Psoriasis Update: 2012 Part 2

POINT: COUNTERPOINT – MACE and Its Relationship to IL 12/23 Inhibition

Ken Gordon, MD

Dr. Gordon presented a counterpoint to Dr. Leonardi’s perspective regarding the association of IL 12/23 inhibition with MACE events. Dr. Gordon feels that while there is not a definitive answer at this time regarding the association it is important to discuss both sides to the story.

When a dermatologist thinks about the data that has been presented, specifically on ustekinumab, one needs to consider whether IL 12/23 has a true effect on MACE events. There are two approaches to this: 1. Observe the world, here is the observation and it needs to be explained; 2. Utilize the Scientific Method.

In the context of IL 12/23 and looking at MACE events, there has been an inductive moment, and that is the paper that Dr. Leonardi referred to, i.e., the Meta-analysis regarding IL 12/23.

In reviewing the overall conclusions that were presented in the meta-analysis of the association of IL 12/23 inhibition and MACE events, Dr. Gordon concluded that at least in the case of ustekinumab, there may not really be an answer. It is important to remember that meta-analyses have two required aspects in order for them to be effective: 1. The trials have to be similar in structure; 2. The intervention that is used has to be similar. In combining the trials using ustekinumab with those using briakinumab one can see that despite their effect on IL 12/23 these drugs are actually quite different in the dosages used. For example, Dr. Leonardi pointed out that briakinumab had issues with infections and malignancies.   Briakinumab has opportunistic infections; whereas, ustekinumab does not. Additionally, there are a large number of squamous cells carcinomas developed in patients treated with briakinumab. There is a change in squamous cell carcinoma to basal cell carcinoma ratio in briakinumab versus placebo.  This was not seen with ustekinumab.  Therefore, putting the trials using briakinumab and ustekinumab together in a meta-analysis is difficult.

Regarding other differences, looking at the long-term data and only patients who are tolerant of medication in the ustekinumab trials is unfair. Dr. Gordon would argue that if you look at data over time, the retention rate was over 80% over five years in the ustekinumab trials.  He pointed out that the high percentage rate of retention is rare in clinical trials and he doesn’t feel that eliminating a large number of patients is  an issue here.

When you look at 0.11 what does that mean?

Dr. Gordon feels that the P value being 0.11, as presented by Dr. Leonardi, is very significant. If the experiment were redone 100 times, one would expect to find a difference between the intervention and the placebo 89 times out of 100. That is quite significant.

However, we have a P value and a standard for statistical significance for a reason and that is because we need to be stringent about our conclusions and when they get too close together, it can be difficult to draw any final conclusions. It doesn’t say the magnitude of the problem, only that the two populations will be different.

With meta-analyses, there is another problem, and that is when trials are combined, you can have a trial that is the “driver”, i.e., one or two of the trials out of a larger group of trials will drive the results in one direction and everything else will be inconsistent with that; therefore, the validity of the meta-analysis can be called into question. In particular, when you combine drugs that are distinct and have a driver that is utilizing one of the medications, the validity can be questionable.

(Of note, Dr. Gordon is an author on the meta-analysis with Dr. Leonardi and feels that it is the best analysis that we can have)

A recent article in JAMA (August 2011) reported that there are two studies that are the drivers of all of the IL 12/23 data. The first of which is the briakinumab trial, the second of which is the ustekinumab Phase II trials in which the drug was given in a different fashion than it was given in Phase III. In fact, the numbers in the Phase III trials do not appear to have any statistical significance in the occurrence of MACE events. This makes it very difficult to draw conclusions on ustekinumab and MACE events. In fact, ustekinumab, at the doses given during the phase III, does not seem to statistically show effects at all—observationally, less so than anything else that has been seen.

Dr. Leonardi pointed out the initial increase in risk of MACE events with the initiation of treatment and then it levels off.  However, other data presented shows that there are events (randomly) throughout the course of treatment. Regarding the p40 subunit serum levels, there may not be enough information to draw conclusions based on this time course and the multiple events that are seen.

What does Dr. Gordon do for patients on ustekinumab?

Do you warn patients for potential cardiovascular risk?  Yes, patients should be aware of the potential risks.

Do you put patients on aspirin? In general, Dr. Gordon does not put people on aspirin; however, if the patient is at risk and should be on aspirin, then he recommends it. If a patient does not have risk factors, is under 40 and is hypertensive, he does not use aspirin.

Conclusions

This is a very difficult topic and many people have many differing opinions and feelings on it.  The answer regarding ustekinumab is not fully understood.  Regarding briakinumab, Dr. Gordon feels that there is a definite. Only with experience and time will clinicians have the answers regarding IL 12/23 and MACE events.

 

 

 

 

 

 

 

Psoriasis Update: 2012 Part 1

Craig Leonardi, MD

IL-12/23 Safety Issues

Cardiovascular Safety in Psoriatics Using Biologic Drugs.  Does a Signal Exist in the IL12/23 Pathway?

Case Report MACE in a Ustekinumab-Treated Psoriasis Patient

  • 47 year old construction worker
    • Caucasian male
    • Weight: 290 lbs
    • Negative Hx: DM, HTN, Tobacco
  • Psoriasis
    • 20 yr history
    • 15% BSA; PGA: M-S; DLQI: 12
    • No evidence of PsA
    • Past Tx: MTX, Etanercept, Infliximab, Golimumab
  • Current PsO Tx
    • Ustekinumab 45mg x 4 doses à 90mg x 2 doses
    • MTX 15mg SC QWk
    • Folic Acid 1mg QD
    • ASA 81mg QD (* This is something that Dr. Leonardi uses as add-on therapy)
  • Anterior wall MI
    • Normotensive
    • HgB A1C: 6.2
    • LDL-Chol: 108
    • Ejection Fraction: 45%
  • Two stents were placed

The Cardiologist commented: “Young for this type of event given his health status”

The question lies…what is it about this patient and his health status and the drug that he is currently taking, does it give him any protection about MACE events that can occur?

The answer is: no one knows right now and this is a hot debate that we all try to answer as best as we can…

Psoriasis patients have a wide and rich subset of many of the components of the Metabolic Syndrome such as diabetes mellitus, hyperlipidemia, coronary heart disease, and arterial hypertension that has been shown in much of the data.

We know from Dr. Joel Gelfand and colleagues, that our patients with psoriasis are at increased risk for myocardial infarction.

Methotrexate Reduces Incidence of Vascular Diseases in Psoriatics

  • Retrospective VAMC cohort study
    • 7615 patients with psoriasis
    • 6707 patients with rheumatoid arthritis
  • Covariates included age, sex, DM, HTN, dyslipidemia, and certain medications
  • MTX-treated pts had decreased vascular disease risk
    • Better: Low dose vs high dose
    • Best: Combination MTX and folic acid

From the Rheumatologists we have been following patients for many years….

So in treating RA patients with a TNF inhibitor, one could reduce cardiovascular events.

PsO: Risk of MI with anti-TNF therapy

This was a Kaiser Permanente psoriasis cohort of more than 24,000 patients. Patients had an ICD-9 of 696.1 (psoriasis) or 696.0 (PsA) for more than 3 prior visits and no MI prior to 2004 at the start of the study. The anti-TNF cohort was defined as receiving an anti-TNF for greater than 2 consecutive months. The oral/phototherapy cohort was anti-TNF-naïve, received oral/phototherapy for more than 2 consecutive months, and the “mild” cohort received no anti-TNF, oral therapy or phototherapy.  The researchers conducted a multivariate analysis using cardiac risk factors too look at a comparison between anti-TNF and other systemic therapy.

IL12 and 23 Blockade: A New Approach to Treating Psoriasis and Psoriatic Arthritis

There are new therapies currently available to Dermatologists, ustekinumab has been available for about 2 ¼ years; however, it is still a relatively new product. Both ustekinumab (IL-12) and briakinumab (IL-23) both block the p40 subunit.

When you block IL-12, you down-regulate a set a cytokines from a Th1 pathway, including INFy, IL-2 and TNF-alpha.  When you block IL-23, you down-regulate IL-17 alpha, IL-17f, IL-6, TNF-alpha, IL-21 and IL-22.

Function of Th17 Effector Cytokines

IL-17a

  • Expressed by memory NK and T cells
  • Increased in psoriatic skin
  • Subcutaneous injection à neutrophilia
  • Enhances inflammation
  • Enhances angiogenesis

IL-22

  • Expressed in high levels by Th17 cells
  • Increased in psoriasis (skin and plasma)
  • Levels correspond to disease activity
  • Induces keratinocyte hyperproliferation (in vivo, in vitro)
  • Stimulates keratinocytes to secrete antimicrobial peptides

 

Both demonstrating positive effects…

Ustekinumab is a high-performing drug for psoriasis patients. One can see, by the data that at week 28, about 71-79% of patients are achieving a PASI 75; this is a huge achievement for these patients. Looking at briakinumab (ABT874), this product seemed to enable patients to achieve at PASI 75 within twelve weeks of treatment. Unfortunately, attached to this positive response was also a safety signal, specifically MACE events that is categorized as cardiac, stroke or death by cardiovascular reasons. There were five MACE events in treated arm and none in the placebo arm. There were also some other troubling issues such as six malignancies, all of which were squamous cell (2 were internal and 4 cutaneous), and again, none in the placebo group and there were five serious infections to one in the placebo arm.  There was an imbalance to MACE events, malignancies and infections as compared to placebo. This is problematic as with malignancies as to the fact that no one knows as to why the cancer issues showed up some early in this trial.  MACE events are very significant as it defies the conventional thought regarding systemic inflammation and cardiovascular disease—we expect that when inflammation is decreased, the cardiovascular status should improve; however, with that in mind, when looking back at the ustekinumab SAEs that occurred within the first twelve weeks, one can see an imbalance in the placebo versus the treated arms. One can see angina, stoke, congestive cardiomyopathy (and death), and CABG. Dr Leonardi points out that angina and coronary artery bypass are not necessarily MACE events, they would not actually qualify. All in all, between the phase II and phase III trials for ustekinumab there were five MACE events, an equal number to that of the briakinumab events.

What about infection rates?

When you’re looking at a subset of the drugs or patients who are doing well, you see positive results; however, that’s the not the case for the patients who are not doing well on drug.

Summary of MACE Events in Randomized Controlled PSO Trials (meta-analysis)

Dr Leonardi, along with a group of other concerned dermatologists, statisticians, cytokine biologists and cardiologists convened for a meeting. The goal of this meeting was to analyze the data from the published studies regarding the MACE events that occurred among these patients. The group was able to tabulate the data that exist among the IL-12/23 drugs and the TNF antagonists.

When looking at the data, one can see that there was one case of MACE reported in an adalimumab trial and there was another MACE event reported in an etanercept trial (one on treatment; one on placebo in the TNF antagonist trials). When looking at the IL-12/23 drugs, there are ten versus zero; that is a pretty compelling number.  Many argue that this is due to an unhealthy status of the patients; however, this is not seen with the placebo arm, so that question still remains.

What are the statistics?

*There was no statistical significance among the TNF trials

In both drugs, we see a flurry of activity and then it flattens out over time; therefore, the kinetics of both drugs seems to be similar.

We expect MACE events to DECREASE when systemic inflammatory diseases are treated. Why are we seeing a paradoxical increase in MACE events?

Dr Leonardi’s hypothesis tells us that when we look at serum p40 subunit levels following a single dose of ustekinumab, they peek at about 3-3 ½ weeks, and then they settle down over a 32-week period. Therefore, one can see an increase in drug concentration and in binding of the ligand, p40, during the initial period. The target for this drug is in the tissue (inflamed) skin; i.e., it is expected to pull p40, presumably in the form of IL-12 or IL-23, into the serum and perhaps it interacts with an atherosclerotic plaque. It could also be an increase in IL-12 or IL-23 delivery, indirectly, to atherosclerotic plaques. Literature also suggests that p40 subunits can also have a form of bioactivity if they dimerize. It is also possible that it is an expected biologic activity of the drug. It is unlikely; however, that it is due to patient selection bias, as it is not apparent in patients taking placebo.

Conclusions

IL 12/23 Antagonists: Possible Next Steps

  • Obtain complete datasets from Abbott, Centocor
  • Time-to-event details
  • Patient details (risk factors, basic demographics)
  • Pharmacokinetic profiles
  • All ischemic non-MACE events
  • Analysis of p40, IL12, IL23 serum levels during long term therapy
  • Routine and frequent safety updates (especially in relevant psoriasis populations)
  • Determine whether a pattern of comorbidities exists
  • FDA, EMA input based on review of both datasets

Ustekinumab: Recommendations for Use (Dr Leonardi’s Approach)

  • Consider all options when selecting a biologic tx
  • Know that psoriatics typically have multiple cardiac risk factors
  • Consider starting with low (45mg) dose regardless of pt weight
  • Consider adding ASA 81mg QD
  • Await further analysis (FDA, EMA, Abbott, Centocor)
  • Remember that all new drugs are ‘new’

 IL 12/23 Blockers and CV Risk? (Dr Leonardi’s Opinion)

Pros

  • Probable class effect demonstrated in 2 drugs
  • Equal number of MACE events in 1st 12 weeks (DBPC)
  • Increased rate of MACE in the early part of trials
  • Rate of MACE appears to decrease over time
  • Peak serum concentrations of drug correspond to MACE activity (ustekinumab)

Cons

  • Unanticipated finding
  • P= 0.11
    • Not significant at traditional levels (0.05)
    • Underpowered study for CV events
    • 11% probability that results (10 vs 0) is “by chance”

 

 

 

 

 

Inflammatory Disease in Little Kids

Lawrence F. Eichenfield, MD

In this presentation, Dr Eichenfield discusses inflammatory diseases in children in a clinically relevant manner.  Dr Eichenfield provides a review of the pathogenesis of atopic dermatitis (AD), the role of filaggrin, and allergies in AD.  He also updated us on new findings in pediatric psoriasis.

Atopic Dermatitis (AD)

When reviewing AD, it is important to consider the issues noted below:

  • Barrier dysfunction
  • Infection
  • Inflammation
  • Allergy
  • Itching

PEARL:  The phenotype, associated with ichtyhosis vulgaris, is associated with peanut allergy. Be careful when you take your atopic child or nephew to a baseball game or circus.

Filaggrin Insufficiency

Filaggrin haploinsufficiency is defined as a 50% reduction in the expression of the filaggrin protein, an important functional protein that influences epidermal function.   Filaggrin mutations are associated with decreased filaggrin production, as well as higher rates of development of associated conditions.  The odds ratios for the risk of peanut allergy, asthma, or atopic dermatitis with filaggrin mutations are greater as compared to individuals without filaggrin mutations. The odds ratios for atopic dermatitis and asthma, from meta-analyses involving several thousand patients display that FLG mutations confer an overall risk of asthma of 1.5, but this risk is restricted to patients with atopic dermatitis. The odds ratio for the complex phenotype of asthma plus atopic dermatitis is 3.3. The odds ratio for peanut allergy is 5.3 and is based on data from a single study.  Of interest is that there is no filaggrin in the mucosal surfaces of the mouth or esophagus so it likely that the peanut allergy is the result of epicutaneous sensitization. (Irvine AD, McLean I, Leung DYM. N Engl J Med 2011;365:1315-27)

The question is how does filaggrin deficiency affect the skin barrier?  The answer is that decrease in filaggrin expression increases skin permeability, increases skin pH, decreases natural moisturizing factor and decreases cell-to-cell cohesion impacting barrier function.

Of importance, even in individuals who do not have the filaggrin mutation, there is decreased filaggrin byproducts in actively, inflamed eczema.

Atopic dermatitis can be triggered by the chronic exposure of barrier-disrupted skin to percutaneous antigens due to abnormalities in filaggrin; however, only 30-50% have FLG mutations and most outgrow AD. 40% of patients with FLG-null alleles do not get AD. Therefore, there are other factors that influence AD development and course other than just filaggrin.

What are some of the traditional approaches and targeted therapies?

  • Moisturizing after bathing
  • Use of emollients
  • Targeted barrier repair products

These measures are part of maintenance care for all patients, and primary intervention for mild AD in infants

What are some of the things that can be done for the prevention of Atopic Dermatitis? In the past, physicians have considered:

  • Formula
  • Maternal diet
  • Infant diet
  • Allergen avoidance (both environmental and food)
  • Probiotics
  • Prebiotics

So far, none of strategies mentioned above have solid data for their efficacy.

Several international studies are currently looking at the role of early intervention in skin care in order to stop AD.

Anti-inflammatory therapy

There are typically two ways that a dermatologist handles a child with AD.

1. “As low as you can go (or just above where they were)”, i.e., the least strong topical steroid that can be used and 2: “Stronger steroids” to start, with tapering to less potent corticosteroids as the AD improves. Both of these approaches are reasonable. Many clinicians tend to “mix and match” the topical corticosteroids with the non-steroid topicals and utilize wet wraps with topical corticosteroids in patients with more difficult remissions.

Over the next few years, dermatologists will be seeing some new agents for the treatment of AD. These therapies include selective glucocoid agonist receptor stimulants, histamine 4 blockers and other molecules as well.

Wet Wrap Dressing with TCS Use: Effective, Rapid Control of Severe AD

Dawn Davis and colleagues conducted a study on wet wrap dressing in 218 patients who were hospitalized. The mean age of application was 6 years (2 months-17 years), the mean duration of hospital stay was 3.61 days (range 1-16) and all patients showed improvement.  45% of the patients showed 75-100% improvement; 38% of patients showed 50-75% improvement and 6% of patients showed a 25-50% improvement.

There are many methods to the use of wet wrap with topical corticosteroids and the benefits are clearly demonstrated.

Another important therapeutic intervention for AD, now recognized internationally, is education.   A struggle that clinicians face, is how to educate patients within the limited time of busy office settings, so that patients understand how to utilize their medicines, while also managing their fears with respect to the utilization of steroids and medications.

Pediatric Pearls and Conclusions

  • Prescribe specific amounts
  • Assess quantities of time
  • Discuss strengths and safety
  • Use Educational and Instructional materials
  • Handouts, Web-sites, Video training modules www.eczemacenter.org
  • Follow-up soon!  Studies show that there is more chance that they will follow their regimen and will have better clinical outcomes

Maintenance Therapy

  • Emollients alone? In 30-40% of infants, this may be sufficient
  • Intermittent corticosteroids
  • TCIs (delicate areas, persistent, frequently recurrent)
  • Targeted-Barrier-repair products
  • BRING THEM BACK when they’ll still be under control

What about the patients who are better, but not great or have persistent, frequent flaring?

  • Ask about feeding practices, atopic history
  • Establish aggressive maintenance plan
    • Intermittent CS and/or TCIs
    • Assess sleep and itching as endpoints
    • Trials of TBRP (targeted barrier repair products) and/or emollients
    • Consider anti-infectives, bleach baths/products
    • Check growth, infection history, differential diagnosis
    • Consider allergy referral

TCI Safety Information

There has been new information collected with regards to TCI safety, but the data have not yet been published. The FDA Pediatric Advisory Committee evaluated emerging data as part of a routine evaluation of TCI safety and use.   They looked at the epidemiology studies, the clinical studies, Data Safety Monitoring Boards and Post-marketing surveillance/Adverse Events Reporting System (AERS). The FDA found that there is no evidence of an association between TCIs and B-cell lymphomas but because of the limited data available, one cannot necessarily form conclusions from the published literature. The FDA also said that a literature review suggests a possible association between topical tacrolimus use and an increased risk of T-cell lymphoma.  The T-cell lymphoma association, however, may be due to use of the TCI in individuals reported as having eczema prior to the diagnosis of cutaneous T-cell lymphoma (known as protopathic effect).

It is important to remember that these are retrospective studies; so drawing conclusions can be difficult for the clinician.

An epidemiologic survey published by Tennis and Gelfand came to the same conclusions, i.e., there is little to no evidence of an increased risk of lymphomas overall or specific sub-types of lymphoma with topical TCI use and there is no evidence indicating that melanoma or non-melanoma skin cancer is associated with topical TCI use.

Microbes

Dr Eichenfield poses the following question to the audience…

Staph aureus in patients with atopic dermatitis:

A.Is more likely to be MRSA than staph in infections in non-atopics

B.is less common than streptococcal infection

C.Is less likely to be MRSA than staph in infections in non-atopics

D.None of the above

MRSA and Atopic Dermatitis

Dermatologists should be aware that atopics have lower rates of MRSA infection than community-acquired staph infections. From an ecological perspective, the question is “does MSSA protect against MRSA?”

Translation into Clinical Practice

Bleach Baths and Alternatives*

  • ¼ to ½ cup for ½ to full tub of standard bleach (6%).
    • 5 cup for 40 gallon full tub is 0.005% concentration
    • Dilute Na hypochlorite and hypochlorous acid (Aurstat: marketed with HylatopicPlus)*
    • Na Hypochlorite body wash (CLn BodyWash)*

The AD market has responded to this and there are now at least two alternatives currently available to bleach baths. One of which is a tube of sodium hypochlorite and hypochlorous acid and it is paired with a ceramide-containing moisturizer. The other product is available over the internet that is a sodium hypochlorite body wash in a can.

Comorbidities and Atopic Dermatitis

Over the last few years the information available on attention deficit disorder has become much stronger as it relates to AD. Clinicians should know that behavioral disorders have been talked about in patients with AD for over 20 years. According to a recent publication in JAMA, as well as an unpublished large database survey study, ADD was seen more in younger children with AD and it was dose-dependent, in that, it correlated with the AD, the higher the severity, the more the risk of ADD. Depression was also higher in teens and adults. While there is no evidence to mandate screening, it should be considered.

Food Allergy and Eczema

About a17% of children with mild AD and 30-40% of moderate to severe children have at least one clinically relevant food allergy. However, food allergy testing (skin testing and IgE testing) can create a lot of false positives; in fact, 4 out of 5 tests may give a positive food allergy test yet there is no clinical relevance to the positive test.

(e.g. Milk: 238 of 1000 tested will have false +;  vs. 50 having clinically relevant allergy)

Consider Food allergy testing for moderate to severe, <5 yr old, with food reaction and/or disease resistant to standard topical regimens

Highlights from the Guidelines

The current guidelines suggest that children less than 5 years of age with moderate to severe AD be considered for FA evaluation for milk, egg, peanut, wheat, and soy, if at least one of the following conditions is met:

  • The child has persistent AD in spite of optimized management and topical therapy.
  • The child has a reliable history of an immediate reaction after ingestion of a specific food

Dr Eichenfield feels that it is appropriate to ask about food allergies and if a child has had a food allergy then an EPIPEN or EPIPEN Jr. should be prescribed.

Clinical Pearls for Atopic Dermatitis

  • Great skin care
  • Anti-inflammatory medication as needed, with most care as topical regimens
  • Maintenance care “as needed”
  • Keep regimens simple
  • Educate…in the office, on the net, wherever!
  • If really hard, seek help!

Pediatric Psoriasis

Obesity is a common comorbidity in pediatric patients with psoriasis. This is an important consideration for clinicians and counseling is important; however, this is being studied as to how this will correlate to adult risk. Regarding psoriatic arthritis in children, the most important screening test that dermatologists should remember to ask is about morning stiffness, i.e., arthritis. Pediatric psoriasis is typically treated with topical corticosteroids and Vitamin-D analogues; however, clinicians should not forget the appropriate placement of light therapy (NB-UVB is the most studied), which can be very effective. There are also combination products currently being studied such as Clobetasol/VitD. The National Psoriasis Foundation has a pediatric site that is kid-friendly and provides much needed information and resources.

Systemic treatment is still an ongoing battle with payors. There are no approved systemic treatments for children and adolescents with psoriasis.

In summary, there is a fair amount of new information for both AD and psoriasis and, in the future, hopefully more treatments will become available for pediatric patients.

 

 

New Drugs 2012 Part 2

Ted Rosen, MD & Neal Bhatia, MD

Imiquimod for Actinic Keratosis

There are three doses of imiquimod: 5%. 3.75% and the new 2.5% (which is approved, but not commercially available at this point).  What are their uses? Where does the 2.5% fit in? According to Dr Bhatia:

  • 5% for solid tumors or more aggressive fields?
  • 3.75% cycle therapies for routine or initial courses? It can also probably still be used for solid tumors
  • 2.5% for low-grade maintenance, weaning down from 6 week cycle, or routine for high-responders
  • Alternate among them?
  • Don’t expect any new trials or indications for awhile, so use your own experience

 

Icatibant

Icatibant is a SQ injected bradykinin B2 receptor antagonist, i.e., has a receptor affinity similar to bradykinin. Icatibant inhibits bradykinin, binding the B2 receptor; therefore, resulting in symptomatic relief and modulation of episodic flares of hereditary angioedema (HAE).

The injection is 10 mg per mL and comes as a 3 ml syringe, 25-gauge needle. Icatibant is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older. Pediatric studies are currently underway. Icatibant is dosed at 30 mg injected subcutaneously in the abdomen. If the response is inadequate or symptoms recur, additional injections of 30 mg may be administered at intervals of at least 6 hours. It is important that healthcare providers and patients know not to administer more than 3 injections in 24 hours. Patients may self-administer upon recognition of an HAE attack.

The pivotal FAST-1 and FAST-2 trials studied icatibant and showed that it had a median time to 50% reduction from baseline symptoms ranging from 2.0 to 2.3 hours. Icatibant was approved in 2011 in the US.

Belimumab

The FDA approved Belimumab (BenlystaTM) for the treatment of autoantibody positive systemic lupus erythematosus (SLE) in March 2011. Belimumab is a human monoclonal antibody that is delivered via IV infusion and targets the soluble B lymphocyte stimulator (BLyS) protein.

BLyS was discovered by the Human Genome Sciences program in 1996 and plays a pivotal role in B-cell survival and B-cell proliferation by preventing normally occurring apoptosis.  During a normal immune response to infection, BLyS facilitates more B-cells to survive, proliferate and produce antibodies to fight infection. In many patients with SLE, higher concentrations of BLyS promote increased B-cell survival including the survival of autoreactive B-cells that in turn can mature into autoantibody-producing B-cells. Belimumab does not bind directly to B cells and does not directly deplete B-cell populations but instead binds BLyS.  In doing so belimumab inhibits the survival of autoreactive B-cells and reduces their differentiation into immunoglobulin-producing plasma cells. Belimumab has demonstrated proven efficacy in reducing SLE disease activity.

Azficel-T

Azficel-T is indicated for the improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults. It is an autologous cellular product; in that, it is made especially for patients from their own skin cells which are harvested via punch biopsy which is then shipped to a specialized lab for harvesting and growth of the patient’s fibroblasts. It is best used for acne scarring and nasolabial folds. It is important that dermatologists screen for any hypersensitivity and allergies. It is also important to recognize that this product is not meant for the “impatient” patient, as one cannot see instant results.

In reality, dermatologists should keep in mind that azficel-T is not inexpensive, i.e., $1000-$2000 to create a personalized bank of fibroblasts and each injection session costs between $700 and $1,000; therefore, the total cost may range from $3,100 to $5,000. There have been isolated cases of vasculitis, collagen vascular diseases, and keloids. There is lots of potential for good outcomes as well as mistakes with the use of azficel-T.

 

New Drugs 2012 Part 1

Ted Rosen, MD & Neal Bhatia, MD

New Treatment for Orolabial Herpes

 Acyclovir 5% + Hydrocortisone 1%

This is a cream formulation that was approved in late 2009. It is designed to supplement the anti-viral effect of acyclovir with an anti-inflammatory effect of hydrocortisone. Inflammation may be responsible for some of the signs/symptoms of HSV-1. There is a concern as to whether or not corticosteroids lead to blunted immune response, worsening of lesions, and resistance; however, the answer is no.

This medication is applied five times daily for five days, starting at prodrome if possible. Success parameters demonstrate:

  • Reduced percent ulcerated:  58% v 74%
  • Reduced time to healing: 1.4 days
  • Reduced lesion size: 78 v 155 mm2
  • Reduced duration pain: 1 day
  • Well tolerated; No major AEs
  • No TK mutations or acyclovir resistance

There is still a good reason to use topical therapy. There are few real or potential side effects. There are also no drug-drug interactions to consider. With topical therapy, there are no long-term health concerns. Other reasons to consider topical therapy include:

  • Easily portable, easily started quickly
  • Directed therapy: onto the pathology
  • Patient empowerment
  • Makes sense: wound healing
  • Cost effective
  • It works….sometimes

New Treatment for Post-herpetic Neuralgia (PHN)

PHN is burning and throbbing that persists after zoster that typically occurs after 90. It is most prevalent in patients over 50 and who have pain greater than 4 at onset. PHN occurs in 9-73% of all zoster cases. It is important that healthcare providers understand that PHN can be difficult to treat.

Treating PHN

Dr Rosen prefers to treat his patients with gapapentin 900 to 1800mg/day (divided dose, TID), pregabalin 150-300 mg/day (divided dose, BID), or the new extended release gabapentin once daily, which was approved in October of 2011. With this new product, patients begin with a 30-day “Starter Pack” to titrate, and then switch to 600mg (three as single dose, QD). It is given QD with evening meal (dinner). Data demonstrated over an 11-week study (2 weeks titration, 8 weeks active therapy and 1 week taper off), the drug far surpassed placebo in its ability to reduce pain. 50% of patients achieved > 30% improvement in pain scores and mean decrease of 2.1 on a visual analog pain scale (0-10). The most common side effects included dizziness (11%) followed by somnolence (4.5%), headache (4.2%) and peripheral edema (3.9%) (> edema, > age).

The Capsaicin 8% Patch is another new treatment for PHN. It works through transient stimulation and then the depletion of nociceptive (TRPV1) nerves. Each patch contains 179mg capsaicin. The healthcare provider, who should wear nitrile, not latex gloves, applies the patch. This is important as the capsaicin penetrates latex. Patients are given a local anesthetic prior to its application. Up to four patches can be applied over painful areas for 60 minutes. When removing the patch, healthcare providers should wipe the area with the supplied cleanser. The patch can be used once every 3 months, as need. The most common adverse event seen with the patch is pain at application site (42%). An uncommon but notable AE is an increase in blood pressure; therefore, clinicians should use caution when utilizing this drug in patients with unstable hypertension. The site may be sensitive to heat for several hours after patch removal, and it is Pregnancy category B.

Ketorolac trolamine is a new intranasal spray analgesic used for post-surgery or herpes zoster. It is a metered dose, one spray in each nostril every six hours and is dispensed as a “five pack” for five days of use. One of the major benefits of ketorolac trolamine is that is provides an analgesic effect similar to an opiate without accompanying sedation. (If patients are old or thin, the dose is decreased)

This treatment can facilitate GI ulcer/bleeding and should not be used in patients with a duodenal ulcer or gastric perforation, or patients with a history of GI bleeding. It shouldn’t be used in patients with advanced renal sufficiency or in the third trimester of pregnancy. The most common AE (15%) is transient nasal irritation, which lasts about five minutes; the next most common AE is transient lacrimation (5%).

New Hepatitis C Medications

Dr Rosen points out that, as a dermatologist, one may not administer the medications for HCV; however, a dermatologist may be the one who diagnoses hepatitis C as it is associated with PCT and LP. There are two new oral drugs available, telaprevir and boceprevir. Both of these drugs inhibit NSE-4A, the protease required for viral replication. They are not used as monotherapy (used with ribavirin and peginterferon-alpha). 60-88% of patients on these drugs achieved viral clearance, i.e., no viral RNA detectable 6 months after the last dose. One of the side effects of these products is anal itching and/or anal pain; therefore, as a result these patients may be back in your office.

HPV Vaccinations

Healthcare providers should be aware that HPV affects males as well.  The quadrivalent HPV vaccine has shown to be effective (per protocol) in 90+% of boys and men age nine through twenty-six. It is effective (per protocol) in 74% at preventing anal cancer in MSM when vaccinated at ages 16-26. The vaccine is FDA approved for use in males, ages 9-26 and the Advisory Committee on Immunization Practices now recommends the use of this vaccine in males, as does the American Academy of Pediatrics.

The standard dosing of the quadrivalent HPV vaccine-dosing regimen is 0, 2, and 6 months. It turns out; however, that 0, 3, and 9 months as well as 0, 6 and 12 months was equally effective which is important because many patients tend to miss follow-up dosing.

Cutaneous Oncology: Recent Drug Approvals Part 2

Keith Flaherty, MD & George Martin, MD

Vismodegib (ErivedgeTM) for the Treatment of Advanced Basal Cell Carcinoma (BCC)

Dr Keith Flaherty, an oncologist at MGH, spoke on ErivedgeTM for the treatment of advanced and metastatic BCC.   Historically,  the treatment of patients with advanced BCC with either metastatic or locally advanced disease employed standard chemotherapeutic regimens using agents such as cis-platinum. Reports of success were few and generally limited to individual case reports until the recent FDA approval of Erivedge® a hedgehog pathway inhibitor.

The “hedgehog pathway” (Hh pathway: Figures 1 & 2) and its role in the development of basal cell carcinomas (BCC) has been the subject of intense research over the last decade.  Aberrant activation of the Hh pathway (Figures 3 & 4) has been identified in both hereditary BCC syndrome ie Gorlin syndrome (Basal Cell Nevus Syndrome) as well as sporadic BCCs.  Gorlin syndrome patients carry a germ-line heterozygous mutation in the PTCH gene and are highly predisposed to developing multiple BCCs. Mutations in the PTCH gene (Figure 3), remove its ability to inhibit the Hh pathway through its inhibition of SMO (Smoothened protein).  Approximately 90% of sporadic BCCs have a PTCH gene mutation and an additional 10% of sporadic BCC have activating mutations in the SMO gene (Figure 4), which is downstream of PTCH, and this mutation leads to overstimulation of the Hh pathway.

Vismodegib (Erivedge®) is a hedgehog pathway inhibitor (figure 5), which binds to and inactivates SMO.  Its use is indicated for the treatment of adults with metastatic basal cell carcinoma (mBCC), or with locally advanced basal cell carcinoma (laBCC) that has recurred following surgery or who are not candidates for surgery or radiation.

Dr Flaherty presented data evaluating the safety and efficacy of Erivedge in mBCC and laBCC obtained from an international, single-arm, multi-center, open-label, 2-cohort phase II study involving 104 patients (Erivance BCC/SHH447g). Patients with laBCC either had histologically-confirmed BCC that was unresectable or were not appropriate candidates for surgery: >1 cm or 2 or more recurrences after surgery; curative resection unlikely; anticipated substantial morbidity and/or deformity after surgery.  mBCC patients had histologic confirmation of mBCC and radiographically measurable tumors. The patient demographics are listed in figure 6. Patients received vismodegib 150 mg/day orally until tumor progression or intolerable drug toxicity.

The objective response rates (ORR) were assessed by an independent review facility (IRF) and were 42.9% for laBCC and 30.3% for mBCC.  The median duration of response was 7.6 months and the median progression-free survival was 9.5 months for both cohorts.

The rate of severe toxicities (grade III + IV) for vismodegib is quite low. Mild to moderate toxicity (grades I + II toxicity) seen with vismodegib included fatigue, muscle spasms and dysgeusia (altered taste).

In summary, vismodegib is dramatically effective for BCC treatment in patients with advanced.  Approximately 80% of patients with advanced BCC have regression of disease with 30 – 60% of patients having objective responses.  Now FDA approved for patients with advanced BCC, it will be interesting to see how this drug will be used both therapeutically and in an adjuvant setting in combination with other surgical and non-surgical modalities.

 

 

Cutaneous Oncology: Recent Drug Approvals Part 1

Keith Flaherty, MD & George Martin, MD

The hot topics of discussion at Maui Derm 2012 were January’s FDA approval of two innovative products in the cutaneous oncology arena: (Picato®), ingenol mebutate 0.015% gel and 0.05% gel for the treatment of actinic keratoses (AKs) and Erivedge®  (vismodegib) for the treatment of advanced basal cell carcinoma.  At Maui Derm, Dr Martin discussed the data on Picato® and Dr. Keith Flaherty, an oncologist from MGH, discussed ErivedgeTM.

Ingenol Mebutate (Picato®): 0.015% and 0.05% gel

Ingenol Mebutate is derived from the sap of the plant Euphorbia peplus, a commonly found plant whose sap has been used in traditional medicine for the treatment of a wide variety of skin lesions ranging from warts to skin cancer. The active pharmacologic ingredient, ingenol mebutate (ingenol‐3‐angelate), has been formulated as a field therapy for the treatment of AKs.

Mechanism of Action

Extensive work has been done to determine the mechanism of action of ingenol mebutate.  In high concentrations it induces tumor cell necrosis. It also up-regulates keratinocyte and endothelial cell cytokine and chemokine production presumably via the protein kinase C (PKC) pathway.  In response to ingenol mebutate, IL-8 a neutrophil chemo-attractant is produced in significant quantities by rapidly proliferating keratinocytes and endothelial cells following exposure to ingenol mebutate.  Also upregulated in response to ingenol mebutate is the expression of adhesion molecules ICAM-1 and E-selectin by endothelial cells, which in turn promotes neutrophil migration into the treatment area. In mouse models ingenol mebutate was show to reduce mutated p53 patches of skin in UV irradiated mice compared to placebo.

Two Strengths/Two Dosing Regimens

Ingenol mebutate was approved for the treatment of AKs using two different concentrations employing different dosing regimens. Ingenol mebutate 0.015% gel applied daily for 3 consecutive days was approved for treatment of AKs of the face and scalp. Ingenol mebutate 0.05% gel applied daily for 2 consecutive days was approved for treatment of AKs on the trunk and extremities.

In two multicenter, randomized, parallel-group, double-blind, vehicle controlled pivotal phase III trials the efficacy and safety of ingenol mebutate 0.015% gel applied daily for 3 consecutive days to the face and scalp was evaluated as a field therapy (4-8 AKs in a 25 cm2 area).  Of the treated patients completing both studies, 37% and 47% of drug treated patients achieved 100% clearance compared to 2% and 5% for vehicle controls.  Partial clearance (≥ 75% lesions cleared) was achieved in 60% and 68% of drug treated patients compared to 7% and 8% for vehicle controls.  Median percent lesion reduction for drug treated side were (83.3%) and (86.6%) compared to (0%) and (0%) for vehicle controls.  These clearance rates are comparable or better than currently FDA approved AK field therapies used on the face and scalp. Hypopigmentation and hyperpigmentation were 1%.  No scarring was reported.  There was no systemic absorption of ingenol mebutate above the limit of quantification in blood samples of subjects evaluated.

The efficacy and safety of ingenol mebutate 0.05% gel applied daily for 2 consecutive days (4 – 8 AKs in a 25 cm2 area) to trunk and extremity lesions (arm, back of hand, chest, back, shoulder and leg) was evaluated in two multicenter, randomized, parallel-group, double-blind, vehicle controlled pivotal phase III trials. Of the treated patients completing both studies, 28% and 42% of drug treated patients achieved 100% clearance compared to 5% and 5% for vehicle controls.  Partial clearance ( 75% lesions cleared) was achieved in 44% and 55% of drug treated patients compared to 7% and 7% for vehicle controls.  Median lesion percent reduction for drug treated side were (69%) and (75%) compared to (0%) and (0%) for vehicle controls. Hypopigmentation and hyperpigmentation were ≤1 %. There was no systemic absorption of ingenol mebutate above the limit of quantification in the blood samples of subjects evaluated.

A 12-month follow-up study was performed evaluating patients who completely cleared their lesions during the phase III studies. No recurrent lesions were observed in 46.1% of patients treated on the face or scalp and in 44% of patients treated for trunk and extremity lesions.  The overall reduction in AKs from baseline to 12 months was 87.2% for face and scalp lesions and 86.8% for trunk and extremity lesions

Clinical Pearls

The take home points on both 0.015% and 0.05% gel is that they have comparable or better efficacy in clearing AKs in comparison to currently FDA approved field therapies, produce sustained clearance in 12 month follow-up studies, cause limited downtime (peak inflammation on day 4 for the face/scalp with resolution of scabbing by day 8; peak inflammation on the trunk and extremities by day 4 – 8 with resolution by day 15), achieve excellent patient compliance with the 3 and 2 day application regimens and induce minimal side-effects post therapy in terms of hypopigmentation, hyperpigmentation and scarring.

Immunogenicity

Bruce Strober, MD, PhD

In this presentation, Dr Strober discusses the important concept of immunogenicity as it relates to the management of psoriasis and the use of biologic therapy. There are several factors that lead to the loss of therapeutic response. These factors include drug level reduction, specifically immunogenicity, suboptimal dosing schedules (e.g. etanercept step-down dosing, infliximab every eight weeks and ustekinumab given every 84 days)  and poor patient adherence. Another issue is that of altered pathophysiology of the disease in the face of the therapy applied, i.e., one can see a loss of therapeutic response without immunogenicity.

What is Immunogenicity?

By definition, foreign proteins are immunogenic. Biologic therapies for the treatment of psoriasis are all foreign, even though they are based on natural forming molecules. Immunogenicity requires that a protein has to be more than just “foreign”, i.e., different biologic drugs exhibit different degrees of immunogenicity. Immunogenicity inhibits therapeutic response and may increase risk.

Do Biologic Medications Lose Efficacy When Treating Psoriasis?

Infliximab begins with very high efficacy, PASI 75 scores are nearly 80%; however, after about one year of Q 8 week dosing, one loses about one third of patients who initially achieved a PASI 75. This could be due to pharmacokinetics; however, in part, it is probably due to immunogenicity.

Initially, 100 % of adalimumab responders achieved a score of PASI 75, but after about two years, only three quarters of those patients were still at a PASI 75.

At week 48, 61% and 63% of patients on etanercept achieved a PASI 75; however, at week 96, that number had fallen by 18%.

Ustekinumab also demonstrated a drop-off regarding therapeutic efficacy.

Clinical Pearl-Loss of therapeutic response is part of the issue when treating psoriasis patients with biologic therapies

The Manufacturers of Biologics Acknowledge Immunogencity

 Infliximab

In psoriasis clinical trials, antibodies were observed in 20-36% of patients treated with 5 mg/kg every eight weeks for one year. A higher incidence of antibodies to infliximab was observed in Crohn’s disease patients receiving infliximab after drug free intervals for more than 16 weeks. In psoriatic arthritis studies, patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and infusion reactions, which is an important safety issue. Antibody development was lower among RA and Crohn’s disease patients receiving immunosuppressant therapies such as 6-MP/azathioprine or methotrexate.

Adalimumab

Approximately 5% of RA patients developed low-titer antibodies to adalimumab at least once during one year of treatment, which were neutralizing in vitro. Patients who were treated with concomitant methotrexate had a lower rate of antibody development than patients on adalimumab monotherapy (1% versus 12%). With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. ACR 20 responses are lower among antibody-positive patients than among those patients who are anti-body negative.

Etanercept

Antibodies to the TNF receptor portion or other protein components of etanercept were detected at least once in sera of approximately 6% of adult patients with RA, PsA, AS, or PsO. Antibodies were all non-neutralizing. The percentage of patients testing positive increases with an increase in the duration of study. There was not a correlation of antibody development to clinical response nor were there any adverse events. There was no effect with methotrexate.

Ustekinumab

In Study 1 and Study 2 looking at ustekinumab and immunogenicity, 3-5% of patients, respectively, showed antibodies against drug. 48% to 90% of patients studied were inconclusive. Data presented at a recent EADV meeting demonstrates that immunogenicity against ustekinumab correlates with reduction in response long-term.

Clinical Pearl-More frequent administration of a biologic tends to reduce immunogenicity

Should we care about “neutralizing” vs. “non-neutralizing” antibodies?

Dr Strober feels that dermatologists should really care about whether or not a drug has an antibody raised against it and if so, does the body remove the drug from circulation…?

In patients, antibodies against adalimumab and infliximab usually bind to the antigen (TNF) binding domain; therefore, they “neutralize” the ability of the drug to bind to TNF. Antibodies that are raised against etanercept fall into what’s referred to as the hinge domain that really mediates the linkage between the Fc domain and the TNF receptor domain. So, while they bind to the molecule, they do not neutralize its ability to block TNF, i.e. “non-neutralizing”.

Open Label Studies

Switching to Etanercept after Failure to either Adalimumab or Infliximab for Treatment of RA

This study evaluated 292 patients with rheumatoid arthritis. 203 patients were anti-TNF naïve. 89 of the patients had been previously treated with either infliximab (n=30) or adalimumab (n=59), and then switched to etanercept. 32% of the patients were non-responders since the start of the treatment with either infliximab or adalimumab and 68% of the patients had lost the initial response. Out of the 89 patients who switched to etanercept, 47 patients (53%) had antibodies against adalimumab or infliximab as measured at baseline prior to the start of etanercept treatment. Patients with detectable anti-drug antibodies had significantly lower doses of methotrexate at baseline compared to patients without antibodies (p=0.031).

Patients who were anti-TNF naive were compared to switchers without antibodies and a DAS28 improvement was significantly larger in patients who were anti-TNF naïve after 28 weeks of etanercept treatment. There was no significant difference in the improvement in DAS28 between patients who were TNF naïve compared to switchers with antibodies. The improvement in DAS28 was significantly larger in switchers with anti-drug antibodies compared to switchers without antibodies. This study concludes that altered disease pathophysiology may play a greater role in patients who lose response without showing immunogenicity. Immunogenicity is only part of the equation.

Anti-adalimumab Antibodies are Associated with Lower Adalimumab Concentrations and Treatment Non-response

This was a prospective observational cohort study looking at 121 consecutive RA patients treated with adalimumab and a concomitant DMARD or adalimumab alone. During 28 weeks of follow-up, antibodies were detected in 21 (17%) of patients. Serum adalimumab concentrations in patients with anti-adalimumab antibodies were significantly lower than in patients without these antibodies (median 1.2 mg/l, range 0.0–5.6 vs median 11.0 mg/ l, range 2.0–33.0; p,0.001). Non-responders had anti-adalimumab antibodies significantly more often than good responders (p=0.006).

Higher concentrations correlate with better clinical response

Extent and Clinical Consequences of Antibody Formation Against Adalimumab in Patients with Plaque Psoriasis

This was a prospective observational cohort study looking at 29 psoriasis patients, 17% (5 of 29) also had psoriatic arthritis. Patients were given standard adalimumab dosing (40 mg) every other week after an initial dose of 80 mg and a dose of 40 mg the week thereafter. Adalimumab trough concentration was measured 12 and 24 weeks after the initiation of treatment. This study correlates with the data presented above (RA) in that the lower the concentration of drug, the lower the response and low antibodies to drug demonstrates better clinical response. Three patients used concomitant methotrexate and none of these patients developed antibodies to adalimumab.

There are a lot of data that suggest that methotrexate blocks immunogenicity. There should be no doubt regarding methotrexate and therapeutic efficacy.

Patients Not Responding to Etanercept Show Lower Trough Etanercept Concentrations Compared to Responding Patients

This was a prospective, single center observational cohort study from Amsterdam. The study looked at 292 consecutive patients with active RA who were given a new etanercept prescription. Clinical response and etanercept levels were collected at baseline and after 1, 4 and 6 months of etanercept treatment. Trough serum etanercept levels were measured by ELISA.

The study showed that patients with good clinical response display significantly higher levels of etanercept than patients who were not responding. Anti-etanercept antibodies were measured by 4 different assays and no anti-etanercept antibodies were detected which is a different response from that of infliximab and adalimumab. The absolute differences in etanercept levels between responding and non-responding patients were small. Immunogenicity may not explain the lack of response in RA patients treated with etanercept.

Effect of MTX on Efficacy with Etanercept

When looking at patients who are methotrexate non-responders and who were either given methotrexate with etanercept and then tapered off the methotrexate or continued the methotrexate, it is clear that those who tapered off the methotrexate did not respond as well; therefore, demonstrating that methotrexate has some effect on etanercept response.

A Basic Approach to Moderate to Severe Psoriasis or Psoriatic Arthritis

Healthcare providers should initiate therapy with methotrexate and allow 12 weeks to demonstrate a response. If methotrexate monotherapy is inadequate, a biologic should be added. Dr Strober continues the methotrexate indefinitely because of the data that demonstrates a better clinical response.

Conclusions

  • Biologics should be dosed without interruption and at intervals that make sense with regard to the drug’s half-life.
  • Concomitant MTX (or, possibly, azathioprine) blunts immunogenicity
  • When given with MTX, biologic agents invariably show greater and more durable efficacy, even when MTX is ineffective as monotherapy
  • A sensible practice is to add a biologic therapy to MTX, not vice versa, as once immunogenicity occurs it may be difficult to reverse

 

 

 

 

 

 

 

 

Pediatric Pearls Restrung: Part 2

Sheila Friedlander, Ilona Freiden

Diaper Rashes

1984 was the introduction of a superabsorbent polymer, sodium polyacrylate. It absorbs a lot of water and converts from powder to gel. These diapers also buffer pH, they have a polyethylene film surface, are less irritant, and are better at containing fecal bacteria.

The lesions for diaper rash tend to appear as kissing lesions; in children with more chronic fecal or urinary exposure, the lesions can spread out.

When managing these children, try to address underlying cause of constant exposure to liquid stool. Barrier pastes e.g. Triple paste, Desitin, etc are often helpful. Clinicians should also consider adding an anti-yeast medication e.g. miconazole-zinc oxide paste or nystatin-HC ointment combination. If the child is not responding, re-think the diagnosis.

Pseudoverrucous Papules and Nodules

These are also known as “Granuloma gluteal infantum”. The papulo-nodular eruption is due to chronic irritation, usually with severe chronic fecal or urinary exposure. They can be difficult to treat so clinicians need to address underlying cause, if possible.

Pampers Dry-Max® are a 2010 product and claim to be two times drier and 20% thinner in order to “let them play on!” However, there was a widespread social media outburst (~12,000 members) among mothers who claimed that the diapers caused rashes and even “chemical burns”. A Consumer product safety commission investigated the issues and found that from April through August 2010, CPSC received nearly 4,700 incident reports about diaper rash. Nearly 85 percent of these complaints came in May and then dropped off significantly. The report from September 2010 stated: To date, the review has not identified any specific cause linking Dry Max diapers to diaper rash. However, if parents think Pampers DryMax are causing their child to have a rash, consult the doctor and change to a different diaper.

Vitamin D Delirium and Sunscreen Phobia

Patients are inundated with conflicting information regarding the benefits of the sun and the role of Vitamin D. Obviously, there are clear risks of the sun and there are also risks regarding the agents used for sun protection. Clearly, patients and parents are confused. It is important, as a clinician, to have a cogent message in mind. It’s important to explain the controversies and provide patients/parents with direction.

The sun is a source of Vitamin D; yet, it is also a source of harmful radiation. The spectrums for these two actions overlap and there is no way to separate them.
The AAD & AAP remain steadfast in their recommendations, i.e., vitamin D should be obtained via diet /supplements.

Vitamin D Requirements—IOM Recommendations
Assume no solar production component!

• Babies 0-1 400IU
• Adults 1-70 600 IU
• Adults 70+ 800 IU
• Safe upper limit – 4000 IU
• Why not more? Stones!

Take Home Message:

• Only clear benefit of Vitamin D relates to bone health
• Get your required amount through diet/supplements
• Things are not as bad as we thought in terms of how many people are deficient (IOM)
• There are risks to too much Vitamin D

Sunscreens

Patients are confronted with several different choices when choosing a sunscreen product. The Environmental Working Group – Watchdog has continuing concerns regarding sunscreen ingredients. Organic sunscreens have a hormonal effect and physical sunscreens have a penetration, persistence via ultramicronized nanoparticles. Their newest concern is Retinyl palmitate, a Vitamin A derivative found in many sunscreens. It is a vitamin A relative (retinyl ester) used to fortify food products such as milk, dairy, cereal. In sunscreens, it acts as antioxidant + aesthetic optimizer. In animal models, RP can generate free radicals. The National Toxicology Program selected RP for study, along with aloe vera, nano-titanium dioxide and zinc oxide.

Regarding baby sunscreen, it’s really an effort of trial and error. It is probably best that the baby is not exposed.

It is important to work with your patients and really weigh the benefits against the risks. The projected risk of melanoma in the US in 2015 is one out of fifty. One American dies of melanoma every hour. Clearly, we know that UB radiation exposure plays a role in this. If sunscreen were applied appropriately, we would be better off.

A study in Australia (Green AC, et al.) looked at patients 25 to 75 years of age to measure the effect of five years of sunscreen application and betacarotene on the incidence of BCC and SCC. The group that used the sunscreen had a lower incidence of melanoma (22 versus 11). There was some controversies around this study; however, an editorial in the Journal of Clinical Oncology stated that the P values were of borderline significance, but the hazard ratios showed a 50% reduction—in situ compared to invasive malignant melanoma and a 73% reduction in hazard related to melanoma alone.

Sunscreen Phobia-Summary

• Sun exposure – Modifiable risk factor
• Many studies – positive effect of sunscreen on mole number, some now show direct protective effect for melanoma
• Concerns raised by EWG re: ingredients; all theoretical re: humans
• If you tell people to avoid sun, they may ask you re: Vit D…. be prepared!

Pediatric Pearls Restrung (Part 1)

 

Sheila Friedlander, MD and Ilona Frieden, MD

What’s really new in pediatric dermatology?  In this presentation, Drs. Friedlander and Frieden discussed the latest and greatest in pediatric dermatology.

Beta Blockers & Hemangiomas

Do hemangiomas go away?  Before 2008 and to this day, many treatments can provide modest efficacy, and are best used in growth phase. These treatments include corticosteroids: systemic, intralesional and topical; other systemic agents such as interferon alpha and vincristine; pulsed dye laser and other treatments such as cryotherapy and imiquimod.

A somewhat recent breakthrough was the discovery of the use of propranolol for the treatment of hemangiomas. These data were published in 2008 in The New England Journal of Medicine.  The general consensus among pediatric dermatologists is that this truly is a breakthrough, along the lines of isotretinoin for severe acne and other major treatment breakthroughs.

Propranolol Q & As

Does it work?

There are more than 75 articles published since original report. It has impressive efficacy with more shrinkage of Infantile Hemangiomas (IH) than with prior treatments

Does it ever not work?

Occasionally; Based on the literature, there seems to be about a 5 to 10% failure rate

What is the usual dose?

1-3 mg/k/day divided BID or TID usually 6-12 months

What is the duration of treatment?

That depends on many factors – usually 6-12 months, sometimes longer

Can rebound occur?

YES!  Literature says about 20-25% of time

Can it be efficacious in older children with a fully-grown hemangioma?

There is some evidence for efficacy in older children up to age 3 to 4

What about for other vascular tumors or malformations (Kasabach-Merritt, Lymphatic Malformations)?

Probably NOT

Safety

Regarding the safety of propranolol, there are potential effects on cardiovascular system but bradycardia and hypotension are usually not an issue. There have been some reports of hypoglycemia, which can happen after weeks to months, mostly in the setting of decreased eating/fasting (anticipatory guidance), this is truly a risk that needs to be monitored. Nightmares, GI upset, asthma exacerbation have also been reported. There is a special concern for children with PHACE syndrome regarding arteriopathy/ “demand related potential ischemia”, which could cause a stroke.

There is really no consensus regarding how to best monitor patients on propranolol; however, there is a randomized control trial underway (sponsored by Pierre Favre). Here is how propranolol is used in Dr. Frieden’s practice at UCSF:

  • Less than 3 months hospitalized for 2 days
  • Over 3 months titrate dose up to 2 mg/k/day over 10 days as out-patient with HR measured for beta-blocker effect
  • Detailed instructions to avoid hypoglycemia

How does Propranolol work?

CD34+ EPCs in proliferative stage express angiotensin converting enzyme and angiotensin II receptor-2. An explant model shows EPCs form proliferative blast-like structures in the presence of angiotensin II. The authors hypothesize that the renin-angiotensin system may account for the response to propranolol. (Itinteang et al. J Plast Reconstr Aesthetic Surg 2010; Online early)

Topical Beta Blockers

There are three recent articles regarding the use of Timolol 0.5%. Timolol Gel-Forming Solution BID may be helpful for some superficial IH.  (Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol. 2010 May;146:564-5.; Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol. 2010 Feb;128:255-6.; Khunger N,  Pahwa M. Dramatic response of a large hemifacial infantile hemangioma associated with PHACE syndrome to timolol lotion. Br J Dermatol Dec 15, 2010) The use of topical Timolol can be monitored by looking at systemic effects and the heart rate.

Treating Hemangiomas Current Status

  • A Randomized Control Trial is underway (for the use of propranolol)
  • Physicians must stay in their own comfort zone
  • Currently many are “drifting toward” propranolol as 1st line:
  • Use local consultants to determine the best approach
  • Frank discussion with parents – still use steroids for some patients early in the course
  • Hospitalize (usually 2 days) to initiate propranolol    if < 3 months of age

Warts and Molluscum

Warts and molluscum can be seen as a very important part of the dermatology practice as they are both extremely common. They are often physically benign; however, they can be extremely psychologically debilitating. Parents may become overly invested in a “clean slate”, and parents can really do damage to the child because of the messages they are giving. You, as the dermatologist, must act as the child’s advocate, as not all warts need to be treated because the risk of the treatment may be worse than the psychological damage that it is going on. It is important to consider what the parent feels because that is what the child is hearing.

Algorithm to Approaching Warts

  • Age
  • Extent
  • Cosmetic impact
  • Child’s concern
  • Parent’s concern
  • Prior therapy
  • Topicals (risk/benefit is often the best treatment)
  • Duct tape (with/without salicylic acid)
  • Triple “whammy”
    • Duofilm
    • Transversal
    • Duct tape
  • No success
    • Liquid N2

It is important to provide a handout for these patients detailing a clear description of the products and an explanation as to how to apply the products. It is important to be sure that patients/parents get the sequence right and that they are warned of any potential adverse effects, i.e. blisters, ring wart, scarring, and terror upon your entering the room.

What else can be done?

  • Topical retinoids
    • Beware of irritation and koebnerization
  • Imiquimod – money/insurance coverage & significant irritation
    • Innoculation may improve efficacy
  • 5-fluorouracil – less money, ? more irritation
    • Concerns re blood levels
  • Laser – a really big gun for lots of money
  • Bleomycin – we just don’t use it much in pediatric dermatology

Other Potential Treatments

According to Dr. Friedlander, Cimetidine can be used to buy you some time. There are some positive reports regarding the use of cimetidine. It appears to work better in children, atopics and in conjunction with topicals. The maximum dose is not really known, Dr. Friedlander generally uses up to 1200 mg, occasionally 1600 mg. It is very important to be aware of drug interactions and parents need to be aware of any other therapies that the child is on or prescribed. Some children don’t like the taste of cimetidine and others have experienced nausea while on the therapy. Dr. Friedlander has found that cimetidine works in about 30% of patients.

Candida, the mighty antigen, is currently a favorite. Candida is a highly immunogenic antigen. It augments the immune response and there is empiric and academic data supporting its use (note that in the first studies many of the patients were also on interferon and; therefore, some patients got sick). Candida is used in a variety of ways; many of the experts adhere to the following:

  • Inject undiluted antigen 0.1-0.3 cc per wart, using 30 gauge needle & tuberculin syringe
  • Inject both intradermally & intralesionally
    Maximum dose:  1 cc per session
  • Repeat in 3-4 weeks, generally 3-4 sessions

Candida does have an effect and it is important to beware of the “painful purple digit”. Do not overdo the injections in the periungual distal finger area.  Candin® the brand name for a candida antigen suspension may be obtained from Allermed Laboratories and a generic Candida antigen is also available.

Molluscum

Molluscum is a large brick-shaped virus. A renewed interest in the virus was came about recently due to the threats of biological warfare. The molluscipoxvirus belongs to the group of Poxviruses. It shares with the true Smallpox virus part of its genome, its specific pathogenicity to humans and its classic “brick-shape”. However, the Molluscipoxvirus is strictly localized to the epidermis and invokes a weak immune response compared to the deadly potential of the Orthopoxvirus.

Who gets molluscum?

The vast majority of people who have molluscum in the pediatric dermatology office are less than eight years of age. Most kids will have less than fifteen lesions, generally on the trunk extremities. A question remains as to whether atopic dermatitis patients have more trouble getting rid of the virus…

We know that molluscum will eventually go away, so why would we treat? There are occasional studies in the literature of molluscum spreading in pools and waterparks, so many physicians advise parents not to let their patients bathe with other children. Spread is a big issue. With molluscum, often times you can see infection and pseudo-infection, along with social stigma so there is a problem in having this disease; therefore, it should be treated.

Options for Treatment of Molluscum

Physical treatment includes curettage (mainly in Canada), cryotherapy and the use of keratolytic agents like salicylic acid. Immunotherapy includes candida, imiquimod, cimetidine and cantharidin. Cantharidin is referred to as “a blistering defense of an ancient medicine.”  It used to be a “Beetle-extract” vesicant and can cause intra-epidermal acantholysis.  Lesions treated with cantharidin heal without scarring and the treatment  is mostly painless. There has been a long history in both folk and traditional medicine regarding its use. In 1962, cantharidin lost FDA approval due to failure of its manufacturers to submit data attesting to its efficacy. The FDA interim policy: Cantharidin on “Bulk Substances List” most commonly used as 0.7% proprietary formulation: ‘topical use in the professional office setting only’

It is also important to conduct test sites and be sure that the family is aware of the blistering. Do not use cantharidin on the face.

A retrospective study on cantharidin looked at 537 children with MCV. Cantharidin treatment was used in 300 children with a follow-up phone interview. The results showed 90% clearing and 8% improvement. The average number of treatments was 2.1. There were blistering sites in 92% of the patients. Temporary burning, pain, erythema, and pruritus were seen in 6-37%. Overall, 95% of the parents reported that they would proceed with the treatment again.

Cantharidin is an excellent treatment for molluscum, but usually needs to be purchased from Canada. (www.ABCpharmacy.com)

Summary Warts & Molluscum

  • Candida antigen really is useful for warts
  • You can purchase it easily
  • Molluscum responds nicely to Cantharidin
  • Use the right formulation in the right places
  • Warn the families of risk of blisters & “marks”