Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. Lindsay S. Ackerman, MD, and Joel M. Gelfand, MD. This program is available as read only and with accompanying audio.
*Scroll to read lecture and/or follow along with audio.
Slide 1: Welcome to Biologic Therapy in the Management of Psoriasis, A Perspective for Managed Markets. This activity is sponsored by Medical Education Collaborative (MEC) and Princeton CME, and is supported through an educational grant from Abbott Laboratories.
Slide 2:
Slide 3: I am Dr. Lindsay S. Ackerman, Clinical Instructor for Tulane Dermatology and Medical Dermatology Fellow for Tulane Dermatology at New Orleans. I will be your presenter along with Dr. Joel M. Gelfand, Medical Director, Clinical Studies Unit, Assistant Professor of Dermatology and Associate Scholar for the Center for Clinical Epidemiology and Biostatistics for the University of Pennsylvania at Philadelphia.
Please remember that to receive continuing education credit, following the conclusion of this activity, each participant must complete the post-test and evaluation form. These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com. Thank you, again, for joining us. Now to begin with our case:
Slide 4: Ms. A.R. is a 42-year-old female presenting for initial evaluation of a few concerns. For the past year she has had a progressive, itchy, scaly skin rash accompanied by joint stiffness and deteriorating joint pain. The patient reports only minimal improvement in her disease state despite the use of various topical prescription ointments, tar baths, and oral methotrexate. The patient reports having elevations in liver function tests requiring the discontinuation of methotrexate therapy after 2 months.
While pruritus is a chronic complaint, she states that a new problem is the severity of the disease affecting her hands, which causes painful fissures on her palms and fingers at least twice weekly. In addition, the patient is concerned about the abrupt and extensive hair loss that has occurred in affected areas of her scalp. Her scalp disease and lesions on the palms are the cutaneous sites of greatest concern, as these areas are unable to be concealed and are the subject of unsolicited glances from clients, causing a great deal of embarrassment.
Ms. A.R. states that her joint pain has progressed from that which was initially intermittent upon awakening, to a problem that compromises her mobility on a daily basis and one that is no longer improved with the use of over-the-counter arthritis medications. She finds herself limited not only upon awakening but also after long periods of time in a seated position and quantifies the pain severity at 8 out of 10 most mornings, improving to a 4 or 5 throughout the day. She is concerned about the security of her job, as she is no longer able to contribute the way she only recently could.
Slide 5: As you can see, there are numerous aspects of the social history that are contributed to by both the cutaneous and psoriatic disease activity. Ms. A.R. notably admits to feeling very withdrawn and depressed about the recent demise in her appearance and the effect this has had on her relationship with her husband. The remaining contributing factors are left for your perusal on the slide.
Slide 6: Prior to 1 year ago, Ms. A.R. had an 8-year history of only limited cutaneous disease concentrated on her elbows, knees, low back, and scalp.
A year ago, her skin disease progressed to involve her arms, legs, back, chest, and abdomen. About 2 months after the acute worsening of her skin disease, she began to notice her joint pains were more severe and relatively unaltered with the use of over-the-counter nonsteroidal agents.
On physical examination, cutaneous examination is notable for the presence of thick, well-defined, red, scaly plaques distributed throughout the scalp, trunk, buttocks, extremities, palms, and soles. Her body surface area of involvement is greater than 50%. The scalp reveals numerous areas that are completely devoid of hair, the affected sites being replaced entirely by scaly plaques.
Slide 7: The palms demonstrate numerous deep fissures within the involved plaques. The fourth digit on the right hand shows diffuse tendinous sheath swelling, while the left hand shows evidence of joint swelling and joint destruction in the second digit and fifth digit, respectively.
Slide 8: As you listen to the main presentation, think about what therapies should be considered for patients experiencing moderate-to-severe psoriasis and how the efficacy of these selected treatments will be measured. I would now like to welcome and introduce you to Dr. Gelfand for his presentation on biologic therapy in the management of psoriasis. Dr. Gelfand.
Slide 9: Thank you, Dr. Ackerman. This is an important topic for managed markets physicians and pharmacists because psoriasis is a common chronic disease with a substantial morbidity, and also treatment options have really expanded dramatically over the last several years.
Slide 10: So let us begin. As an introduction to psoriasis, it is important to understand that this is a chronic inflammatory disease characterized by well-demarcated thick red plaques with adherent silver-colored scales.
Over 4.5 million US adults have psoriasis, and it is estimated that about 1 in 5 of them, or 20% have what we consider moderate-to-severe disease, disease which is impairing enough that it requires treatments beyond just topical creams and ointments.
Any part of the skin can be affected with psoriasis, including the face, scalp, nails, and genitals. And the plaques may be very symptomatic, including: they could be itchy, they could crack and bleed, and these symptoms can lead to disability in patients abilities to work, to sleep, and in their interpersonal relationships.
Slide 11: Shown on the next slide are some clinical features of psoriasis. On your upper left is a classic example, these well-demarcated red plaques with silver scales. Below that on your left is an example of extensive nail involvement, and there are some patients who may only have nail involvement, but you can get a sense of how disabling this type of disease could be if one needs to work with their hands. On your upper right is an example of a well-demarcated psoriasis plaque that has several areas with crusting. This is an example of how psoriasis plaques are very prone to trauma and to bleeding.
This could often result in embarrassment for the patients as well as staining of their clothes. And then finally on the lower right of your screen is another picture of serious plaque psoriasis involving the hands with cracks and fissures, and one could certainly appreciate the degree of disability associated with this type of skin involvement.
Slide 12: On our next slide we look at the features of guttate psoriasis, recognizing that there are different variations of this disease, all of which share a similar pathophysiology. So for guttate psoriasis, this is characterized by small papules, typically about 5 mm in size. They can be very widespread and they tend to be eruptive, frequently associated with upper respiratory tract infections or strep infections. And frequently, patients have remission from their disease, but they may also have episodic flares.
Slide 13: On our next slide we have a picture of pustular psoriasis, another subtype of this disease. Now this involves eruptive pustules, and the patients are often acutely ill. They typically have fever and joint pains that go along with these outbreaks of pustular psoriasis, and typically these patients are systemically ill and they require urgent evaluation and treatments.
Slide 14: And finally, erythrodermic psoriasis, another variant of psoriasis that can be quite severe. This involves having much of the body surface area covered with psoriasis disease and results in impaired epidermal barrier function. Under chronic states, patients can be at risk for high output congestive heart failure; certainly infection is a big concern.
Often, sepsis can result from this type of problem, and patients frequently will have electrolyte disturbances. So when patients present with this degree of psoriasis, frequently they will require hospitalization to quickly try to reverse this condition.
Slide 15: Now I want to move on to discuss a comorbid aspect of psoriasis, which is psoriatic arthritis on your next slide. Psoriatic arthritis is very common in people who have skin disease from psoriasis. The frequency of prevalence of psoriatic arthritis among people with psoriasis varies somewhat based on how severe their skin disease is.
So for those patients who have very limited skin disease, say only 1% to 2% of their body surface area, their prevalence of psoriasis is significant but much less than those who have more moderate-to-severe skin involvement, where reportings of the prevalence of psoriatic arthritis in this group range from 20% to 30%.
This paper I am showing you here is based on reports from a US population-based study of the epidemiology of psoriasis and psoriatic arthritis in which over 27,000 patients were surveyed for this disease.
It is important to understand that psoriatic arthritis often occurs with the onset of psoriasis or many years after the onset of psoriasis. And psoriatic arthritis can be progressive. It can cause permanent joint damage. So that often will affect our treatment algorithms, as some of the damage from psoriatic arthritis can be irreversible.
Slide 16: Shown here are clinical features of psoriatic arthritis. This is a disease defined as a seronegative, inflammatory spondyloarthropathy. The symptoms typically involve morning joint stiffness that improves during the course of the day. The joint pain often gets better with activity.
The patients can often have clinical signs such as swollen or tender joints, dactylitis, and enthesitis. So shown on the pictures to your right are some examples of these clinical features of psoriatic arthritis. You see on your upper left examples of swollen distal joints as well as some associated nail disease.
Below that on your left you see the patients second toe is swollen and purple, and coloration is an example of dactylitis. On your upper right is a patient of mine who has joint deformity from his psoriatic arthritis, and below that picture on your right is an example of enthesitis where you have inflammation and erythema where the tendons are exerting into the joint space.
Slide 17: So now we have covered the phenotypes of psoriasis and discussed concombinant psoriatic arthritis. We are going to discuss a little bit of the economic burden of this disease and its impact on health-related quality of life.
Slide 18: So the economic burden of psoriasis is quite substantial not only to society, but also to patients. The direct costs are estimated to be at least $650 million per year. That is based on a study that now is now quite old, from 2002. More recent work has estimated that indirect costs associated with psoriasis are much higher, exceeding $16.5 billion per year.
And this is because a variety of research demonstrates that those with psoriasis often have impairment at work, frequently miss days of work related to caring for their disease, as well as have to spend a lot of time committing to trying to take care of their skin disease. Therefore, the indirect costs are far beyond the direct costs that we typically measure.
Along this line of thinking is the fact that psoriasis severity of the skin is associated with decrements in income, and this we demonstrated in a paper we published a few years ago looking at representative population-based data in the United States.
Another important consideration to put this in perspective for you is that a recent survey done by the National Psoriasis Foundation found that almost ¼ of people with psoriasis spend more than 60 minutes per day treating their disease, and that is an enormous amount of time that patients need to take in order to effectively manage this condition.
Slide 19: We will now touch on some of the impacts on health-related quality of life and psoriasis. And one way of discussing these issues instead of a purely quantitative notion, is to first talk about some descriptive studies, which gives an insight into what aspects of burden are created by this illness.
So this is a summary of a paper that was published in a qualitative research journal where they basically conducted structured interviews of patients who had severe psoriasis to get a sense of what are some of the common themes that affect these patients.
So these are some of the quotes that arise out of this type of work. One patient noting, "We almost never talk about it, so I feel alone with my disease and all that it entails.” People with psoriasis often face a lot of discrimination. It is a severely socially isolating condition.
The second concept is a quote by another patient saying, "The only thing you think about is scratching, bathing, and putting on ointment 24 hours a day.” This brings back some of the concepts that we brought in earlier about how time consuming it is for patients to deal with this disease, and how all-consuming this condition can become for patients.
And then finally another patient noting that, "On remission I suddenly felt myself singing for joy. It was like getting out of prison. You were free. There was nothing holding you back anymore." This is actually a very interesting statement. I think it very well captures how patients often feel with this disease.
Often patients cannot go to the beach because they are discriminated against, or they cannot go to public pools, they cannot go to salons, they may be discriminated against at work or by people that they see in public places. So it is a tremendous relief to patients when they are in remission.
And many of my own patients, as I have treated them successfully, have expressed this exact same sentiment to me. So we could also learn about psoriasis on the next slide by studying some case histories of famous people who had this disease to get some further insight into how it affects people.
Slide 20: On your right is a picture of John Updike. He is a famous poet born in Pennsylvania. He has won the Pulitzer Prize. Mr. Updike suffered with psoriasis from early childhood, and he has written about it frequently in many of his writings. In one place he has a chapter in his memoirs essentially called "At War With My Skin."
And he makes the following quote: "Only psoriasis could have taken a very average boy and made him into a prolific, adaptable and ruthless enough writer.” And what Updike meant by this statement is that having to deal with psoriasis as an adolescent and a young adult, one had to get very used to people criticizing you because that is essentially the experience these patients often have.
People are constantly coming up to them saying, "What do you have? Why do you have this? Is it contagious? Why can't you get rid of it?” And what Updike was getting at here was that this ability to deal with this aspect of psoriasis made it easy for him to then put out his work into the public and handle the criticism that comes to any artist.
Slide 21: Now your next slide is a somewhat less sympathetic figure in history. This is Joseph Stalin. He was also known to have suffered with psoriasis of his skin and also possibly his joints. And there is an interesting story about his treatment. Stalin was initially treated with a alternative medicine, if you will, called lysates by a guy named Kazikow. Kazikow was an internist, and Stalin was so impressed with the response that he had to the lysate therapy that he started to close the state institute of skin and venereal diseases in favor of a new institute for Kazikow to study lysate therapy.
And to put this in perspective for you, the Department of Dermatology where I work at the University of Pennsylvania is probably one of the largest departments in the United States for dermatology. And so it is as if he shut down our entire department, put us all out of work, and said, "No, Kazikow now will take this over and only study this lysate therapy for psoriasis."
Unfortunately, Stalin’s psoriasis relapsed. When he was re-treated with the lysate therapy, he had no response. The ultimate result was that Stalin had Kazikow tried and executed. So this is an example of the perils of not practicing evidence-based medicine.
Slide 22: On our next slide now we will talk about things that are not descriptive, but more quantitative in their analysis, which would give us sort of a more numerical understanding of how this disease relates to healthcare-related quality of life and functioning.
This is an example of a frequently quoted paper from the Journal of the American Academy of Dermatology published in 1999, in which the investigators studied patients who had psoriasis in their patient practice. And they had them complete the Short Form-36, which is a frequently used measure of health-related quality of life, not only in physical functioning but also mental functioning.
And they compared the psoriasis patients scores to normative scores based on studies that have been done throughout the United States. And what they found is that for mental functioning, people with psoriasis scored worse than most diseases including diabetes, people with recent heart attacks, and congestive heart failure. And they found that only those with severe lung disease or depression had more impairment in mental functioning than their patients with psoriasis.
To the right of your screen shows how patients with psoriasis compare on physical functioning. And what they find again is that patients with psoriasis perform poorly on these measures, demonstrating that they have more impairment in physical functioning than other diseases such as recent myocardial infarction, lung disease, and even diabetes. Only patients with congestive heart failure fared worse than people with skin disease and psoriasis.
Slide 23: And then we need to think about the psychological impact of psoriasis, shown on the next slide. This is beyond the idea of their mental and physical health functioning, but also some of the psychological and psychiatric morbidity associated with this disease.
Several studies have demonstrated that people with psoriasis have a higher frequency of depression and depression symptoms based on Beck Depression Inventory scores. These are ways of measuring depression symptoms.
Other descriptive studies have found that in large cohorts of patients with psoriasis, about 10% of patients often report a wish to be dead, and 5.5% of patients report active suicidal ideation, demonstrating the severe impact this disease has on peoples mental well-being.
And of interest, more recent data published in the journal Lancet in 2006 demonstrated that effectively treating psoriasis with etanercept, one of the newer therapies for this disease, is associated with a decrease in depression symptoms and in fatigue symptoms, particularly those who have concombinant psoriatic arthritis, and this is based on the gold standard RCT data from placebo-controlled trials.
So in these studies, those who were treated with etanercept for psoriasis compared to placebo patients, those who had active treatment had improvement in the depression symptoms and fatigue symptoms compared to those who were on placebo. So it is possible that treating the skin disease not only will improve skin symptoms, but may also improve broader health overall with respect to depression and symptoms of fatigue.
Slide 24: The next concept we are going to touch on is that of psoriasis and comorbid conditions. And shown on this slide is sort of an overview, if you will, of how psoriasis may play in with other comorbidities.
Slide 25: On the left of your screen is this concept that to develop psoriasis one needs a combination of genes and environmental exposures to develop the phenotype of psoriasis that you see in the middle of the screen.
And certain environmental exposures such as smoking and obesity have recently been linked fairly strongly to the risk of developing psoriasis. Now once someone has psoriasis there are mediating factors to this disease. The disease is characterized by chronic inflammation, hyperproliferation of the epidermis, and angiogenesis, all of which could really result in possibly certain adverse health outcomes.
There are also treatment factors that could affect outcomes related to disease, and clearly the psychosocial impact of the condition that could relate to other health behaviors. There has been much literature published looking at rates of cancer in people with psoriasis, such as lymphoma, vascular disease, metabolic disease, and arthritis, showing that all these outcomes seem to be elevated in people who have moderate-to-severe psoriasis.
And the association of psoriasis with these comorbid conditions can be best summarized by recent work we published in "The Archives of Dermatology," which should be coming out in December of this year, in which we show that people with severe psoriasis die about 3 to 4 years younger than those who do not have severe psoriasis.
This is based on a population-based database used from the United Kingdom. And this is a significant amount of years of life lost in those with severe psoriasis, equating to about 5% of a persons lifespan.
Slide 26: Now I am just going to briefly touch on 2 papers for you to be aware of. One is a paper by our group called Risk of Myocardial Infarction in Patients with Psoriasis. This was published in JAMA in 2006.
Slide 27: On the next slide you can see the results of the study. We basically ran a multivariable model to look at the risk of having a heart attack in people with either mild psoriasis or people who had severe psoriasis compared to those without psoriasis.
And this model was adjusted for the typical reasons why people develop heart attacks, such as hypolipidemia, diabetes, obesity, smoking, and hypertension. And when we are controlling for major risk factors for cardiovascular disease, we found that people with severe psoriasis and mild psoriasis to some extent had an increased risk of having a heart attack despite controlling for the major reasons why most people have myocardial infarctions.
We also found that this relative risk was highest in younger patients. The box on your right shows that for a patient with severe psoriasis who is age 40, they have a more than doubling of the risk of having a heart attack related to having psoriasis than a patient without this disease.
And by the time someone is 60, that patient now has about a 40% increased risk of having a heart attack related to psoriasis. So the risk attributable to psoriasis appears to decrease somewhat as patients age and competing risks for heart disease tend to increase.
Slide 28: On the next slide is another study recently published in the British Journal of Dermatology called Psoriasis: A Possible Risk Factor for the Development of Coronary Artery Calcification. On the right of your screen is an example of a CT scan that shows atherosclerosis affecting the left anterior descending coronary artery, where you see sort of the white highlights of calcium in that vessel.
Slide 29: The next slide sort of summarizes that result. They found that the prevalence of coronary artery disease was significantly higher in their psoriasis patients compared to their matched controls. There was almost 60% prevalence of coronary disease in the psoriasis patients compared to only about a little under 30% in those who were controls. They also found out within patients who had coronary disease, those who had psoriasis had more severe coronary disease than those without psoriasis who also had coronary artery disease.
And finally when they controlled for the major reasons why people typically develop coronary disease, such as age, gender, hypertension, hypolipidemia, family history of cardiac disease, diabetes, smoking, body mass index, and CB active protein levels, they found that psoriasis still independently predicted having atherlosclerotic disease of the heart.
So these 2 studies combined suggest that something about psoriasis itself may lead to excess rates of atherlosclerosis and myocardial infarction. And this is a similar finding that has been shown for other chronic inflammatory diseases such as rheumatoid arthritis.
Slide 30: OK, so now we are going to discuss the pathophysiology and treatment of psoriasis.
Slide 31: Shown on this slide here is an example of a cartoon which shows you the pathophysiological features of psoriasis. You see access activity of antigen presenting cells. These are results of recruitment of T-cells above the CD4 and CD8 variety.
These T-cells, antigen presenting cells, as well as the epidermis release cytokines and these cytokines can stimulate increased proliferation and decreased differentiation of the epidermis resulting in a phenotype of psoriasis. This process occurs not only in the skin; in some patients it can occur in the joints and also can measure abnormal levels of cytokines in the blood of patients with psoriasis.
Slide 32: Now there is a variety of treatment options for psoriasis. These therapies include topical approaches such as topical steroids, vitamin D analogues, topical retinoids, and then some older therapies that are not as well accepted by patients due to either the smell of the agents or irritation from the agents and staining from the agents, such as tar and anthralin.
There are oral agents for psoriasis. These include methotrexate, acitretin, and cyclosporine. There are phototherapy treatments for psoriasis which include broadband, ultraviolet B phototherapy, narrow-band ultraviolet B phototherapy, and psoralen when taken by mouth to make them photosensitive plus UVA, and this is called PUVA.
Finally, we now have an expanding array of treatments for psoriasis called biologics. There have been more treatments approved for moderate-to-severe skin psoriasis in the last 4 to 5 years than in the last 30 to 40 years. And these include medications that target either the cytokines such as TNF inhibition which is done by etanercept, infliximab, and adalimumab. And then T-cell inhibitors such as efalizumab and alefacept.
Slide 33: Your next slide describes patients who are believed to be candidates for phototherapy or systemic treatments in biologics. This is based on a consensus statement which I was a part of recently published in the Archives of Dermatology based on the medical board of the National Psoriasis Foundation consensus statement.
And based on this consensus statement it was determined that patients who had at last 5% or more of their body involved with psoriasis are candidates for systemic treatment or biologics. And this is largely because once a patient gets into this degree of extensiveness of psoriasis, it is often very difficult for topicals to work successfully in this patient population. And often it is difficult for patients to comply with these regimens.
Patients who have vulnerable areas affected, such as the face, the nails, the scalp, the genitals, intertrigunitaries of the hands and feet, these are other areas that can cause significant morbidity in patients and therefore may be candidates for more aggressive treatments.
People who have psoriatic arthritis are certainly candidates for disease-modifying antirheumatic drugs (DMARDs). Those who have less frequent variants of psoriasis, or most patients of psoriasis, about 80% have plaque psoriasis, but less frequent variants of pustular disease, erythrodermic psoriasis, and guttate psoriasis. These often require phototherapy or systemic agents to treat them.
Pustular and erythrodermic psoriasis can be acute medical emergencies, and guttate psoriasis, because of its widespread nature, can be very difficult to treat with topical medications alone.
Then finally patients who have more limited body surface area, less than 5% but who are failing topical therapy and the disease causes significant disability or impairment in their physical or mental health functioning.
Slide 34: The next slide describes sort of our traditional therapies for psoriasis and some of the unmet needs of psoriasis patients based on these therapies. On the second column it is phototherapy, either ultraviolet B or PUVA, and in the column on your right are systemic agents, such as cyclosporine, methotrexate, and retinoids.
And in terms of unmet needs, these are summarized in the first column on the left. So with respect to long-term safety where phototherapy modalities are concerned, chronic use of these treatments, ultraviolet B treatments can result in skin aging as well as skin fragility over time.
There is certainly some concern of carcinogenicity not only with ultraviolet B but certainly with PUVA, which can result in a substantially excess risk of squamous cell carcinoma, basal cell carcinoma, and possibly even melanoma with chronic use.
Long-term safety issues with our traditional oral agents include concerns for renal toxicity with cyclosporine, liver toxicity with methotrexate and retinoids, potential carcinogenicity related to immune-suppression related to cyclosporine and methotrexate, and severe issues of teragenicity with methotrexate and retinoids which are both category X medications.
There are also concerns about efficacy with these agents. With PUVA and UVB they have a very slow rate of onset; therefore, they are really inappropriate for patients who are having rapidly acutely flaring disease such erythrodermic or pustular psoriasis or severely flaring plaque psoriasis.
Systemic agents such as methotrexate and retinoids also do have a slow onset of response, and the time on treatment is limited to alleviate safety concerns for methotrexate, cyclosporine, and retinoids. This is particularly problematic given that psoriasis is a disease that once one develops it is chronic and will require decades of therapy to control it.
Finally there are convenience issues for phototherapy. There are access-to-treatment issues for the different phototherapy modalities. Only a minority of dermatologists have actually offered these treatments in their office, so oftentimes patients do not even have it available to them.
And then for the patient there is a substantial time commitment. They are going to the office 2 to 3 times per week for several months at a time to achieve appropriate response to these treatments. With systemic agents all of them require very complex lab monitoring, intensive lab monitoring which requires a lot of blood draws from patients, and careful monitoring and follow up with their physician.
Slide 35: The next slide highlights the top safety concerns of long-term treatment of psoriasis with oral systemic therapies, highlighted again just to give you a sense of why so few patients are able to stay on these drugs for a long period of time.
With methotrexate, there is a concern of cirrhosis with long-term treatment with this drug. When patients approach treatment levels of 1 to 2 grams of methotrexate, the risk of methotrexate toxicity on the liver increases. Currently it is recommended that patients get regular liver biopsies throughout their treatment with methotrexate, and this becomes a major problem for many patients on this drug.
Cyclosporine is another medication that is highly effective for psoriasis. However, chronic use can lead to kidney failure, and currently guidelines limit its use to only 1 year's period of time.
And finally, acitretin. This is a drug which is Category X and there is a 3-year window of Category X status for a patient on acitretin. So a woman of child-bearing age who has been on acitretin is recommended not to get pregnant for at least 3 years afterwards because the drug can stay in the body's tissues.
There can also be liver toxicity concerns with chronic use, and also changes in the bones and ligaments that can lead to hyperostosis with chronic use. So as a result, patient factors often result in potential contraindications for some of these traditional therapies.
So for a woman of child-bearing age, we typically cannot use acitretin in this type of patient, or even methotrexate if they are planning on becoming pregnant. Alcohol use is very prevalent among people with psoriasis as a comorbid psychosocial behavior, and this makes use of high-powered toxic drugs like methotrexate and acitretin very problematic. Those who have advanced age or multiple comorbidities can be at excess risk of side effects from these drugs, as is true for most medications.
As a result, rotational therapy has been advocated for those on traditional agents to limit long- term toxicity where patients may be treated with methotrexate for a period of time then cyclosporine then acitretin then phototherapy and the cycle continues itself. This is something that was advocated for many years, however never really has been empirically proven to improve long-term outcomes associated with these treatments.
Slide 36: The next slide summarizes the pathophysiology of psoriasis and how these medications work for this disease. Efalizumab and alefacept are shown to work on the T-cell and edge-presenting cell interaction, whereas etanercept, adalimumab, and infliximab all work by blocking TNF, tumor necrosis alpha factor in inflammatory cytokine.
Slide 37: The next slide summarizes the various biologics, their structures and their targets, how we dose them, as well as some of the pharmacokinetic information for each of the different drugs. And there are some differences that I will highlight between the drugs that are important to be aware of.
For infliximab, it is a drug that is given by intravenous administration, whereas alefacept is given by intramuscular injection, IV is no longer available in the United States. And then adalimumab, efalizumab, and etanercept are all given subcutaneously.
The drugs have varying half-lives. Etanercept has probably the lowest half-life and then alefacept and possibly adalimumab may have longer half-lives. And it becomes important sometimes because when patients develop an infection we often will hold therapy in order to allow the body's immune system to manage the infection as best as possible.
Slide 38: In terms of how we assess response to treatment, in clinical trials we use what is called the Psoriasis Area and Severity Index or PASI. This involves an investigator making an assessment of the patients plaque thickness, its color, how scaly it is, and also how much body surface area is involved.
And the primary end point for clinical trials has been a 75% reduction in the PASI score, which is similar to being clear or almost clear on a physical examination. That being said, several papers have come out that suggest that a 50% reduction in PASI, although not our primary end point for psoriasis trials regulated by the FDA, is still a very clinically meaningful improvement in skin scores associated with improvements in health-related quality of life.
Now PASI is unfortunately very time-consuming to generate, and they are really only used in the clinical trials setting. A clinician is not generally trained in performing PASIs, nor are PASI scores easily interpreted by the clinician. So these are not something that really are used in a clinical environment. They are really only used for research purposes.
Slide 39: Other ways of assessing psoriasis: efficacy of treatments including physician global assessments. In clinical trials these are done with what are called static measures in which the investigator will state the degree to which the plaques are red and scaly and thick on a scale of 1 to 5, however in clinical practice most doctors will simply compare the patient's progress compared to their previous visit, notes, and their recall, and suggest the patient is a certain amount better or a certain amount worse.
Body surface area is another way of assessing psoriasis. This is typically not done in a clinical setting but can be done by estimating the amount of skin that can be covered by the patients palm equaling about 1%. So if the patient had about 5 palms of psoriasis, that would be equivalent to about a 5% body surface area.
Finally, in clinical trials we often will measure health-related quality of life. The dermatology life quality index (DLQI), which was developed in the United Kingdom, is the most common instrument used for clinical trials. It is not really used in clinical settings in the United States and, therefore, it is not entirely clear how scores on this instrument should be acted upon for clinical decision-making. More work needs to be done in this area.
Slide 40: If you want to look at some of the evidence of efficacy based on the large pivotal phase 3 trials, this is a summary slide looking at PASI 75 responses of the different biologics in their large phase 3 clinical trials.
Now, it is important to understand that these are not head-to-head comparisons, therefore it is difficult to know for sure if one drug is definitely more effective than another drug. Also, it is important to understand that, for most of the trials, the placebo response rate was quite low, 5% or less of patients getting placebo achieve a PASI 75. I think this is true for all the trials except for perhaps alefacept, in which the placebo response rate was slightly higher, at around 10% to 12%.
Now what we see in these charts is that adalimumab, the first bar on your left, had a PASI 75 of about 70%, meaning that approximately 70% of the patients are clear or almost clear at the time of primary end point, which for this study, I believe was at week 16.
For etanercept, 2 different doses are shown here. That is the second drug on the right. The first bar is at a lower dose of etanercept at 25 mg subcutaneously twice weekly and then 50 mg subcutaneously up to twice weekly has a higher response, showing the dose-response effect.
Infliximab has apparently one of the higher response rates at almost 80%. And this is at week 10. And alefacept and efaluzimab show response rates in the low to high 20% response rate categories.
Slide 41: Our next slide summarizes some of the safety issues related to these drugs. They divide into common reactions that occur in more than 5% of patients, uncommon reactions that occur in 0.1% to 5% of patients, bad reactions that occur in less than 1 in 1000 individuals, and also whether or not there is a black box for the product.
So adalimumab, one of the TNF inhibitors, the most common reactions are typically injection site reactions. Patients can develop positive ANAs in the blood of unclear clinical significance, and upper respiratory tract infections, headaches, nausea, and elevated alkaline phosphatase and cholesterol have been observed with low frequencies, and there are no recommendations from the FDA on monitoring for these type of abnormalities.
Uncommonly, patients can develop neutralizing antibodies, serious infections, and rarely patients could develop tuberculosis, malignancy, lupus-like syndromes, hypersensitivity reactions, hepatitis B reactivation, demyelination events such as multiple sclerosis, congestive heart failure, and pancytopenia. And this drug does carry a block box warning for infection based on tuberculosis, sepsis, fungal and opportunistic infections.
Alefacept is one of the T-cell inhibitors. Commonly patients can experience lymphopenia that is essentially asymptomatic; uncommonly they can develop LFT elevations and serious infections. And rarely, malignancies and hypersensitivity reactions have been reported. There are no black box reports for alefacept.
For efalizumab, it can be associated with flu-like symptoms, particularly early on in the course of injections. Patients can have mild psoriasis flares and lymphocytosis. Uncommonly, patients can have severe flares of psoriasis, particularly if the drug is stopped suddenly. They could have serious infections, thrombocytopenia, arthritis-type events, hypersensitivity reactions, and LFT elevations. Rarely malignancies and homolegoumena as well as pancytopenia have been reported. There is no black box warning for this drug.
For etanercept, one of the TNF inhibitors, injection site reactions and positive ANAs are considered to be potentially common reactions. Uncommonly are serious infections and rarely are the type of side effects that are seen with TNF inhibitors already described for adalimumab. Etanercept carries no black box warning.
Infliximab is also a TNF inhibitor given by IV. This drug can be associated commonly with infusion reactions, positive ANAs, elevated liver function tests, and neutralizing antibodies. Uncommonly are serious hypersensitivity reactions and serious infections, and then rarely it can be associated with severe hepatic injury as well as similar outcomes we discussed for the other TNF inhibitors.
Infliximab carries a black box warning for infections including tuberculosis, sepsis, fungal and opportunistic infections as well as rare cases of hepatosplenic T-cell lymphoma reported mainly in the Crohns disease population.
Slide 42: The next slide summarizes the long-term safety concerns of these biologics. They all work by being immunosuppressive and, therefore, may be associated with increased risks of infection and malignancy with long-term use.
Extensive studies have been performed for TNF inhibitors mainly in the rheumatoid arthritis population, suggesting that these risks appear to be very low. However, long-term studies are ongoing particularly for patients with psoriasis where the findings in the rheumatoid arthritis population may not extend to people with psoriasis, as patients with RA are often treated with multiple immunosuppressants at one time such as methotrexate plus a biologic plus prednisone, whereas a patient with psoriasis tend to be treated more with monotherapy when it comes to systemic treatments.
Nevertheless, this remains an area of ongoing concern and controversy.
Slide 43: The next slide summarizes the required screening tests, lab monitoring based on the US FDA prescribers information. For adalimumab, it is recommended that we screen for latent tuberculosis infection, and then we should evaluate patients who are at risk for having hepatitis B prior to beginning therapy.
Etanercept and efalizumab have similar recommendations. For etanercept, it is actually not recommended by the FDA to screen for latent tuberculosis prior to starting therapy. However, in clinical practice, most physicians do this as etanercept can be associated with reactivation of latent TB.
For infliximab, it is also recommended that patients with some of the symptoms of liver dysfunction be evaluated for evidence of liver injury. For alefacept, it is recommended that baseline C4 T-cell counts be done and that they be continued during therapies every 2 weeks.
There are then recommendations for holding treatments if patients develop significant lymphopenia. It is also recommended that patients with alefacept who assuage the symptoms of liver injury be fully evaluated.
Finally, with efalizumab, a platelet count is recommended baseline in every month during the course of treatment initiation, and every 3 months thereafter with continued therapy. The FDA recommends that patients should be closely observed for psoriasis worsening upon discontinuation of this medication, including people who are not responding to the drug.
Now although these are the recommendations by the FDA, most dermatologists tend to check labs on a regular basis on these patients to look for any signs of idiosyncratic organ injury or blood count effects.
Slide 44: Finally we are going to touch on the issue of cost-effectiveness of the different therapeutic options. This is a paper that was recently published in the Journal of Dermatologic Treatment examining the cost of different therapies per PASI 75 responder. And what we see is that for the biologic agents, infliximab, etanercept, efaluzimab, and alefacept, is that all these drugs are more expensive than the more traditional therapies, such as PUVA, narrow-band UV therapy, and our more traditional medications, methotrexate, acitretin, and cyclosporine.
These are, of course, cost-minimization studies, and they do not give any information on the incremental cost-effectiveness of these drugs compared to more traditional therapies.
Slide 45: An important concept to be aware of, however, is that the estimated cost of phototherapy versus biologics can be highly variable depending on whose perspective we are looking at. When we look at the patients perspective, a chart on your left shows the annual direct cost to the patient.
So for a patient on phototherapy, because they have to pay a copay with each visit, it is estimated that it costs them about $1800 per year, and at a patient direct cost for that treatment compared to only about $840 or $780 for biologic therapies. This does not include the fact that people with phototherapy have enormous indirect costs associated with having to take time off from work and their other activities to see the doctor 3 times a week for their treatments.
On the right-hand side of your screen, is an example of the cost of phototherapy to insurers on an annual basis compared to etanercept and efaluzimab. So clearly, the costs are much more substantial for certain biologic therapies compared to phototherapy, but the cost to patients is much higher for phototherapy, and this often becomes a major disincentive for patients to be treated with this modality.
Slide 46: Finally, some summary data looking at the impact of healthcare utilization when patients are treated with etanercept over time. This is data from the controlled clinical trial published recently in “Value and Health,” now available online, and what it shows is that those receiving either continuous or interrupted therapy with etanercept have decreases in the number of days that they are hospitalized, decreases in their utilization of emergency care, and decreases in the number of nondermatology physician office visits compared to the time prior to initiation of therapy with these medications.
So it is possible that treatment of psoriasis can result in a lower health cost on some domains over time.
Slide 47: So in conclusion, we have demonstrated psoriasis is a serious medical condition that has pervasive impacts on health-related quality of life and well-being. We have shown that biologic therapies may be associated with less organ toxicity than oral agents based on the prescribing information and in known side-effect profiles of our traditional medications.
And clearly they are much more convenient for most patients than phototherapy, as patients can either simply inject themselves at home or, in the case of infliximab, go to the doctors office periodically for infusions as opposed to having to come to the doctor's office 3 times per week over many months’ time to manage their disease with phototherapy.
And finally for many patients with psoriasis, biologics are necessary to achieve long-term control of their disease.
Slide 48: So we will now turn back to Dr. Ackerman for discussion of the case study presented at the
beginning of this activity.
Slide 49: Thank you, Dr. Gelfand. Let us revisit the case. Our patient is a 42-year-old female with clinical manifestations of progressive, symptomatic psoriasis and psoriatic arthritis. She has a moderate-to-severe level of cutaneous disease with >50% body surface area of involvement and disease- associated quality-of-life concerns that are severe. The medical history includes overweight status and hyperlipidemia.
Treatment options that have proven ineffective or intolerable include prescription topicals for her skin, over-the-counter nonsteroidal agents for her joints, and methotrexate for her skin and joints. Phototherapy is a treatment option that can address her skin disease but leaves her joints untreated. In addition, phototherapy requires multiple doctor visits weekly, which is likely not the best option considering the more recent tenuous situation of her employment status.
Additional systemic treatments include both acitretin and cyclosporine, both of which have reasonably predictable efficacy in the treatment of cutaneous psoriasis but neither of which are able to address the progressive joint disease associated with psoriatic arthritis.
Unfortunately, methotrexate remains an unsafe option, as our patient likely has fatty liver, a condition common in individuals with overweight status and hyperlipidemia. Biologic modifying agents of the anti-TNF family which include etanercept, infliximab, and adalimumab are the only currently available therapies that improve and reverse joint disease in psoriatic arthritis.
While each of these agents demonstrate improvement in cutaneous psoriatic disease, only etanercept and infliximab currently have FDA approval for both indications. Adalimumab, FDA approved for psoriatic arthritis, is pending FDA approval for the treatment of cutaneous psoriasis.
Slide 50: Our patient was prescribed therapy with 1 of the biologic agents of the anti-TNF family. She returned to the clinic for follow-up 1 month postinitiation of treatment and was elated at the extent of her improvement.
While the body surface area involved remained consistent with her previous examination, the scale overlying her plaques had diminished greatly. The thickness of the plaques was far less. The pruritus had nearly gone away, and she had experienced only 2 fissures on her palms all month. More than anything, she says she is most pleased by the significant improvement in her joint pain.
Two weeks ago she resumed walking in the morning, and last week she revisited the opportunity of resuming her position as Regional Sales Manager at work per consequence to her disease activity. A.R. and her husband are communicating better, and she is grateful to have a re-energized outlook on life.
Thank you for your participation.
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