"I think the future looks bright... for our psoriasis population"

[Steely_Dan]

Interesting interview with a US dermatologist:

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[pcoll]

oops , dont get anything but a sign in thing?? , maybe you can post the link to the artical ?

[Steely_Dan]

Psoriasis Is a Systemic Disease: An Expert Interview With Alan Menter, MD  CME/CE
Alan Menter, MD   
Disclosures
 
 
Editor's Note:
The last 5 years have been an important time in the history of psoriasis. The biologics have helped transform both our understanding of the pathogenesis of the disease and its treatment, and shifting paradigms are elucidating the importance of seeing psoriasis as a systemic disease. Alan Menter, MD, Chair of the Baylor Psoriasis Research Unit at Baylor Research Institute, and Chief of Dermatology at Baylor University Medical Center, Dallas, Texas, has been at the forefront of these developments and a passionate advocate for improved psoriasis care. Medscape Dermatology Editorial Director Kristin Richardson talked to Dr. Menter after the recent Summer American Academy of Dermatology Meeting.

Medscape: Let's talk about the current state of psoriasis care. As you know, National Psoriasis Foundation (NPF) data show that 39% of people with severe psoriasis are not in treatment.[1] A recent paper found that 40% of people with severe psoriasis were on topicals alone.[2] What do you think are the factors that contribute to the undertreatment of psoriasis?

Dr. Menter: The other number that you can add is the approximate 65,000 patients taking biologic therapy, which is 1% of the total psoriatic population at large. If you add those numbers together with the survey, there is an obviously vast undertreatment of psoriasis.

I think there are 2 reasons. One, the underrecognition of psoriasis as a systemic disease -- and that is not just dermatologists; it is also the general medical community. In fact, our International Psoriasis Council (IPC) group recently had a comprehensive meeting with internists, cardiologists, diabetologists, liver specialists, and cholesterol specialists to lay the groundwork for the increased recognition internationally of psoriasis as a systemic disease and to try and come up with a consensus for lifestyle modifications for our obese psoriatic population.

The second reason is the fact that dermatologists struggle to get approvals for the new agents, particularly the newer biologics. It is a hassle. It is time-consuming, and a lot of dermatologists might not have the infrastructure to spend the necessary time with patients to allow them to take systemic medications. I think aesthetic and surgical dermatology is gaining more ground. I wouldn't say that medical dermatology is under siege, but it is struggling to have enough people who have the time to spend to create the infrastructure. It is not a very financially rewarding thing to do, but it is certainly rewarding in many other ways.

 

[Steely_Dan]

Medscape: In an article last year in The Lancet, you wrote that "archaic approaches, especially combination ones, are routinely used by some clinicians with inadequate prospective or comparative evidence."[3] Is this an issue as well?

Dr. Menter: Prior to biologics, we really didn't have good evidence-based medications. We had methotrexate; we had cyclosporine; we had retinoids. These are still frequently the first group of drugs of choice for people with moderate-to-severe psoriasis. But in the old days, when we ran out of options we would add a secondary drug to methotrexate or a secondary drug to cyclosporine for further therapy.

We certainly still use a lot of methotrexate with the 3 tumor necrosis factor [TNF]-alpha agents to maintain efficacy or if patients have joint disease. However, it is very evident that the biologics are underused in psoriasis. If you take rheumatoid arthritis [RA] and Crohn's disease as comparative diseases with equal long-term implications and equal quality-of-life issues -- psoriasis certainly doesn't have to take a backseat to them as far as the quality-of-life perspective is concerned -- the use of biologics in RA and Crohn's is significantly higher than in psoriasis.

Medscape: I remember at an American Academy of Dermatology (AAD) meeting 5 or 6 years ago, Dr. Alice Gottlieb was wearing a T-shirt with the slogan "Real Derms Use Biologics."

Dr. Menter: I think to some extent that we had felt, in particular with Alice being a rheumatologist as well as a dermatologist, that if we could create enough noise about psoriatic joint disease it might enable our colleagues and the general medical profession to take psoriasis more seriously. Unfortunately, I don't think that happened. I believe we are now going to have to talk more about comorbidities: cardiac issues, fatty liver issues, obesity issues, metabolic syndrome issues to try to sustain psoriasis as a viable systemic disease.

Also, a lot of residents may not necessarily get exposure to a significant amount of biologic use in their residencies. There is currently a big push by the IPC, the NPF, the AAD, and others to try and make psoriasis more mainstream. LeAnn Rimes is coming out about her psoriasis.[4] But it is going to take much more noise about the disease, and as much as the biologic companies have poured resources into it, it certainly has not yet been met with a sustained response from the medical and dermatology community. A lot of patients, for instance, don't know that they have a systemic disease. Education is thus very important as well.

Medscape: Could you talk a bit more about the comorbidities associated with psoriasis?

Dr. Menter: There has been more statistical evidence over the last 2 years relating to metabolic syndrome, hyperlipidemia, cholesterol, obesity, and cardiac issues. There are definitive databases to show that people with moderate-to-severe psoriasis have more risk for cardiac disease, and I think the reason is because of the inflammatory nature of psoriasis causing inflammatory changes in coronary arteries, etc, which are very similar to the inflammatory mediators in psoriasis. Joel Gelfand[5] published an article recently about increased mortality in psoriasis patients, but this information is still not in the mainstream thought process in medicine.

We have recently done a review, yet to be published, in which we took all of the phase 2/phase 3 clinical studies for the 5 biologic drugs. We were able to come up with over 10,000 patients, although admittedly some of the patients may have been in multiple studies. Using the NHANES [National Health and Nutrition Examination Survey] weight/height database we came up with a body mass index of 30.6 for the psoriasis population, with an average kilogram weight of 93 kg -- that is in the obesity range.

There were several posters presented at the summer AAD meeting on psoriasis and comorbidities, and more studies are forthcoming. [Editor's note: See Dr. Bruce Strober's conference report for a discussion of these posters.] Let's look at obesity rates; let's look at diabetes; let's look at the blood sugars and everything else that goes with it. There are very significant data there. I think that as these data come out and become better understood, we will hopefully get an increase in interest not just from dermatologists but also allied health professionals and specialists.

[Steely_Dan]

Medscape: It has been about 5 years since the first biologic...

Dr. Menter: January 30, 2003 was when the first patient was dosed with a biologic, incidentally here in Dallas.

Medscape: How have the biologics changed the landscape of psoriasis treatment?

Dr. Menter: I think there has been a tremendous explosion in the understanding of psoriasis that has come out in the last 5 years as a result of the biologics. The whole new subset of T cells, Th-17 cells, was not even on the horizon 5 years ago, and with the Th-17 subset of T cells has come an understanding of IL [interleukin]-12, IL-23, which also was not known about 5 years ago.

There is now a wealth of knowledge, particularly with the TNF-alpha agents, which were created for RA and Crohn's and have been given exposure to us as well in dermatology. These drugs have now treated over a million and a half patients, with databases going back 10 years. We also now have 5 years of experience with the 2 T-cell agents, specifically for psoriasis. We can now mine these datasets and get a better comfort factor so that we can reduce liver biopsies in our methotrexate patients. We also will not have to keep people on cyclosporine for too long, a drug seldom used by dermatologists today because of its side-effect profile.

We don't have the data yet on psoriasis to say that biologics are safe, and we don't have 5 years or 10 years of data, but it is coming. The longest dataset base is a 3-year paper that was recently published in the British Journal of Dermatology[6] looking at the administration of efalizumab for 36 months, with no increase in side effects noted with long-term, continuous administration.

Medscape: Now there are drugs targeting the P-40 subunit of IL-12 and IL-23.

Dr. Menter: Yes -- ustekinumab and ABT-874.

Medscape: Could you describe the mode of action of these drugs?

Dr. Menter: We know that IL-12 and -23 have a major role to play in the pathophysiology of psoriasis. That has been shown in the last 5 years, and there is now really good evidence that there are genetic polymorphisms in the genes that encode the P-40 subunit of IL-12, for instance, and IL-23 to a lesser degree, which are now linked to psoriasis genetically. We have a wonderful combination of proven genetic polymorphisms in genes that encode the P-40 subunit in IL-12 and IL-23 and the knowledge that IL-12 and IL-23 have a major role in the pathophysiology of psoriasis. We now know that the P-40 subunit of IL-12 and IL-23 is overexpressed in psoriasis. With all of this knowledge, trying to create drugs that will reduce and modulate the levels of IL-12 and IL-23 was a very logical way to go, hence ustekinumab and ABT-874.

Ustekinumab is a human monoclonal antibody that binds to the P-40 subunit of shared subunits of IL-12 and IL-23 with a high degree of affinity. The ABT-874 drug acts similarly; it is also a human monoclonal antibody against IL-12 and IL-23. The overexpression of the genes and the messenger RNA relating to them and skin lesions, and the identification of the variance in these 2 genes, have shown increased risk, particularly in Caucasian patients in Europe. Coming up with a neutralizing antibody to the two is a very logical step, hence the great studies that we have recently been reading about.

[Steely_Dan]

Medscape: Could you give an overview of the PHOENIX data?

Dr. Menter: The PHOENIX 1 study[7] is a placebo-controlled study with 766 patients with moderate-to-severe psoriasis who received 2 different dosages of ustekinumab, either 45 mg or 90 mg, at week 0 and week 4 and then every 12 weeks thereafter vs placebo. The study looked at both short-term and long-term responses. The PASI 75 [PASI, or Psoriasis Area and Severity Index, is a psoriasis severity assessment tool. PASI 75 represents 75% improvement in disease severity from baseline.] data at 12 weeks are very significant -- 63% -- but I think the long-term data are much more significant. I keep telling people that psoriasis is not a 12-week disease. All of us can do a good job with cyclosporine (and to a lesser degree methotrexate) and obtain good 12-week data with a patient, but we want to see how we are going to do over a longer period. The nice thing about this PHOENIX study is that a group of people went on to receive ustekinumab long-term, and the response rate was pretty dramatic. Most of the drugs we have tend to lose response over time, unfortunately. It appears that over at least a 76-week period, we were able to not only maintain but also improve the response with ustekinumab. We are getting figures in some of the studies of up to almost 50% to 60% PASI 90 scores with the 2 IL-12/23 drugs, which is as dramatic as we have ever seen over a 1-year period. The nice thing is that there was no real increase in further side effects over the 76-week study, because it is obviously a concern that over a longer period there might be increased risk for side effects such as infections. It is probably too early yet to know about the cancer risks. That may take 5 years. It looks as if the US Food and Drug Administration will probably create a registry for ustekinumab to ensure that long-term safety profiles are maintained.

Medscape: There have been some questions about malignancies in animal studies.

Dr. Menter: We haven't yet seen the data relating to this. If you look at serious adverse effects over the period of 52 weeks in PHOENIX 1, they were less than 5%, which is pretty similar to what we have had from other long-term drugs. But obviously there is this concern about adverse events: serious infections, tuberculosis, skin cancers, cardiovascular events. I think the drug is going to be a significant tool for moderate-to-severe psoriasis, but we need long-term data on thousands of patients to be able to feel more comfortable and reassure our patients.

Medscape: ABT-874 has just completed enrollment for phase 3 studies, no?

Dr. Menter: Yes. It looks like ABT-874 is approximately 2 years away from reaching our general psoriasis population. The phase 3 study is under way. If you look at the phase 2 data in the paper published in the Archives of Dermatology that came out in February,[8] we can for the first time look at patients who are PASI 90, which is something that we have never seen before. The dosing schedule has to be determined by a phase 3 study, and the longer-term data will obviously have to show whether this dramatic improvement is maintained over the course of a 1-year and longer study with no increase risk in side effects.

Medscape: We have covered quite a lot of territory. Is there anything else you would like to add?

Dr. Menter: It is important to understand that there are other drugs coming down the pipeline as well; it is not just the IL-12 and IL-23 drugs. There are new antibodies on the horizon in phase 1 and phase 2 that look very promising and that are based more on the newly discovered Th-17 profile in psoriasis. I think the future looks bright for researchers, clinicians, and our psoriasis population. I hope we can get everybody to understand the importance of using these drugs in patients with significant disease.

[Nicknackwack]

Makes good reading Dan ~ thx for that

Looks like the alchemists are working toward genetic therapy imo. Interesting that they mention 'lifestyle' as a factor too, something I've always advocated when managing p.

But those side effects still make me shudder especially if it compromises my general good health.

Nick

[engadine]

Thanks for your contribution, Steely, it's always encouraging to see things seem to push towards a better future for us and a worse one for P. We-will-win 

engadine