New Drugs 2012 Part 2

Ted Rosen, MD & Neal Bhatia, MD

Imiquimod for Actinic Keratosis

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

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

 

Icatibant

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

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

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

Belimumab

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

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

Azficel-T

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

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

 

New Drugs 2012 Part 1

Ted Rosen, MD & Neal Bhatia, MD

New Treatment for Orolabial Herpes

 Acyclovir 5% + Hydrocortisone 1%

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

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

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

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

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

New Treatment for Post-herpetic Neuralgia (PHN)

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

Treating PHN

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

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

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

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

New Hepatitis C Medications

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

HPV Vaccinations

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

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

Cutaneous Oncology: Recent Drug Approvals Part 2

Keith Flaherty, MD & George Martin, MD

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

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

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

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

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

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

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

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

 

 

Cutaneous Oncology: Recent Drug Approvals Part 1

Keith Flaherty, MD & George Martin, MD

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

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

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

Mechanism of Action

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

Two Strengths/Two Dosing Regimens

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

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

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

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

Clinical Pearls

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

Immunogenicity

Bruce Strober, MD, PhD

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

What is Immunogenicity?

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

Do Biologic Medications Lose Efficacy When Treating Psoriasis?

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

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

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

Ustekinumab also demonstrated a drop-off regarding therapeutic efficacy.

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

The Manufacturers of Biologics Acknowledge Immunogencity

 Infliximab

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

Adalimumab

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

Etanercept

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

Ustekinumab

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

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

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

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

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

Open Label Studies

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

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

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

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

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

Higher concentrations correlate with better clinical response

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

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

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

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

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

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

Effect of MTX on Efficacy with Etanercept

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

A Basic Approach to Moderate to Severe Psoriasis or Psoriatic Arthritis

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

Conclusions

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

 

 

 

 

 

 

 

 

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.

Anti-IL12/23p40 Antibodies in the Treatment of Psoriasis and Psoriatic Arthritis

Craig Leonardi, MD

The much anticipated introduction ustekinumab (Stelara®) for the treatment of moderate to severe psoriasis came about in 2010.  This fully humanized monoclonal antibody directed against the p40 subunit of IL 12 and 23 has demonstrated in phase II and III studies that it is a “high performance” drug: fast acting, long duration of action and great efficacy.  However, according to Craig Leonardi, MD, a principal investigator for ustekinumab, there appears to be a potential cardiovascular safety signal which came in the form of MACE events (Major Adverse Cardiovascular Events ie myocardial infarction, stroke and sudden death).  These MACE events appear to be a “class effect” as it is also found in the other anti p40 antibody briakinumab, which is in phase III development.  When both phase II and III data were analyzed for both anti-IL12/23 blockers there were 10 MACE events in the 3,100 drug treated patients and none in the 1,400 placebo treated control group. Because these studies are not powered to demonstrate statistical significance of this small but finite signal none was found.   It should be noted that MACE events do not encompass other cardiovascular signals such as angina, coronary bypass surgery or TIAs. The incidence of these non-MACE events is unknown.  This MACE safety signal has not found in the numerous trials involving thousands of moderate to severe psoriasis patients who received anti-TNF therapies who presumably have the same metabolic risk factors for MACE events.  Comparator groups such as those found in the Framingham study population really do not apply. Drug study populations preselect for healthy patients.  The placebo-controlled group is still the best comparator group and there were at least 1,400 patients in that group for both.

Dr Leonardi pointed out that MACE events occur early in the course of the drug therapy, usually within the first 8 months and level off.  Speculation regarding a mechanism for the MACE events would likely involve some form of plaque disruption. There is some independent investigational data that demonstrate a significant rise (a 13-fold increase) in serum p40 levels at week 12 which decrease back to baseline by 8 months after injection of these anti- p40 molecules.  This finding seems counter intuitive to what one would expect after introducing an antibody against p40 cytokines.   The elevation likely comes from an intracellular reservoir that enters into the serum over a period of time. Interestingly, the course of p40 subunits in the serum roughly parallels the development of MACE events. It is known that p40 can dimerize and become pro-inflammatory which if we continue on our speculator path could lead to plaque disruption and a MACE event.

Briakinumab’s application to the FDA for approval has been pulled and in July of 2011 Abbott halted all clinical trials involving briakinumab pending further evaluation of MACE events. Additionally there are many questions to be answered including regarding briakinumab’s early SAE’s such as infections  cutaneous and systemic squamous cell carcinomas reported in the first 28 weeks following the introduction of the drug in study patients.

Unlike the history behind TNF inhibitors which had long-term safety profile in the rheumatology and gastrointestinal field the IL 12/23 blockers are new and dermatology specific. In light of the current cardiovascular signal where does ustekinumab fit in our therapeutic tool box for psoriasis patients?

Dr. Leonardi’s Recommendations:  It should be understood that this is a “class effect” of the IL 12/23 blockers not observed in analysis of TNF inhibitor safety data.  Consider all options when selecting a biologic therapy.  Patients with moderate to severe psoriasis typically have cardiac risk factors.  Consider starting with a low dose regardless of the patient’s weight.  Although there is not data to support its use consider starting a patient on 81 mg of ASA.  Await further analysis of the safety data. Unlike the anti TNF therapies that came to us from rheumatology and gastroenterology, the IL 12/23 blockers have no point of reference.  Scientific analysis of the p40, IL 12 and IL 23 serum levels during long term treatment.

To add to Dr. Leonardi’s recommendations, in my patients with early signs of psoriatic arthritis such as enthesitis (inflammation of the insertions of ligaments and tendons into bone) with possible early join involvement I still favor the use of anti-TNF therapy when considering a biologic agent because of their longstanding efficacy in psoriasis patients with early signs of psoriatic arthritis.

Post Maui Derm Footnotes:

Since Dr. Leonardi’s presentation a paper co-authored by Dr. Leonardi discussing this potential safety signal among antii-IL 12/23 antibodies was published in JAMA (JAMA Aug 24/31 Vol 306 No. 8 (864 -871).  The article concluded: “Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti–IL-12/IL-23 antibodies or anti–TNF treatments. This study may have been underpowered to identify a significant difference.”

Centocor recently released Stelara’s 4-year safety data, which did not demonstrate any new safety signals. This comes as good news particularly when one considers that the appearance of Raptiva’s (efalizumab) safety signal (PML) occurred at year 4.

 

Melanoma

What’s your strategy in managing this lesion?

  1. In 1970 the overall melanoma survival rate was less than 60%. Today the overall survival rate is over 90%. Much of this improvement in melanoma survival can be attributed to earlier diagnosis.
  2. Diagnosis of melanoma at earlier stages of evolution is, in part, due to increased awareness and increased surveillance.
  3. The notion that the in vivo diagnosis of melanoma is solely dependent on its clinical primary morphology derides the true complexity involved in diagnosing this malignancy. Components of the clinical examination used in the evaluation of skin lesions include touch, patient-derived anamnestic data, analytical reasoning (e.g., ABCD), comparative recognition (e.g, change), and differential recognition (e.g., ugly duckling sign).  The human cognitive process integrates this clinical information, extracting the pertinent information and rendering a diagnosis.
  4. Utilizing total body photography, dermoscopy, and dermoscopic short-term mole monitoring has contributed to the detection of many clinically subtle melanomas (improved sensitivity) and has also increased our diagnostic specificity. This translates into an improved ability to detect melanoma while concomitantly decreasing the number of unnecessary biopsies being performed on benign lesions.  Pigmented lesion experts utilizing baseline photography and dermoscopy remove approximately 5 benign nevi for every MM found. In contrast, non-experts remove as many as 30 benign nevi for every MM found.
  5. Future technologies such as confocal microscopy, computer vision, telemedicine, etc. are likely to continue to enhance the sensitivity and specificity for diagnosing early melanomas.

Maui Derm 2010: Surgical Management of Melanoma   K. Tanabe MD

In the surgical management of melanoma it is critically important to obtain adequate surgical margins. Ken Tanabe, oncology surgeon at MGH, discussed surgical margins for melanoma and the role of sentinel node biopsy and lymphatic mapping.  Recommended margins: melanoma in situ – 0.5 cm;  < 1 mm thickness – 1 cm;  1 – 2 mm thickness – 1 – 2 cm;  > 2 mm thickness – 2 cm.  These recommendations have been developed from the results of prospective randomized trials.  These margins may be modified to accommodate for anatomic or functional considerations in cases of melanomas of the face and hands.

In patients who are potential candidates for lymphatic mapping and sentinel node biopsy what does one need to know?   Dr Tanabe stated that while both offer clear advantages in enhancing accuracy of staging and regional disease control, their value in improving likelihood of long term survival remains a subject of debate. Sentinel node biopsy should be discussed with all patients with invasive, clinically localized melanoma before definitive wide local excision. Sentinel node biopsy should be considered in the following groups of patients with clinically localized melanoma > 1 mm Breslow thickness; < 1 mm Breslow thickness with positive deep margin, or > 1 mitoses, or ulceration. Patients with metastatic melanoma identified in their sentinel nodes should undergo completion lymphadenectomy, since approximately 20% of these patients will have additional (non-sentinel) nodes with melanoma. What can we offer our patients with advanced disease?  According to Dr Tanabe, in patients with hematogenous metastases, immunotherapy with IL-2 produces rare, but durable complete responses.  Conventional chemotherapy (e.g. dacarbazine) has limited activity.  Based on early trial results there is much interest in agents that target specific molecular pathways, such as Braf mutant tumors.