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”

How to Start a Walk-in Dermatology Clinic

Dale Westrom, MD, PhD

Why did Dr. Westrom start his walk-in clinic? In 2007, Dr. Westrom read an article by Jack Resneck stating that it was easier to see a dermatologist for Botox® than a changing mole. Dr. Westrom who felt that the article reflected very poorly on our profession took this article very seriously.

Dr. Westrom practices with four dermatologists and a nurse practitioner.  He typically sees six patients per hour, so he and his office manager decided that he would stop at 3:45 and open the walk-in clinic from 4:00-5:00. Dr Westrom’s practice averages about 15 patients per session. (4 days a week in one office and 3 days a week in another office) In the walk-in clinic, he tends to see more new patients and more cash-paying patients.

The walk-in clinic would best be characterized as “speed derm”.  The key to its success is making a timely and accurate diagnosis, treating the skin condition or doing a biopsy and then setting up any necessary follow-up visit and moving onto the next patient. The urgent dermatology care clinic is not for patients with complex problems requiring a lengthy consultation.  This point is emphasized to referring physicians/clinics and to patients who sign in.  “This is a great way to build one’s practice through new patients and retaining current patients,” added Dr. Westrom. The clinic works well for patients who have irregular schedules and cannot necessarily plan several weeks out as well as for those patients who recognize that their problem “can’t wait” to be seen.

The patients who come into Dr. Westrom’s clinic  receive a notice explaining that “the purpose of this clinic is to evaluate and treat single urgent skin problems, e.g. changing or new growths, infections, severe rashes, etc.   The intention of this clinic is to detect skin cancers early, treat infections before they spread, and control rapidly developing rashes. Patients will be seen in the order that their paperwork has been completed and the chart is “put up”. “First chart up…. first seen”.  Understandably, established patients will usually have most of their paperwork completed before they sign in so they may be seen before someone ahead of them on the list while that person’s paperwork is being completed.  Everyone who signs in by the end of the scheduled clinic hours will be seen, no matter how long it takes.  Because of the urgent nature of their clinic and the fact that it is being conducted at the end of the day, no HMO patients will be seen without a referral in hand unless they sign a waiver and agree to pay privately (no retroactive referrals will be accepted).”

In a walk-in clinic, patients will be seen on a first ready/first served basis. It is important that the staff understand that during the walk-in clinic, no appointments may be scheduled. When running a walk-in clinic it is important for you and your staff to consider the variety of insurance reimbursement profiles regarding procedures.  Staff training and standardizing procedures are extremely important with walk-in clinics.

The walk-in clinic has been publicized via announcements to patients and other healthcare facilities, the yellow pages, and online.  Dr. Westrom noted that the vast majority of patients who are treated at his urgent dermatology clinic are very polite and appreciative.

 

 

 

Acne: Pathogenesis Revisited

Panelists: James Del Rosso, MD, Alan Shalita, MD, Guy Webster, MD, PhD

For decades the pathogenesis of acne has centered on the formation of the microcomedones as the initiating event followed by an inflammatory cascade. This dogma is now being questioned in a “chicken vs. egg” scenario as being raised as to whether the microcomedone came first or was it precipitated by inflammation that came first.  Data coming out of the lab of Sewon Kang has taken a close look at the issue of what initiates the acne process.  In their work using immunohistochemical and histologic methods, they looked at patients with active acne lesions, normal skin in acne patients and compared them to a control group of people without acne. It was found that in acne patients there appeared a population of inflammatory cells with an absence of neutrophils in the majority of the locations that were evaluated.  This inflammation appeared before the development of hyperkeratinization and microcomedone formation indicating that the microcomedone might not be the initiating lesion. Dr. Kang’s group tracked the development of acne lesions and they found that about three out of ten of the lesions developed into an inflammatory lesion without a visible comedonal lesion.

The take home point is that when looking at an acne patient even normal appearing skin may be harboring inflammation in the follicle that can lead to follicular hyperkeratosis and microcomedone formation so it is important to treat the entire acne prone area proactively and possibly more aggressively.

Case Study

A 33 year-old Asian female presents with a several year history of late onset facial acne and had “clear skin as a teen”.  Her acne has been poorly responsive to treatment with over-the-counter medications as well as topical BPO gel and 0.025% tretinoin cream (“irritates my sensitive skin”) and only modestly response to a 3-month course of oral doxycycline.  She notes some flaring around menses. Her frustration led her to stop all meds and she is not on oral contraception and has two children.

It was noted by the panel that this age group of women have a high level of frustration regarding their acne and several management issues need to be considered including pregnancy.  These “issues” include resistance to the idea of taking oral antibiotics, oral contraceptives and potentially oral medications like spironolactone. Skin sensitivity is also clearly an issue patients such as this one.

Topical Formulations for this Patient Subset

Data for tretinoin 0.05% aqueous gel show that the percent of patients reporting adverse reactions over the 12-week treatment period experienced significantly less incidence of skin related adverse events than with tretinoin microsphere gel 0.1%.

Other topical retinoids available for use with lower potential for cutaneous irritation include Tretinoin Microsphere Gel 0.04%, Adapalene Lotion 0.1%, and Adapalene Gel 0.3%.

Data looking at Clindamycin/Tretinoin 0.025% Gel over one year show that the researchers did see patient improvement increased over time. The percentage of patients with “clear” or “almost clear” skin increased with longer use of CLIN/RA Gel. 57% of patients had “clear” or “almost clear” skin at 12 months. The majority of the patients (78%) were being treated with CLIN/RA Gel as monotherapy; 22% were receiving one or more products (oral antibiotics [12%]; topical therapy [9%]; and isotretinoin [<1%]).

One important consideration is that of P. acnes and antibiotic resistance. Results from a 16-week single-center, double-blind, randomized, parallel-group study of 79 patients with acne who used either a 1% clindamycin/5% BPO gel or clindamycin 1% gel alone show that the combination gel reduced total mean baseline P. acnes count by 99% at week 4, and this was maintained throughout the study. In the clindamycin monotherapy group, the total mean bacterial count was reduced by 87.9% at week 16. Clindamycin-resistant P. acnes counts remained at or below baseline values with the combination gel throughout the treatment while they increased to >1600% of baseline by week 16 with clindamycin monotherapy (P=0.018 vs. combination gel). In addition, drug-resistant, coagulase-negative staphylococci were increased to > 3500% of baseline by week 16. (P<0.001)

A pooled data analysis from pivotal studies stratified by gender looked at male and female patients aged 12 and older with facial acne vulgaris who were randomized to receive either topical dapsone gel (n = 1453; 48% male/52% female) or vehicle gel (n = 1445; 47% male/53% female). The results show that females tended to have better results than males, in both treatment arms. The researchers have not broken the study down by age at this point, nor can they confirm that the results were related to better adherence/compliance.

Hormonal Therapy for Post-teen Acne

Spironolactone is highly effective in post-teenage acne in females. The majority of patients will do well at or below 100mg/day. It is important that clinicians realize that this therapy is highly individualized based upon what dose works best for each patient. Spironolactone can also be used in combination with other topical treatments and oral antibiotics. Safety considerations for oral spironolactone include pregnancy plans and any underlying disorders such as PCOS or endocrinopathies, a risk for hyperkalemia (e.g., use of ACE inhibitors, cardiac disease, diabetes), high intake of K+ containing sports drinks and any significant or potential drug interactions.  There is a question as whether or not clinicians should monitor serum K+ levels. Generally it is not needed, provided there are no risk factors; however, that is the decision of the individual clinician. The general consensus regarding breast cancer history and oral spironolactone is that there does not appear to be a risk; yet, there is no definitive answer about that at this point.

 

Update on Topical Therapies:

The panel discussed vehicle selection, active ingredients, combination regimens, regimens for application/sequencing, and long term data. The major players in the topical therapy playing field today are benzoyl peroxide (BP), retinoids, and clindaymycin (1%). Combination therapy provides incremental improvement and tolerability is based upon selecting products with favorable vehicles.

Can Benzoyl Peroxide reduce comedonal acne lesions?

Yes, and sometimes, markedly.  Sometimes, using BP can give patients a “jump-start” to getting a quicker effect against comedonal lesions.

Is Benzoyl Peroxide 2.5 Enough?

Yes, but it depends largely on the formulation’s ability to deliver the BPO. Combining multiple therapies can provide patients with a faster and greater response. Several studies have demonstrated this benefit.

Studies have shown that Clindamycin has a therapeutic benefit. A thorough literature reviewof five recent studies (N>2000)2 have shown a relative benefit in combination with other agents and it adds to efficacy of benzoyl peroxide/retinoid.

Optimal Oral Antibiotic Use for Acne

Dermatologists prescribe less than 1% of all oral antibiotics, but dermatologists do prescribe 20% of the oral tetracyclines for treating acne and rosacea. Doxycycline and minocycline are the two most commonly prescribed.  Oral antibiotics are used to augment the therapeutic benefit and to speed up the response for moderate -to-severe acne vulgaris, especially for inflammatory lesions. Reduction of P. acnes correlates with therapeutic benefit.

It is important to remember that doxycycline has reported adverse events of serious ulcerations and esophagitis, so it is extremely important to remind your patients to take this medication with large glasses of water and not before reclining. Patient education is key to the therapeutic success of this drug. Minocycline does have a higher risk of drug-induced hypersensitivity however a few cases that have also been reported with doxycycline. Both doxycycline and minocycline have a “grandfathered” approval for acne by the FDA.

 

 

 

 

 

 

 

Drug-Induced SCLE-An Update

Rick Sontheimer, MD

In his presentation, Dr Sontheimer summarized recent observations characterizing drug-induced SCLE (DI-SCLE).  In 1977 he and Jim Gilliam co-authored along with the seminal paper on SCLE.  Dr. Sontheimer suggests that when a physician sees a new SCLE patient it is important to ask whether it is idiopathic SCLE or is this a drug-induced form of the disease.  If the dermatologist can pinpoint the drug causing the condition, an internist or family physician, for example, could stop the drug or prescribe a different drug in a different class of medication, which should result in resolution of the rash and symptoms.

 

The idea that SCLE could be drug-induced was introduced in the mid 1980s in a paper reporting five patients whose otherwise typical Ro/SS-A autoantibody (+) SCLE skin lesions appeared after starting HCTZ & resolved upon discontinuing the HCTZ. Ro/SS-A antibody persisted in all except one patient after SCLE skin lesion resolution and one patient was re-challenged with a thiazide-related diuretic with the reappearance of SCLE skin disease activity that resolved after the initial drug discontinuation.

 

Dr. Sontheimer co-authored a recent paper on the subject of DI-SCLE.   (Lowe, G., et al  A Systematic Review of  Drug-Induced Subacute Subacute Cutaneous Lupus Erythematosus Brit J Dermatol 2010:1365-2133)   Data were abstracted prospectively from 117 articles published up to August 2009.  The authors addressed 8 key questions pertaining to clinical and immunologic issues. They found these patients to be, on average, 15 years older than the typical patients, which, may not actually be all that surprising in that, older patients are more likely to be on more medications. The triggering drug classes are below in Figure 1.

There were marked differences among the various triggering drug classes regarding the length of incubation before the rash/symptoms resulted and time to resolution of the DI-SCLE following cessation of the triggering drug. The cardiovascular drugs seemed to have longest incubation period from 6 months up to 5 years. The anti-fungal drug, terbinafine, had a mean incubation time of 5.1 weeks (29 cases) and 1 case with griseofulvin had an incubation time of 2 weeks. The chemotherapy drugs had an incubation time of days to weeks. It is important to remember that the DI-SCLE didn’t occur in patients until after about 2 weeks and in some cases even longer. The research found that RO/SS-A and La/SS-B antibodies remain present after the resolution of DI-SCLE.

There are several interesting reports on the kinetics of autoimmunity and systemic LE. The Oklahoma Medical Research Foundation conducted a study utilizing the military blood bank. The researchers analyzed antibody levels in blood samples taken prior to the individual developing SLE. Approximately 70% of these individuals, who eventually developed SLE, had RO antibody 5 years prior. The idea here is that there is loss of tolerance to auto-antigens that slowly builds up over time, the autoimmune response matures to a point that it either becomes associated with the development of clinical disease in SLE or these antibodies and their immune complexes are involved in creating the clinical phenomenon.

 

The study also found that histone autoantibodies were, in general, not associated with DI-SCLE unlike drug-induced SLE.  There were no data available to answer whether patients who have experienced DI-SCLE have a subsequent risk for developing idiopathic SLE or Sjogren’s syndrome (SjS). The data were also not available to show the pathogenesis of DI-SCLE. Dr. Sontheimer mentioned that a large number of the drugs recognized to trigger SCLE are photosensitizers known to induce photosensitizing skin reactions without associated lupus-like autoimmunity.

What is the optimal medical management of DI-SCLE? Dermatologists should identify and coordinate with the patient’s internist or FP discontinuation of the triggering drug. It is important to remember that it will probably take 6 to 8 weeks before one can determine whether or not the SCLE was due to a specific drug because it takes that amount of time for the drug to “leave” a patient’s system. DI-SCLE can be treated the same as idiopathic SCLE and clinicians should continue to follow-up on the development of SLE/SjS.

In summary, Dr Sontheimer raises the question of drug-induced SCLE versus drug-precipitated SCLE; he feels it is more the latter. The prognosis for subsequent SLE/SjS development is uncertain and there is a need for a biomarker of drug class triggering SCLE considering the setting of poly-pharmacy and conundrums that clinicians face.

 

 

 

Treatment of Cutaneous LE

The fundamental principles behind the treatment of Cutaneous LE and even Systemic LE have not changed much over the past 50-60 years. Basic principles of sun avoidance/broad spectrum UV protection are mandatory in these patients.   Local treatment may include topical steroids/TCIs.  Systemic therapies are introduced depending on the patient medical status with a stepwise progression from hydroxychloroquine, hydroxychloroquine +chloroquine, chloroquine + quinacrine; retinoids, dapsone, thalidomide; MTX, azathioprine, cyclosporine and mycophenylate.

Management of the “difficult to treat” patient often involves an experimental approach.   According to Dr. Sontheimer, monoclonal antibodies that neutralize class 1 interferon, i.e., interferon-alpha activity have been studied in SLE patients who had skin lesions. They were able to follow the skin while they treated the patients so that they could see clinical improvement in addition to looking at laboratory parameters and skin biopsies. Preliminary data suggests that this approach of modulating the pathologic up-regulation of interferon-alpha in the skin could be of clinical benefit.

Other approaches are currently being explored for various refractory forms of cutaneous LE.  These include TNF-inhibition, phosphodiesterase 4 inhibition, IFN-gamma interfering antibodies and small molecule inhibitors CXCR3 receptors.

In conclusion, it is important that dermatologists have a strong knowledge base of these conditions and an understanding of the optimal approaches to treating the conditions and are aware of some of the recent advances currently being studied.

Filler Complications

Joel Cohen, MD; Director, About Skin Dermatology and DermSurgery; Englewood and Lonetree, Colorado

Dermatologists across the country are using dermal fillers on a daily basis and the products available in the US are believed to be safe and effective provided that they are used correctly. In his presentation, Dr. Joel Cohen discussed the importance of understanding, avoiding and managing dermal filler complications. Filler complications can be stratified into something that doesn’t look very aesthetic when it is superficially or inappropriately placed to situations involving skin necrosis and infection. Regarding aesthetics, Dr. Cohen commented that unfortunately many patients are still walking around with features due to inappropriate use of dermal fillers, which can create an artificial look. This has resulted in patients tending to shy away from using fillers. Dermatologists need to be aware of the agents available and what has been reported as well as different injection techniques.

The key for clinicians, with regards to dermal fillers, is to make things appear natural. Dr. Steve Mandy wrote a review in April 2007 in Dermatological Surgery which reviewed the lip and how important is to place the filler in the right area so that it looks natural.

Injecting the Infra-Orbital Area

Many people prefer different agents to be used in this area and it is important to keep in mind that, in general, this is a very deep injection. If one is to inject superficially, then there is a risk to having the appearance of nodules. There are various hyaluronidase agents available, for example, Vitrase, Amphadase, compounded hyaluronidase, and Hylenex (human hyaluronidase that is currently off the market) . Most of these products are of animal origin, so it is important to do a skin test.

Other issues regarding superficial injection include Artecoll and Artefill. Research has shown that there was not consistency in the particle size of Artecoll; therefore, they were easily ingested which could lead to fibrosis. Some people have had great experiences with Artefill as there is much more consistency in the particle size.

Radiesse (calcium hydroxyappetite) became available in 2003/2004, and many clinicians initially believed that it could be used anywhere.  However, we have learned that it can’t be used in the lips. Sculptra (poly-L-lactic acid) has shown great results as a volumizing dermal filler for the cheeks.  As is the case with all dermal fillers the key to success is knowing how it should be injected.  Careful attention needs to be paid to reconstitution time, volume of injection per location, and the proper injection depth. Sculptra requires longer reconstitution times (at least eight hours prior); higher volume reconstitution, i.e., mix the solution with 5+ cc of sterile water and add 1 cc 1% lidocaine prior to injection; and, inject deeper, i.e., into high fat. It is also important to be careful to avoid injecting precipitate at the end of the syringe. Following these simple points will help in avoiding SQ papules.

Dr. Cohen and others wrote a protocal on the management of visible granulomas following periorbital injection of Poly-L-Lactic Acid in Plastic and Reconstructive Surgery.

Bruising and swelling happens to many patients. It is unfortunate, but it does happen from time to time. There are some things that patients can avoid, such aspirin. Patients on anticoagulants also have to be managed; however, it can be done. There is also a whole list of vitamins that can potentially interfere with bleeding; so again, something to keep in mind.  Clinicians need to be realistic with their patients, so that can expect some bruising and/or swelling which may last up to ten days. It is really important to talk with your patients prior to the procedure.

What can patients do to minimize bruising and what to do when it occurs?

Dr. Kevin Smith wrote an article on the role of ice. Not only will ice decrease pain, it also decreases the bruising and swelling. There are also agents that patients can rub directly onto their skin. Topical Arnica has not proven to be very effective however, oral Arnica may also help regarding swelling and bruising. What is most practical and most helpful solution to resolving bruising quickly in Dr Cohen’s experience is to use a pulsed-dye laser to treat bruising.

Filler Bruising: Treatment with PDL
At 2 days post-filler

  • PDL
  • 7.5 J
  • 6 ms
  • 10 mm spot 1

There is really about a two-day window to treat patients who experience significant bruising. There are also other devices that can be used such as IPL, which is done at short pulse durations (10 ms).

Injection speed is something else that clinicians need to consider.  A clinical trial with Glogau, et al, they found that if healthcare providers inject quickly, it could actually lead to more bruising and swelling (about .3 cc per minute). The study also found that a fan-like injection leads to more bruising and swelling.

Dermatologists need to be aware of potential infection, as it can occur. Treatment includes I & D of the suspected infection, culturing the material, and initiating oral antibiotics.

Necrosis is another important issue to be aware of. There are certain areas that clinicians must pay a particular interest in, e.g. the glabella. It is important to watch the skin as you inject. You should aim superficial and medial, and aspirate. Regarding treatment of a pending area of necrosis if you identify sudden blanching of the skin following injection is to immediately apply warm gauze, repeatedly tap the injected area, apply nitro paste to the treatment site immediately while the patient isin the office and heparin treatment (low MW, SQ). Regarding impending necrosis, hyaluronidase in multiple stabs along and perhaps into the adjacent artery has shown to be a novel treatment. It is very important as a healthcare provider to intervene immediately and not “wait and see what happens” in the cases of impending necrosis.

Sudden blindness has also been reported with different injectable agents around the eyes. Healthcare providers should inject shallow in this area and be extremely careful, keeping the facial arteries in mind.

The risk of sensitivity with the newer agents is extremely low.

In conclusion, clinicians must pay careful attention to the injection site area, take all precautions, and talk to their patients in order to set realist expectations.

  1. Karen JH, Hale EK, Geronemus RG. A simple solution to the common problem Ecchymosis. Arch Dermatol. 2010;146(1):94-95.

Update in the Management of Rosacea

Panelists: James DelRosso, MD; Alan Shalita, MD; Guy Webster, MD, PhD

The diagnosis of rosacea is based upon clinical findings; there are no specific diagnostic tests. The National Rosacea Society Expert Committee on the classification and staging of rosacea has developed provisional diagnostic guidelines for rosacea.1

The guidelines recommend the presence of one or more of the following primary features:

  • Flushing (transient erythema)
  • Non-transient erythema
  • Papules and pustules
  • Telangiectasia

In addition, one or more of the following secondary features often appear with the primary features listed above, although can occur independently in some patients:

  • Burning or stinging
  • Plaque
  • Dry appearance and scale
  • Edema
  • Ocular manifestations
  • Peripheral location
  • Phymatous changes

 

 

 

 

 

Case 1

The panel was presented with the case of a 41 year old white female with a 6-7 year history of waxing/waning facial redness that waxes and wanes and is associated with red bumps and pustules on the nose, cheeks and forehead.  She has “sensitive skin” which is often dry and flaky. Her skin improved on an oral antibiotic for a respiratory infection. She is seeing you to “get rid of the condition”.

It is important to identify the subtype of the disease as that will help dictate the response to treatment. Clinicians should recognize that these patients have increased transepidermal water loss (TEWL) from the central face. Dermatologists need to understand the importance of appropriate skin care in order to address the symptoms and, ultimately reduce the baseline symptoms. Studies have demonstrated that the skin characteristics of patients with rosacea show that about half of the patients scale and become itchy, about one third of the patients experience stinging and burning and these patients do not always have seborrheic dermatitis.

Etiology of Rosacea

The etiology of rosacea is unknown, although research suggests that symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Studies have shown that patients with rosacea express abnormally high levels of cathelicidin in their facial skin and the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme in the epidermis.2

Therapeutic Options: Topical Agents for the Treatment of Rosacea

 Metronidazole works through the inhibition of ROS generation from neutrophils. Azelaic Acid also works through the inhibition of ROS generation from neutrophils. Azelaic Acid also has decreased KLK-5 activity (serine protease activity); therefore,  decreasing the cathelicidin. It also downregulates the Toll-like receptor 2 (TLR2), similar to topical retinoids.

Retinoids also have a variety of ways in which they can modulate the disease, for instance they work through the inhibition of ROS generation from neutrophils and also have the downregulation of TLR2 and modulation of MMP activities, i.e., repair of dermal matrix degradation.

The tetracycline derivatives have a variety of down-regulating properties that appear to help with rosacea. They reduce inflammatory cytokines: IL-1b, IL-6, and TNF-1-a. They inhibit the serine protease activation of catheclicidin. They inhibit MMPs collagenase-8, -13, gelatinase -2, -9, elastase -12 and pro MMP activation and protect TIMP. Tetracyclines also inhibit nitric oxide activity and the arachidonic acid pathway.

Data on minocycline show the suppression of serene protease activity. Specifically, when patients were on minocylcine, the serene protease activity decreased, when they stopped it increased, and when they went back on the minocycline, it again decreased. (Yamasaki et al. Nature Medicine (2007) Aug 13 (8) 975-80)

As far as oral therapies for the treatment of rosacea, the tetracyclines are used; however, they are not FDA approved and there is reason to believe that dermatologists only need to use the subantimicrobial doses in order to garner the anti-inflammatory effect. These doses have widespread use and years of clinical experience. There are multiple pharmacokinetic and microbiologic studies. They are FDA-approved with large pivotal trials. Data exists with regards to the combination with topical therapy. Their efficacy is comparable to doxycycline 100 mg daily and there are potential safety advantages.

With the use of doxycycline (40mg Extended Release, QD) once can see demonstrated efficacy in papulopustular rosacea, there is a lack of antibiotic effect, efficacy is the same as that of doxycycline 100mg/QD, and there is a favorable safety profile. One 12-week study looking at doxycycline 40mg demonstrated that by week 4, close to half of the patients achieved clear or near-clear skin and by week 12, about 75% of the patients achieved clear or near-clear skin. The data were similar to that of patients utilizing add-on therapy in addition to doxycycline.

In conclusion, healthcare providers should be aware that there are a lot of data that show the efficacy of these agents for the management of papulopustular rosacea.

When comparing doxycycline 100mg to doxycycline 40mg, the effects were essentially the same based on one trial. Patients do not need to be exposed to changing their bacterial flora unnecessarily by starting with this treatment first, and; therefore, patients are not exposed at an antibiotic effect.

Case 2

The second case presented to the panel was a 42 year-old White female presents with a 7 year history of central facial (nose/malar eminences/chin) redness which waxed and waned in intensity over the years but is now persistently red There is central facial predominance.  She does not relate ever having any “red bumps” or “pus bumps” developing on her face, including during flares.  She has “sensitive skin”. She occasionally complains of itching and burning. She is interested in the correct diagnosis and treatment. Her health history is unremarkable otherwise.

Medical Treatments for the Redness of Rosacea

Erthematotalngiectatic rosacea (ETR) is more common than papulopustular rosacea. Available therapies include topical agents, such as metronidazole, azelaic acid, and oral agents such as the tetracyclines all of which improve primarily perilesional erythema. These products can occasionally help patients with their rosacea, but the background redness type does not always respond very well.  The critical issue is the presence of persistent telangiectatic mats in the affected areas.  The telangiectasias can be reduced when treated with laser/light devices.  Topical vasoconstrictors that can be used to reduce erythema (Oxymetazoline and Brimonidine) are in clinical trials and have shown excellent clincial responses during these clinical trials.

 

References:

1. Wilkin, J, Dahl, M, Detmar, M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 2002; 46:584.

2. Yamasaki K, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. 2007. Nat Med;13(8)975-980.