Combining Technology for Facial Rejuvenation

Suzanne L. Kilmer, MD

 Clinical Pearls: When Combining Devices with Injectables and Other Devices

In this presentation, Dr Kilmer reviews the techniques for combining the various technologies that are currently available for facial rejuvenation in order to obtain optimal cosmetic improvement for patients.

Dr Kilmer stresses the importance of remembering the 4 Rs:

  • Relax
  • Refill
  • Resurface
  • Redrape

During her initial consult with patients Dr Kilmer discusses the 4 Rs and how the various techniques that she uses in combination for facial rejuvenation can aide in maximizing the outcomes. It is also important, as dermatologists that full disclosure regarding outcomes is presented. Dr Kilmer informs her patients that she does not “have a magic wand or a crystal ball”; therefore, she can’t predict the outcomes of any given patient.

Relax

It is important to relax the skin with a botulinum toxin to keep both the muscles and the skin from moving as much as it otherwise would. If she is going to laser the skin, the results are improved when the skin/muscles are not moving. Dr Kilmer also uses fillers, in conjunction with the toxins and lasers to fill in lines, tighten up the skin and remove brown/red spots.

Clinical Pearl: Never use toxins, lasers, or any other device that can cause significant swelling on the same day. This can result in the toxin migrating to other places where you do not want it.

 Refill-Restore Volume Loss

When using dermal fillers, the objective is to restore volume based on a patient’s specific needs. Fillers can be placed in various areas locally such as the nasolabial folds, marionette lines, deep glabellar rhytids, tear troughs, and the nasal bridge. Fillers can also be used globally in the cheeks and temples.  It is important to remember that there may be a lag time resulting in delayed gratification.

It is very important to keep in mind that one can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed.

If all of these procedures are being done in one patient, Dr Kilmer typically tries to slow down the movement and relax the muscles. Discussions with patients regarding the overall procedures that could be performed are very important. Considerations for patients include money, down time, and fear factor, i.e., what are they willing to go through? In these consultations, Dr Kilmer and her patients decide on the best approach based upon their issues and the issues that she sees.

 Combination Treatments

  • Best order
    • Start with toxins to stop movement and relax muscles.
      • Relax frown, smile and lip lines when doing facial rejuvenation
      • Relax DAOs and neck bands when doing fillers, tightening or resurfacing
        • May need less filler and patients are happy sooner with tightening devices
        • Then filler or laser depending on a patient’s specific needs (and ability for downtime)
          • Never do toxins and lasers that cause swelling at the same time because toxins can migrate.
          • Typically end with filler if still needed after toxins and laser
            • Sometimes the combination will diminish the need for filler
            • If able to tell that will need volume, can do before or at same time as laser

Caveats of Combining Treatments

  • Toxin with Filler
    • Can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed
    • Toxin with Laser
      • Can’t do toxin same day as Fractional lasers – swelling can lead to migration
      • Can do botulinum toxin with PDL, IPL, CoolTouch, SmoothBeam, Thermage, Titan
      • Filler with Laser
        • Can do filler same day but do first if doing fractional as swelling can mask need for filler.
        • Fractional with nonablative RF tightening
          • Same day – do Thermage 1st because need intact skin but when you do the fractional laser the skin may still be sensitive. (wait an hour or two because the sensation will decrease with time)

Combining Fractional with other Devices

  • Fractional laser with other lasers/txs
    • Lentigines – pre-tx QS lasers, KTPs, etc
    • AKs – LN2
    • Sebaceous hyperplasia, nevi – 1450 nm
    • Vascular lesions – PDL, KTP, Alex
    • Downtime from other treatment is simultaneous and shortened
    • Fractional resurfacing with ablative resurfacing
      • Almost always do fully ablative to upper eyelids
        • More tightening/more predictable – do inner canthi
  • Can ablate/sculpt edges of scars, upper lip lines and elevated lesions
  • Ablative fractional and nonablative fractional resurfacing
    • Nonablative fractional to face, ablative to neck for more tightening /crepiness – useful for those with hx ablative resurfacing/chemical peels/dermabrasion

Other Combination Therapy

Other combination therapy includes fat loss and tissue tightening (CoolSculpting + RF tissue tightening, lipo/laser lipo + tissue tightening); Fractionated RF ((ePRime) + QS/KTP/PDL); and Fractionated US ((Ulthera) + QS/KTP/PDL).

Now that the 4Rs have been implemented, dermatologists need to be particularly aware of reassessing. Combination treatments may minimize the need for other treatments; therefore, increasing the interval for maintenance. For example, one can decrease the need for the amount and frequency of dermal fillers and one can conduct fewer fractional treatments when lentigines are specifically targeted. There may also be the possibility of foregoing vascular laser treatment if the fractional laser used to treat facial vessels was sufficient. Patient concerns should be addressed, i.e., were his/her expectations met? Is there anything new on the patient that has become noticeable since the initial treatment needs have been performed and met? Normally, with time, additional needs will become apparent.

 Summary

In summary, botulinum toxins, fillers and lasers can be used synergistically to minimize the signs and sun damage and aging. To produce the optimal results, expertise in the techniques are required, one should use the best possible modalities and watching and treating for any possible complications is imperative. Combining these modalities may obviate the need for more invasive procedures.

Managing Pemphigus and Pemphigoid: How to Avoid Getting Sued

John J. Zone, MD

In general, Dermatologists see very few blistering diseases. Therefore, managing these autoimmune conditions can often be a challenge in practice.  Dr Zone, an expert in the field of autoimmune blistering diseases, discusses these conditions and optimal strategies for managing these patients from his perspective.

Dr Zone came upon this topic because over the years he has managed a large number of people with both pemphigus and pemphigoid. He always asks himself “what would I do if I was sitting here?”

Virtually, all medications for the treatment of pemphigus and pemphigoid are used off’-label.

 

Case Study 1

In this first case, we can see a lot of acnatholysis and one would assume that it looks like pemphigus.

The above picture shows the direct immunoflourescence, the epidermis is at the top and is totally black.

This case was actually Hailey Hailey disease; therefore, histology alone does not make a diagnosis. According to Dr Zone, treating people on the basis of histology alone is a mistake.

Pemphigus- How do I biopsy people?

Biopsy of the wrong location for direct immunofluorescence is the single greatest problem that is seen in the specimens that are received. Dr Zone would not biopsy in the crusty area; he would biopsy the clinically normal appearing skin (see circle above) near the lesion. That is where one would find the classical cell surface antibody of pemphigus.


Dr Zone also sees a lot of mucosal pemphigus and pemphigoid. Again, it is important to biopsy the normal appearing mucous membrane immediately adjacent to the lesion. There is antibody all around the lesion so there is no need to get involved in in areas with intense inflammation that disrupt the antibody deposition pattern.


Ocular and Esophageal Pemphigoid

In the case of ocular pemphigoid (above), it is important to biopsy the reddish area NOT the bands of scar tissue called symblepharon that are usually negative on immunofluorescence. This should be done by an ophthalmologist.

Clinical Pearl- Dr Zone believes that rituximab should be used as initial therapy for ocular pemphigoid. Dr Zone has seen seven patients who have gone blind from this disease. Dermatologists should biopsy for direct Immunofluorescence if considering immunobullous disease. It is imperative that the biopsy is performed on clinically normal appearing skin adjacent to a lesion. 

 Pemphigus Antigens

Pemphigus foliaceus  (PF) and pemphigus vulgaris (PV) have different desmoglein antigens. The PF antigen is Dsg 1 and the PV antigen is Dsg 3, both of which are calcium-dependent adherence molecules. Desmoglein causes epithelial cells to stick one to another. Dr Zone finds that these antibody levels correlate extremely well with disease activity.  (see figure below)

In this case, Dr Zone treated this patient with azathioprine; however, he wasn’t fully responding.  The  “dip” in antibody levels reflects plasmapheresis. From there, he stopped the azathioprine and the patient was started on CellCept and the levels went up. Dr Zone, remembering that azathioprine induces thiopurine methyl transferase and patients become resistant to the drug, went back to azathioprine at very large doses, to the point of leucopenia, and eventually the patient went into remission.

These levels allow Dr Zone to predict how the patient is responding to therapy.

This (above) case represents a case where the antibodies were presumably against non-pathogenic epitopes.  Dr. Zone used plasmapheresis at the beginning of her clinical presentation (seen in the antibody titer drop)  In this particular case the high titer antibodies were likely against non pathogenic epitopes, and the patient went into remission without a corresponding decrease in antibody levels.

Indirect Immunofluorescence (IIF). Dr. Zone commented that the pemphigus antibody titers on IIF were found to correlate roughly with disease activity however the correlation with clinical activity was not as good as we now see with the ELISA technique. IIF has low accuracy and reproducibility .

Clinical Pearl- Dermatologists should biopsy for direct Immunofluorescence if  they are considering immunobullous disease. Biopsy clinically normal appearing skin adjacent to a lesion. It is important to monitor response with serial antibody level.

Pemphigoid

For antigen identification it is important testing using salt-split skin or ELISA.  This allows identification of specific antibodies that can then be used as an index of response to therapy. BP180(BPAg2) is the most common antigen and can be quantified using ELISA.

This patient’s BP180 antibody levels correlated very well with her disease activity.

Several studies have shown the correlation of disease activity with these antibodies.

Why is this important to test for antibodies?

Research has suggested that ant-epiligrin (laminin 332)  usually found in mucous membrane pemphigoid has a strong association with cancer. In a study of 35 patients with laminin V (332) mucous membrane pemphigoid there were 10 solitary solid cancers. There was a temporal association (14 months before or after the onset of the tumor in 9 out of 10 patients). The control groups indicated a relative risk of 15.4 (5.7-33.6). Ascertainment bias and treatment bias are unlikely because of time course. If a patient’s antibody goes the dermal side of salt split skin on indirect immunoflourescence, and binds to laminin 332 on immunoblot, that patient has a one in three chance of having cancer.

Type VII Collagen

The epidermolysis bullosa acquisita antigen (type VII collagen), which is present in the skin, is also present in the wall of the normal human colon. Research has shown that type VII collagen antibodies are associated with Crohns disease.  What does this mean? If you have antibodies to type VII collagen and epidermolysis bullosa acquisita (IgG antibodies that go to the dermal side of salt split skin on indirect immunoflourescence ) then you have a very significant chance of having Crohn’s disease or ulcerative colitis. If Dr Zone finds out that these people have antibodies to type VII collagen, then he screens them for Crohn’s and ulcerative colitis .

Clinical Pearls- Biopsy for direct Immunofluorescence if considering immunobullous disease; Biopsy clinically normal appearing skin adjacent to a lesion; Identify antigen if possible; Monitor response with serial antibody levels

Dr Zone prefers a topical steroidal therapy to control mild disease, especially in the mouth, and little to no systemic steroids. Dr Zone has found that over the years, systemic steroids have caused more problems to patients. If systemic steroids are required, Dr Zone suggests starting patients on a bisphosphonate, prior to starting the steroids, possibly alendronate (70 mg/wk). Patients should also be started on an H2 blocker or a proton pump inhibitor, the risk of gastritis is very high and it is very real.  A study from the New England Journal of Medicine looked at the comparison of oral and topical corticosteroids in elderly patients with bullous pemphigoid. Since the elderly have a low tolerance for oral corticosteroids the researchers evaluated whether potent topical steroids could decrease mortality and morbidity while controlling disease. Topical steroids were associated with significantly fewer problems with infection, diabetes and psychiatric symptoms.

The above table illustrates all the more reason to utilize topical steroids.

Dr Zone’s Algorithm for the Treatment of Pemphigoid

The dose for doxycycline (if tetracycline is not available) is 100 mg PO BID and niacinamide is 500 mg PO BID. This can be used effectively in mild pemphigoid.

Rituximab should be for any ocular or esophageal pemphigoid. For moderate and severe pemphigus rituximab has a definite benefit and Dr. Zone uses it in this clinical situation.

Rituximab and its Use in Autoimmune Disorders

  • Vaccinations before hand for pneumococcus, influenza, DPT boost 4 weeks earlier if possible
  • Stop immunosuppressives if possible (may have increased complications when used in conjunction with rituximab)
  • Premedicate with steroids and antihistamines to minimize infusion reactions
  • Dosing: 375g/m2 weekly x 4
  • OR 1000mg twice – 2 weeks apart (dosing most often used by rheumatologists)

A study by Joly, et al in the New England Journal of Medicine looked at a single cycle of rituximab for the treatment of severe pemphigus vulgaris in resistant patients (14 PV and 7 PF). The patients received a single cycle of rituximab, 18 of the 21 patients were in complete remission at 3 months and 2 of the 21 patients were in complete remission by 12 months. 9 patients experienced a relapse at 12 months and 2 of the patients required a second cycle. 8 of the 21 patients required no systemic therapy afterward. The Dsg antibody levels correlated with treatment response.

In another study looking at rituximab and autoimmune disorders, the researchers found that serious infections do not appear to be substantially increased but isolated reports are bothersome. Progressive Multifocal Leukoencephalopathy in non-HIV autoimmune patients treated with rituximab has created a significant concern.  Their total serum IgG was not significantly lowered.  When studying rituximab for patients with refractory mucous membrane pemphigoid, Le Roux-Villet et al, looked at 25 patients given 1 or 2 cycles of rituximab (375 mg/m2 weekly for 4 weeks). There were complete responses in all affected sites (ocular and/or extraocular) in 17 patients (68%) by a median time of 12 weeks after the first cycle and 5 additional patients responded completely after a second cycle, yielding an 88% complete response rate. 9 of the 10 patients became noninflammatory within a mean of 10 weeks. Severe infection occurred in 3 patients (12%) who developed severe infectious complications, 2 (8%) died; they had been receiving concomitant conventional immunosuppressants and high-dose corticosteroids. The immunosuppressants were discontinued in all other patients and no other infections were observed. 10 patients experienced a relapse after a mean of 4 (range, 1-16) months after achieving a complete response and were re-treated.

In 2009, Jones, et al published a multicenter survey of ritxumab therapy for refractory anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA vasculitis) in Arthritis and Rheumatism. 49 of the 65 patients (75%) achieved complete remission. 15 of the 65 (23%) achieved a partial response and 1 (2%) had no response. The median time to remission was 2 months (range, 1-5 months). Immunosuppressive therapy was withdrawn in 37 of 60 patients (62%). 28 of 49 patients experienced a relapse (median 11.5 months) and B cell return preceded the relapse in 14 of 27 patients (52%).  Serious adverse events seemed to be associated with the underlying disease so it is important to remember that the underlying disease is still a problem for several months. 46 SAEs occurred in 25 patients, and some patients experienced more than 1 SAE. Most patients received immunosuppression either immediately before (37) or during (14) rituximab therapy.  This study was reviewed to allow understanding of potential side effects of rituximab independent of the presence of pemphigus or pemphigoid.

Take Home Points

  • Make certain of the diagnosis
    • DIF and serology
    • Identify specific antigen whenever possible and follow antibody levels
    • Minimize systemic steroids
      • Use bone and stomach protection
      • Rituximab for severe disease
        • Sooner rather than later
        • Rituximab is the best initial treatment in ocular pemphigoid
        • The underlying disease is still a problem for months
        • Beware of simultaneous immunosuppressive therapy

 

 

The future of personalized medicine could be monoclonal antibodies that are directed against antigen specific B cells. Dr Zone feels that we will see a lot more of this over the years to come.

Inflammatory Diseases in Little Kids: Part 2

Pediatric Psoriasis

Lawrence F. Eichenfield, MD

Obesity appears to be a common comorbidity in pediatric patients with psoriasis.   It is uncertain if the cardiovascular risks seen in adults with psoriasis is fundamentally related to obesity, skin inflammation, or other factors.  It is reasonable to discuss these issues with families of children with psoriasis, though much research is needed about long-term risks and modifying them.

Regarding psoriatic arthritis (PsA) in children, consider asking children with psoriasis about morning stiffness, as this can be a sign of PsA.  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.  The National Psoriasis Foundation has a pediatric site that is kid-friendly and provides much needed information and resources.

Systemic treatment is appropriate for severe psoriasis in children and adolescents, though it can be much work to have third party payers cover the costs of systemic therapies including biologic agents as there are no specifically approved systemic treatments for children and adolescents with psoriasis.

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

 

 

Inflammatory Diseases in Little Kids: Part 1

Inflammatory Disease in Little Kids

Lawrence F. Eichenfield, MD

 

In this presentation, Dr. Eichenfield discussed inflammatory diseases in children in a clinically relevant manner.  Dr. Eichenfield provided 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

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 a 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 are 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 fillaggrin; 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 as well as other molecules.

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 patients 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 while they are still 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

New information has been 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 posed 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.ir

Comorbidities and Atopic Dermatitis

Over the last few years atopic dermatitis has been associated with higher rates of attention deficit disorder and other mental health disorders.  Recent evaluation of a large healthcare database displayed higher rates of ADD in individuals with atopic dermatitis as compared to those without atopic dermatitis, with evidence of higher rates proportionate to severity of ADD.   Depression was also higher in teens and adults with AD.  While there is may not be enough evidence to mandate screening of atopic dermatitis patients, clinicians should be aware of the association.

Food Allergy and Eczema

About 17% of children with mild AD and 30-40% of moderate to severe children have at least one clinically relevant food allergy.  Food allergy testing (skin testing and IgE testing), however, yields many false positive tests; in fact, it is estimated that 4 out of 5 positive tests may not be associated with true food allergy, but only with IgE sensitization (e.g. Milk: 238 of 1000 tested will have false + ;  vs. 50 having clinically relevant allergy). 

Highlights from the NIH Food Allergy 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; 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!

Diet and Acne & Rosacea

Diet and Acne & Rosacea
Alan Shalita, MD

In this presentation, Dr Shalita discusses the role of one’s diet and its relationship to acne and rosacea. Unfortunately, there is not a lot of information about diet and acne; however, there is a tremendous amount of interest in this subject. Dr Whitney Bowe conducted various aspects of this review, during the time she spent at SUNY Downstate with Dr Shalita.

With regards to rosacea, recent research by Dr. Richard Gallo and co-workers suggests an important role for innate immunity. Patients should avoid foods that cause vasodilatation, e.g. spicy, hot, etc. This has not been demonstrated in clinical trials; however, Dr Shalita feels it is something that should be studied.

Acne and Diet
Historically, any food that teenagers enjoyed were said to provoke or aggravate acne, e.g. chocolate, sodas, french fries, other candy. We know that the common denominator was that all of these foods were rich in sugars. In the 1970’s, Fulton et al conducted a study looking at chocolate bars versus control bars (carob), and they found no difference, i.e., both had same sugar and fatty acid content. The glycemic index between both bars was about the same. The researchers concluded that chocolate does not cause acne.

Dr Anderson studied 27 students assigned to consume chocolate, peanuts, milk or coca cola for one week. He, too, found no relationship to acne; however, the study was too short, underpowered, there were no lesion counts and no statistics.

In 1931, published in the British Journal of Dermatology, Dr Campbell showed that there was impaired glucose tolerance in patients with acne. In 1951, Dr Belisario, who published research in the Australian Journal of Dermatology, found that acne patients should avoid excessive carbohydrates and food that was high in sugar. Unfortunately, these reports were largely ignored. More recently, the relationship between diet and acne has been called back into question. It appears that carbohydrates and dairy products are considered by some to be the “real offenders.”
Researchers are examining the glycemic index and the glycemic load of various foods.

Examples of Low and High Glycemic Foods

In more recent studies, Dr Cordain et al, in 2002, examined 1300 subjects in Kitavan Islanders of Papua New Guinea or Ache hunter-gatherers of Paraguay. The researchers found no acne among the subjects. The reason, they feel, is due to diets low in carbohydrates and low glycemic loads. There are ways to criticize this study, in that, there were no controls and perhaps this group is not genetically predisposed to acne. Nonetheless, their conclusions led them to believe that the western diet may lead to hyperinsulinemia resulting in hormonal effects on acne.

A studied conducted in Australia by Dr Smith among students with acne found a positive correlation between glycemic index and acne; yet, a study by Dr Kaymak et al, in Turkey found no relationship in acne patients with a high carbohydrate load versus those on a low carbohydrate diet.

Dr Brian Berman, at the University of Miami, conducted a preliminary study looking at the South Beach Diet. In a survey, individuals who were on the South Beach Diet claimed to have had less acne.

It is important for Dermatologists to remember that a true low-carbohydrate diet can be very difficult to follow and requires very careful monitoring. Patients may benefit from food diaries and reminders. Dr Shalita mentions that he has seen a failure in compliance among the Caribbean population at Downstate because they do not want to give up certain foods.

Many believe in the effect of dairy on acne because of the hormones; however, it may very well be due to the sugar in the diary products. In 2005, a paper published in JAAD, showed the correlation between dairy products and acne. Dr Shalita believes that it may be due to the sugar content but this has not been confirmed.

There are other dietary factors that have been studied such as zinc. Dr Shalita conducted a study many years ago looking at whether or not zinc could be beneficial in acne. The study looked at students in a reform school in Hartford, CT. It was a placebo washout study and demonstrated that after one month of placebo there was a 50% improvement, so the question is could they have gotten better if they had taken zinc? They did not.

Vitamin A, when taken in high doses, can have the same effect as isotretinoin. No one has established whether or not fish oil and antioxidants have an effect on acne.

In conclusion, there may very well be a role for diet and acne, but at this point we do not know what it is. Dr Shalita suspects that it is related to the glycemic index of foods, but further studies are needed.

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.