients were “channelled” to the various therapies based on “real world” clinical decision making. The results show that the persistence of ustekinumab therapy in PSOLAR was significantly better than anti-TNF therapies in biologic- naïve and experienced psoriasis patients, with lower rates of stopping/switching and higher median days on therapy.

In a third study, the researchers aimed to describe and compare the drug survival of different biologic (infliximab, etanercept, adalimumab,and ustekinumab) and systemic drugs (acitretin, cyclosporine, and methotrexate) in moderate-to-severe psoriasis by analysing data from the BIOBADADERM registry. 1956 patients were included in the analysis (1240 on biologics and 1076 on classic drugs) with a median follow-up time of 3.3 years. When looking at the demographic data, you can see age differences across the board as well as widely varying PASI scores. Patients with more severe disease appeared to be going on infliximab with other less severe patients going on other biologics or even acitretin.

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Over half of these patients were on prior therapy. There were 2,209 discontinuations during the study time with the main reason being a lack of efficacy (36.4%), followed by remission of the disease (27.2%). In Europe, sometimes patients are treated until remission and then they stop drug. This is not something that we necessarily do here in the United States. The results of this study demonstrated that biologics, especially ustekinumab and infliximab, showed a superior drug survival than classic agents. In conclusion, the number of patients with moderate-to-severe psoriasis in continuous therapy decreases with time for all the systemic drugs included in the cohort, both classical systemic drugs and biologics. There seem to be a high number of factors that influence drug survival rates in psoriasis treatment making survival studies prone to bias and not necessarily the best approach to evaluate drug efficacy and safety in this specific setting, especially when comparing different drugs.

Nevertheless, ustekinumab, across three different studies carried out in very different geographic settings and with different methodology, demonstrated the most durability among the various agents used psoriasis treatment. Whether this is artefact or real may be validly debated.

 

 

 

Psoriatic Arthritis: Key Developments in 2014

Arthur Kavanaugh, MD

At Maui Derm 2015, Dr Kavanaugh, a Rheumatologist at the University of California, San Diego, presented some of the important developments in psoriatic arthritis (PsA) from 2014.

The diagnosis of PsA remains a challenge. Data from the Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) survey looked at 3,426 patients with psoriasis and/or PsA. Among those patients, 712 (20.8%) had PsA. (Lebwohl MG, et al. J Am Acad Dermatol. 2014;70:871-881.) According to the survey, the average was five years between PsA signs and symptoms and diagnosis. What symptoms do we need to recognize in these patients? In this survey, symptoms included:

  • Joint pain in knees (41%), fingers (26%), hips (19%), back/spine (18%), ankles (19%), and wrists (16%)
  • Pain or swelling in heels (45%) and “sausage digits” (31%)

Approximately 16% of these patients did not see a healthcare provider in the past year, and most of the PsA patients in the survey were not treated by a rheumatologist. These results imply a huge unmet need as many psoriatic patients are going untreated. We may need to think about the realization of PsA at the primary care level so that these patients can be referred to rheumatologists or dermatologists for appropriate treatment.

Among those with PsA in the MAPP survey, the majority of patients were not on therapy (28%) or on topical therapy (31%). Of the patients surveyed who had ever used biologic therapy (including those with psoriasis or PsA), 45% had discontinued treatment.

The literature suggests that only half of patients with PsA are diagnosed, and only half of the diagnosed patients receive drug treatment. This is something that we can and must do better.

In rheumatology, Dr Kavanaugh comments that we are still fighting the historical viewpoint that PsA is not as bad as rheumatoid arthritis (RA). But, if you take people who have polyarticular disease, you will see that they are every bit as severe as the RA patients.

It has been shown that a delay in the diagnosis of PsA correlates with worse outcomes for patients. In a study of 283 patients fulfilling CASPAR criteria from a single Irish center, the mean lag from symptom onset to seeing a rheumatologist was about one year. This study demonstrated that if the patient didn’t get to the rheumatologist within 6 months, he/she had 4 times the chance of already having joint damage. Even a short delay in diagnosis is associated with increased morbidity. (Haroon M, et al. Ann Rheum Dis Epub 27 Feb 2014)

Diagnosis

Diagnosis of PsA can be a bit tricky. Among the patients with psoriasis, who are the 25%-30% of patients who have PsA? Because skin symptoms often precede joint symptoms, dermatologists play an important role in the early diagnosis of PsA.

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Psoriatic Arthritis Screening and Evaluation (PASE)

  • Dermatology or shared clinic
  • 15 questions in subscales
  • No skin and nail assessment

82% sensitive; 73% specific

Toronto Psoriatic Arthritis Screening Questionnaire (ToPAS)

  • Dermatology, rheumatology, family medicine clinic
  • 11 questions and pictures
  • Skin and nail assessment

87% sensistive; 93% specific

Psoriasis Epidemiology Screening Tool (PEST)

  • Community and hospital clinic
  • 5 questions plus joint exam
  • Skin and nail assessment

97% sensistive; 79% specific

 

Treatment of PsA

TNF inhibitors have dramatically changed our overall approach to the management of PsA. They remain the main focal point of how we treat patients with moderate-to-severe disease activity.

What’s new with TNF inhibitors? One very important consideration is that of biosimilars. There is a biosimilar infliximab that is widely used in Europe. It was studied in RA and a small study was also conducted in ankylosing spondylitis; however, its approval was across the board for all of infliximab’s indications. An etanercept biosimilar that was studied in psoriasis was just approved in Korea for all six etanercept indications.

What about the relationship between serum concentration and efficacy? Vogelzang and colleagues studied serum adalimumab concentrations and clinical response in 103 PsA patients treated with 40 mg over 28 weeks measured by ELISA. The researchers found that adalimumab concentrations of 5-8mg/L achieved optimal clinical benefit in PsA as previously seen in RA.

What about remission? Can we taper or discontinue therapy? According to Dr Kavanaugh, the short answer is that we really don’t know. Studies in PsA have shown that the possibility of reaching a drug-free remission is low and discontinuation of DMARD therapy is not recommended. (Araujo E G et al. Ann Rheum Dis. doi:10.1136/annrheumdis-2013-204229) An observational cohort study of the PsA patients in the CORRONA registry also looked at stopping TNFi therapy and the data can be interpreted a number of different ways. There were some patients who were able to stop therapy and still do well and others flared around or just before two years after stopping therapy. The challenge is identifying the patients who will do well. There are dozens of studies in RA that are looking at this issue. The trouble is, we cannot compare from study to study because there are so many different variables to consider such as the tapering plan, the “target” for remission, duration, prior/concomitant therapy, disease activity, definitions of failure, length of follow-up, efficacy of retreatment, sequelae of flares, predictors of response, study design, motivation, and specific biologic target/agent. (Yoshida K, et al. Ann Rheum Dis 2014;73:e5; Kavanaugh A, Smolen JS. Clin Exp Rheumatol 2013;31(Suppl.78): S19–S21)

Immunologic Targets in PsA

What about other pathways? Even though we’re doing much better than we were in years past, there is still an unmet need until we can cure everyone.

Interleukin-17A has been found to be a unique pathway in immune-mediated diseases, i.e., psoriasis and psoriatic arthritis. The human monoclonal antibody, secukinumab, selectively neutralizes IL-17A and has demonstrated very positive ACR responses at week 24 when compared to placebo in the FUTURE 1 study. (Mease P, et al. ACR Annual Meeting. Nov 14-19, 2014; Boston, MA; Oral 953)

What about patients who have been on the TNF inhibitors? Those patients can be more difficult, but they’re the ones who we really want to know about as we typically utilize TNF inhibitors first. As we have previously seen with the ustekinumab data and other RA studies, the people who are naïve to TNF inhibitors did better overall than those who had previously been on TNF agents; but, the responses were still good.

IL-17 also has a positive impact on joint damage, in that it inhibits radiographic progression with treatment. This is very impressive data as these studies are becoming harder and harder to conduct for ethical reasons.

The PASI 75 and 90 responses through week 52 also demonstrate strong evidence for the use of secukinumab. Patients were receiving either secukinumab 10 mg/kg IV + 150 mg SC or secukinumab 10 mg/kg IV + 75 mg SC. At week 52, 76.9% and 65.7% of patients, respectively achieved a PASI 75.

In the FUTURE 2 study, there was no IV loading dose; they studied secukinumab subcutaneously only. When looking at the positive ACR responses at week 24, we can see very little difference between secukinumab 300 mg versus 150 mg.

However, we do see a difference in dosing when looking at TNF naïve versus TNF exposed patients. In the FUTURE 2 study, patients were receiving secukinumab 300 mg, 150 mg, 75 mg or placebo. Among the TNF naïve patients, 38.8%, 44.4%, and 24.6%, respectively achieved an ACR 50. Among the TNF exposed patients who achieved an ACR 50, the results were 27.3%, 18.9%, and 5.9%, respectively.

Ustekinumab, an IL-12/23 inhibitor, was approved in September 2013 for the treatment of PsA. In addition to demonstrating clinical efficacy, ustekinumab has also shown the ability to stop X-ray progression. (Kavanaugh, A et al. Ann Rheum Dis. 2014 (Epub 2014 19 Feb)

Cytokine-based Disease Taxonomy

We’re now learning many different facets of disease and Dr Kavanaugh believes that we will begin discussing responses to these different targets more than we ever have before. Interestingly, IL-17A appeared to have no clinical efficacy in RA and may have even worsened the crohn’s disease.

Intracellular Signaling

The two-year data for Apremilast, which will be presented at EULAR in June 2015, shows that 86% of the patients stayed on drug and about 20% achieved an ACR 70 response.

The earlier data for apremilast, while not quite as robust as that of the TNF inhibitors, still shows good clinical ACR response rates.

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Among patients receiving apremilast 20 mg BID and 30 mg BID, 34% and 51%, respectively, achieved a PASI 50 and 18% and 21%, respectively, achieved a PASI 75. Some patients do very well with this drug. The safety and tolerability issues with apremilast are very important for patients, as most adverse events are either mild or moderate and there is no need for laboratory monitoring.

In conclusion, Dr Kavanaugh feels that the future of PsA is very bright. We have lots of therapies on the horizon. GRAPPA is currently in the process of updating the PsA guidelines so as to incorporate some of the newer data.