March 2014 – Maui Derm

Psoriatic Arthritis Update

March 20, 2014

Arthur Kavanaugh, MD

Dr Arthur Kavanaugh is a Rheumatologist and a Professor of Medicine at the University of California, San Diego. At MauiDerm 2014, he provides the practicing dermatologist with an update on PsA and the latest treatment advances…

The reported estimates of the prevalence of PsA among psoriasis patients have been highly variable, i.e., six percent to 42 percent. It is currently estimated that between 20 and 30 percent of psoriasis patients also have PsA. In addition, psoriasis precedes PsA in over 85-90 percent of the cases, though we’re not sure why. Dr Kavanaugh believes that in 20 to 30 years, we may have that answer. In 2012, there were an estimated 1,600,000 PsA patients in the United States. Of those patients, about 485,000 were diagnosed and only about 345,000 received treatment. Now that we have treatment available, Dr Kavanaugh feels that healthcare providers will be seeing more of these patients. As dermatologists, it is important to remember that PsA is a serious condition; approximately 20 percent of patients with PsA will develop destructive, disabling arthritis. PsA results in radiological damage in up to 47 percent of patients at a median interval of two years. Remember that other comorbididites often exist among PsA patients; these include, metabolic syndrome, CAD, uveitis, IBD, impaired function and quality of life, and economic implications.

Recent data presented at the 2013 American College of Rheumatology, suggest that a delay in the diagnosis of PsA correlates with poor patient outcomes. A study of 283 PsA patients, fulfilling the CASPAR criteria, demonstrated that even a six-month delay from symptom onset to the first visit with a rheumatologist contributed to the development of peripheral joint erosions, sacroiliitis, and worse long-term physical function.

Diagnostic Criteria for PsA (CASPAR)

The diagnostic criteria for PsA includes an established inflammatory articular disease (joint, spine, or entheseal), plus three or more points from the following five categories:

Psoriasis
- Current-psoriatic skin or scalp disease present today (2 points)
- History-a history of psoriasis
- Family history-history of psoriasis in a first or second degree relative
- Nail Changes-typical psoriatic nail dystrophy
- A negative test for RF-by any method except latex (preferably ELISA or nephlemetry)
- Dactylitis
  - Current-swelling of a current digit
  - History –history of dactylitis
  - Radiological evidence of juxta-articular new bone formation-ill-defined ossification near joint margins (but excluding osteophyte formation) on plain X-rays of hand or foot

The CASPAR criteria are very sensitive and very specific; but, in the clinic, the question lies as to whether or not the patient has inflammatory arthritis. That is a tougher question and we don’t have a perfect answer for that. Several questionnaires and screening tests have been developed for this, such as the Psoriasis Epidemiological Screening ProjecT (PEST), Toronto Psoriatic Arthritis Screen (ToPAS), and Psoriatic Arthritis Screening and Evaluation (PASE). All of these instruments did relatively well in the development studies; however, remember that with these screening tests come trade-offs. The more sensitive an answer is, the less specific it is and vice versa. There is no perfect questionnaire and how they perform is based upon how you define them. The difficulties are the oligoarticular and differentiating osteoarthritis from inflammatory arthritis. The utilization of more sensitive imaging (ultrasound and MRI) can help to determine what is inflammatory versus what isn’t inflammatory.

GRAPPA PsA Treatment Recommendations

The chart below outlines the GRAPPA treatment recommendations; however, these guidelines are currently being updated to incorporate some of the newer treatment modalities.

Treatment choices are based on the severity of the different domains.

Clinical Pearl-PsA requires a clinician to really listen to the patient, examine the patient, and formulate and appropriate treatment plan with the patient.

We know that the data on the TNF blockers for the treatment of PsA is very positive for both joint symptoms and skin symptoms. Currently, we even have data that demonstrate the effects of TNF blockers on issues that are important to the patient, such as nail involvement, enthesitis, and dactylitis. In the past, we didn’t have we didn’t have quantifiable ways to measure these, but now we do.

Data also demonstrate that TNF inhibitors slow down the damage to the bone. Getting patients under good control allows them to be functional and go about doing the things they do in their daily life.

Certolizumab Pegol

Certolizumab Pegol (CZP) was approved for the treatment of PsA in September of 2013 and is the fifth TNF inhibitor available for the treatment of PsA. The RAPID-PsA study is important to us, as clinicians, because the researchers looked at switching, i.e., may have failed a previous TNF inhibitor. The phase III results of the 24-week, double-blind, placebo-controlled study showed that the ACR20 response at week 12 was significantly higher in the CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo (58.0% and 51.9% vs. 24.3%) and PASI75 response at week 24 for patients with ≥ three percent psoriasis body surface area at baseline (61.6% randomized set) was 62.2 percent with CZP 200mg Q2W and 60.5 percent with CZP 400mg Q4W versus 15.1 percent with placebo. This data demonstrate that CZP is effective in PsA, including patients with prior TNF inhibitor exposure. This is very important for our patients who may not have responded to previous therapy. This data as also been confirmed in other registries; therefore, indicating that switching from one TNF inhibitor to another in PsA is a viable option.

In PsA, we don’t know whether a TNF inhibitor plus methotrexate (MTX) is additive or synergistic. In Rheumatoid Arthritis, there is data that demonstrate that even a dose of MTX as low as 10mg gets you synergy. This is something that as a practitioner, you need to negotiate with your patients.

What about obesity and weight loss?

Currently, the data on obesity are very strong and very consistent. We know that PsA patients have shown an increased prevalence of obesity. A study by Di Minno and colleagues demonstrated that within 12 months of starting a TNF inhibitor, patients with PsA achieved minimal disease activity (MDA). The prevalence of obesity was lower in the group achieving MDA. Patients who lose weight and then begin a TNF inhibitor have a much better chance of doing well, than those who are obese. When you look at the CORRONA database, a study of 392 patients starting a TNF inhibitor showed that only obesity was significantly associated with the discontinuation of treatment. This tells us that patients who are obese do not do as well on therapy and have more disease activity. This is true not only for fixed-dose treatment, but weight-based treatment, such as infliximab, as well. Obesity is inflammatory and this is a very dramatic effect. In fact, it has changed the way Dr Kavanaugh approaches his patients regarding discussing the importance of weight loss.

Biosimilar (CT-P13)

A randomized, double-blind, phase III study of 606 patients demonstrated the clinical equivalence of CT-P13 to infliximab when co-administered with MTX in patients with active rheumatoid arthritis. The results were maintained after the switch from infliximab to CT-P13 from weeks 52 to 104. CT-P13 received a favorable opinion by the EMA and is now available in Europe. CT-P13 was studied in rheumatoid arthritis and ankylosing spondylitis and because it was clinically equivalent it received approval for all of the indications for which infliximab is approved. The FDA has not yet weighed in on how it will approach biosimilar approvals; however, they are here and this is coming. Cost is a major issue, i.e., they could be available at 20-25 percent less than the branded products.

Emerging Therapies

We know that TNF inhibitors work well in GI disease, skin disease, rheumatoid arthritis, etc.. Dr Kavanaugh points out that we have made a somewhat switch from “bench to bedside” to “bedside to bench.” He states that “we are dissecting these diseases by our therapies” with hopes to find more specific treatments for specific groups of patients with these distinct diseases.

Ustekinumab (USK) was approved for PsA in September of 2013. The PSUMMIT trial included 615 adult PsA patients with active disease despite DMARD and/or NSAID therapy. Patients were randomized to receive USK 45 mg, 90 mg, or placebo at weeks 0, 4, and q12 weeks thereafter. At week 16, patients with less than five percent improvement in tender joint count and swollen joint count entered blinded early escape (placebo to USK45 mg; USK 45 mg to 90 mg; 90 mg to 90 mg). Stable concomitant MTX use was permitted but not mandated. Patients treated with prior anti-TNF agents were excluded. The primary endpoint was an ACR20 response at week 24. A significantly greater proportion of USK-treated patients (versus placebo) had an ACR20 response at week 24. Significant improvements were also observed with USK 45mg and 90 mg for ACR50/70 responses and DAS28-CRP responses at week 24 versus placebo. Through week 16, adverse events were similar between patients receiving USK and placebo with infections being the most common AE. No malignancies, serious infections, tuberculosis, opportunistic infections, or deaths occurred through week 24. PASI 75 response at week 24 also demonstrated positive efficacy among the USK 45mg and 90mg doses versus placebo.

The PSUMMIT 2 study looked at USK in patients with active PsA who were previously treated with an anti-TNF agent. This data show some improvement in ACR 20/50/70 and demonstrate that it is safe and could be modestly effective for PsA TNF inhibitor-experienced patients.

Dr Kavanaugh and his colleagues, utilizing an integrated data analysis of two phase III randomized, placebo-controlled studies, also demonstrated that USK inhibits radiographic progression in patients with active PsA.

IL-17

Genovese, et al. studied brodalumab, an anti-IL-17RA in patients with PsA. ACR20 was achieved at week 12 by 37 percent and 39 percent of patients in the 140- and 280-mg brodalumab groups, respectively, compared with 18 percent of placebo patients. The percent of ACR20 responders (observed) increased at week 24 (44%, 51%, 64%, in prior placebo, prior 140 mg, and prior 280 mg groups, respectively). The percent of ACR50 responders (observed) across all groups increased from week 12 to week 24. There were improvements in other secondary endpoints such as DAS 28, CDAI, and several components of the ACR from baseline to week 12 that continued through week 24 in all treatment groups. Adverse events were similar among all treatment groups and placebo. This demonstrates that brodalumab is associated with significant clinical response with continued improvement from week 12 to 24 and further studies of brodalumab for treatment of PsA should be conducted.

Small Molecules

Apremilast, an inhibitor of PDE4, is currently under development for the treatment of PsA. Data from the PALACE 1 study are statistically significant for the apremilast group(s) versus placebo for both ACR 20/50/70 scores and PASI75. At week 24, significantly more apremilast 20 mg BID (36%) and 30 mg BID (45%) patients achieved ACR20 versus placebo (13%). There were also significant improvements in key secondary measures (physical function, psoriasis) with both apremilast doses versus placebo.

One of the major advantages of apremilast is its safety profile. Laboratory monitoring may not be needed with this drug.

Conclusions

Since the availability of biologics, the interest in PsA has increased exponentially. This is exciting for us, as healthcare providers, and very promising for our patients. Lastly, remember the importance of tight control in early PsA. If patients are not responding the way you feel that they should be, then their management strategy needs to be modified. Data demonstrate that using a treat-to-target approach can significantly improve both joint and skin outcomes for newly diagnosed PsA patients.

MauiDerm News Editor-Judy Seraphine

New Drugs

March 20, 2014

Neal Bhatia, MD & Ted Rosen, MD

In this presentation from MauiDerm 2014, Dr Neal Bhatia, an Associate Clinical Professor at Harbor-UCLA Medical Center and Dr Ted Rosen, a Professor of Medicine at Baylor College of Medicine, bring us the latest information on drugs that are, or will be available to the practicing dermatologist.

Part 1

Neal Bhatia, MD

This information is extremely important, as dermatologists need to continue to stay up-to-date with regards to the new data and literature. As healthcare providers, it is imperative to pay attention to the serious drugs for a number of reasons, in that, many dermatologists are losing their skills and letting good medicine pass them by.

Apremilast

Apremilast is an inhibitor of PDE4 and is currently in phase III trials for a number of diseases, including ankylosing spondylitis, psoriasis, and psoriatic arthritis along with orphan status for Bechet’s disease. A published case report studying cutaneous lichen planus with apremilast (20 mg bid for 12 weeks then a four week holiday) (Paul et al. JAAD, 2013) demonstrated that 30 percent of the patients experienced a 2-grade improvement and all patients had some improvement. This is important because this data will help us to eventually learn the dose and how to titrate the drug. This study was; however, small in numbers, treatment time and dosages.

Apremilast was also studied in discoid lupus erythematosus (DLE). Remember that DLE is Th1 mediated and apremilast blocks the Th1 process by inhibiting the production of IL-12, 23 and Th-17. There is also subsequent suppression of the Th-1 and Th-17 profile. Eight patients started in the study and four patients finished the 85-day course. There were some gastrointestinal side effects and sensory neuropathy. (DeSouza et al. JDD, 2012) This indicates a need for larger studies.

Omalizumab

There is a lot of good data demonstrating that sub-cutaneous omalimuzab shows promising results for the treatment of chronic idiopathic urticaria with the treatment spaced four weeks apart. The best data was with the 300mg dose, whereby the patients received the four weeks and then were observed for 16 weeks. Most of the patients had very good severity scores as well as significant reduction. For patients with severe chronic urticaria who are done with antihistamines, cannot handle topicals, and do not know the triggers, omalizumab plays a promising role.

Dr Bhatia commented on the new treatments for onychomycosis and feels that we have a “flood year of antifungals this year.” What we need to know:

Naftifine 2% gel—data suggest that there is residual active drug available in the stratum corneum even up to 4 weeks after treatment
Luliconazole is approved for the treatment of tinea pedis
Efinaconazole and Tavaborole are not approved as yet—but the data for both medications show promise
Itraconazole 200 mg tablets with new dosing protocol—coincidentally around the time of the oral ketoconazole black box warning
Ketoconazole gel (Xolegel) for use on the face and Itraconazole tablets (Onmel) are back
Econazole Foam is coming and the data is encouraging with a new vehicle

In a Phase II study of luliconazole cream 1 percent for the treatment of interdigital tinea pedis, the researchers found that complete clearance was 26.8 percent and 45.7 percent in subjects in the two-week and four-week treatment group, two weeks post-treatment. The antifungal effect persisted several weeks post-treatment resulting in increased rates of mycologic and clinical cure. Four weeks post-treatment, complete clearance rates were 53.7 percent and 62.9 percent, respectively.

Niwano and colleagues looked at in vitro and in vivo antidermatophyte activities of luliconazole and found that it exhibited strong antifungal activity against Trichophyton spp with minimum inhibitory concentrations one to four times lower than lanoconazole or terbinafine. They also found that seven-day topical therapy (0.5% solution) was more effective than lanoconazole or terbinafine (0.5%) and luliconazole was the only drug that achieved complete mycologic cure with a three-day therapy.

Efinaconazole inhibits fungal lanosterol 14α-demethylase, which is involved in ergosterol biosynthesis at concentrations below minimum inhibitory concentrations. Efinaconazole is 4.8 times more potent than itraconazole in inhibiting ergosterol biosynthesis in T. mentagrophytes and is 7.3 times more potent than clotrimazole in C. albicans. Data on efinaconazole for toenail onychomycosis show favorable efficacy. The chart below demonstrates that you do not need occlusion to see any benefit with efinaconazole.

Tavaborole, representing a new class of anti-fungals, i.e., a novel boron-based compound, met all primary and secondary endpoints in the treatment of nail fungus when compared to ciclopirox lacquer in two studies and more importantly, demonstrated a negative culture of 87.0 percent vs 47.9 percent and 85.4 percent vs 51.2 percent, respectively. We will begin to see more and more phase III data in the near future.

Ketoconazole gel 2 percent has the same side effect precautions as oral products, on label, but these are doubtful. It’s important to remember that the brand name in some markets may be cheaper than the generic. Also of importance, rates of mycological cure and effective treatment (secondary efficacy endpoints) were observed in the Econazole Nitrate Foam 1% group relative to the Foam Vehicle in both phase 3 studies (P<0.001).

Itraconazole (200 mg) (OMNEL) utilizes Metrex® technology which improves bioavailability. It is now available with a new dosing protocol, which is more convenient for patients. In one study, itraconazole (200 mg tablets) demonstrated statistically significant efficacy across all endpoints compared to vehicle at week 52 and was found to be noninferior to itraconazole 100-mg capsules at 52 weeks. The treatment duration of 12 weeks allows for 40-week follow-up. Remember that the nail grows out one tenth of a millimeter per day; therefore, every patient who is on any drug will not get a new nail for two hundred days. So, follow-up can be a slower process. The safety profile of Omnel is not statiscially different from that of itraconazole; however, there is a slight elevation in ALT.

Part 2

Dr Rosen continues the presentation with more dermatologic treatment advancements….

Pliagils (Lidocaine 7% + Tetracaine 7% Cream) is a topical, local analgesia for superficial dermatological procedures, such as filler injection, PDL or mild laser abrasion, and tattoo removal, which requires a longer application time. Pliaglis is self-occluding and forms a pliable peel. It is applied 20-30 minutes for most minor procedures and 60 minutes for more major procedures and is available in 30,60 and100gm tubes. A dosing chart is available pending on what area you are trying to anesthetize.

Sitavig (acyclovir 50mg Buccal) is indicated for recurrent oro-labial HSV. The Novel Lauriad® technology is a natural polymer derived from milk which adheres to the mucosa; therefore leading to high local drug concentration, but minimal blood levels. It is one tablet, applied within one hour of prodrome onset, on the upper gum at the incisor on the same side as the HSV lesion. After holding pressure for 30 seconds, the patient should allow the tablet to remain until it falls off (approximately six hours). Sitavig has shown to reduce the duration of an attack by 0.5 days based upon a randomized controlled trial of 775 patients.

Another advancement includes the approval of carbinoxamine maleate susp (Karbinal ER), which is a mildly sedating H1 antihistamine in an extended release formulation. It is used for the treatment of allergic rhinitis and conjunctivitis, uncomplicated urticaria, angioedema, and dermatographism. The advantages of this drug are that it is in a liquid form and there is infrequent dosing (2 times per day). It is also indicated for children as young as age two.

Vashe Skin and Wound Hydrogel, an aqueous-based, emollient containing, non-oily hydrogel, is a hypochlorous acid-containing material. It is intended to relieve pruritus, burning or pain from atopic, allergic contact and radiation dermatitis, as well as thermal burns. The drug maintains a moist environment, encourages autolytic digestion and prevents contamination. It works through the chlorination of histamine, leading to a less active derivative. It oxidizes many groups and subsequently directly and indirectly neutralizes the effects of cytokines, leukotrienes, alpha-1 antiproteinases, and cysteine proteases. This product is Aurstat with which you may already be familiar. It came from a partnership between PuriCore and Onset Dermatologics.

Old Drugs, New News:

Adapalene/BPO 1.2%/2.5% (Epiduo®)–Now FDA approved down to age 9
Desoximetasone 0.25% (Topicort®) –Now available as a spray
Ketoconazole 200mg tab (Nizoral®) –Severe limitations on use due to liver and adrenal toxicity, as well as drug interactions
Certolizumab pegol (Cimzia®) –Now approved for psoriatic arthritis, maybe psoriasis at some time in the future

Certolizumab Pegol (Cimzia®)

Cimzia is approved for the treatment of psoriatic arthritis (PsA) at 200mg sq QOW. A phase III, multi-center, randomized, double-blind, controlled trial (RAPIDTM-PsA study) looked at 409 patients with adult onset PsA. The loading dose was 400mg or placebo at baseline, week two and week four, followed by 200mg qowk, 400mg q4wk, or placebo qowk. Adverse events were found in 62 percent of the patients versus 68 percent (placebo). ACR 20, 50, and 70 response rates at weeks 12 and 24 were higher for each Cimzia dose group relative to placebo; however, patients treated with Cimzia 200mg every other week demonstrated greater reduction in radopgraphic progression at week 24. Patients treated with Cimzia 400mg every four weeks did not demonstrate greater inhibition of radiographic progression at week 24, compared with placebo-treated patients.

Overall, treatment with Cimzia resulted in improvement in skin manifestations in patients with PsA (62.2 percent to PASI 75). It is important, as dermatologists, to recognize that the safety and efficacy of Cimzia in the treatment of patients with plaque psoriasis has not been formally established and the use in psoriasis is off-label.

In conclusion, clinicians should pay special attention to the Nizoral FDA warnings published in July of 2013. (www.fda.gov) The FDA states that:

Oral ketoconzazole should not be used as first-line therapy for ANY fungal infection
Ketoconazole should be used only for the treatment of life-threatening mycoses when the potential benefits outweigh the risks and alternative therapeutic options are not available or not tolerated
Oral ketoconazole is no longer indicated for dermatophyte or Candida infections
Oral ketoconazole is not indicated for fungal infections of the skin or nails
It is contraindicated in anyone with liver disease

If you use this drug and there is any hepatotoxic event, that could cause a great problem as a practitioner.

In summary, the dermatology landscape is continuing to grow with promising new drugs for our patients and it is imperative to stay on top of the latest data.

MauiDerm News Editor-Judy Seraphine

Actinic Keratoses: Clinical Pearls

March 10, 2014

George Martin, MD

Are you using 5-FU to treat AKs?

To minimize the duration of side effects, compliance issues and phone calls when prescribing 5-FU prescribe 0.5% 5-FU therapy for 1 week. Phase 3 FDA data on 0.5% 5-FU used for 1 week demonstrate over 70% individual lesion clearance. Is it worth continuing an extra 3 weeks to achieve a > 90% clearance? No.
What does Dr. George Martin do? He cycles 5-FU therapy: 1st cycle—Face: 7 days 5-FU/Non-facial areas: 10 days 5-FU; Rest period for at least one month; 2nd cycle— 5-FU for at least 2 weeks. Data suggest that 0.5% 5-FU QD is at least as effective as 5% 5-FU BID in percent reduction of AK lesions. The short treatment cycles result in great compliance and minimal downtime.

Treating AKs on the chest?

Avoid 3.75% imiquimod. It is likely to result in permanent depigmentation at the AKs treated sites on the chest in the majority of patients. It is not yet FDA approved for the trunk…and with good reason.
Try: ingenol mebutate 0.05% x 2 nights. Instead of spot treating, cover the entire sun-damaged AK area of the chest with the entire amount in the tube. Best used on moistened skin post shower because it spreads better. Because of its direct cytotoxic effect, in addition to up-regulation of IL-8 induced neutrophil chemotaxis, it produces discomfort within 4 hours requiring analgesia. Be sure to set patient expectations and prescribe analgesia. Patients describe it’s use on large areas on the upper chest as feeling like a “really bad sunburn.” Although not FDA approved to treat areas >25 cm2 and there is no efficacy data, Dr. Martin has found it to produce excellent AK clearance and a great cosmetic result.

Botulinum Toxin 2014: Tips, Thoughts, Science, & Different Formulations

March 4, 2014

Joel L. Cohen, MD

In this presentation, Dr Joel Cohen, a leader in aesthetic dermatology, and the Director of AboutSkin Dermatology and DermSurgery in Colorado, provides us with an update on the use of botulinum toxin. Dr Cohen begins the session by reminding us, as Dermatologists, that every day we have an opportunity to blend our modalities, i.e., medical, surgical, and aesthetic in order to provide our patients with the best possible outcomes.

Currently, there are three FDA-approved botulinum toxins type A; these are Botox (Allergan), Dysport (Medicis/Galderma), and Xeomin (Merz). All three products are approved to treat glabellar lines; however, Botox was also recently approved for the treatment of Crow’s feet.

Cox and Finn a decade ago, found that botulinum toxin type A injections have been beneficial for patients who feel that their faces are not communicating their emotions properly, want to delay the outward appearance of aging, and/or patients simply want to look their best. Data also suggest that botulinum toxin type A injections can also affect self-esteem. A 2010 health-outcomes survey (randomized data), conducted by Dayan and colleagues, found that the injection of botulinum toxin type A injections demonstrated improvements in quality of life (QOL) and self-esteem and injection-naïve patients demonstrated greater improvements in QOL and self-esteem versus those who had received previous injections.

All three of the FDA-approved products contain a core neurotoxin protein (150 kD BoNT/A), this is where the mechanism of action lies. Botox and Dysport are wrapped in protein, which is part of the neurotoxin complex. Xeomin; however, lacks these accessory proteins. All three products have demonstrated efficacy and have established good safety profiles, but remember that it is difficult to make direct comparisons among the approved botulinum toxins. Keep in mind that the products are different, the dosing can be different, the studies were all designed differently and there are differences among the various study endpoints.

Conversation Ratios

Keep in mind that the three neuromodulators approved for aesthetic use are separate products; therefore, there is no TRUE or EXACT “conversion ratio”. As dermatologists, we must learn how to use each product differently in clinical practice. The injection techniques are similar; however, there are no direct specific or perfect conversion ratios. Regulatory agencies around the world, including the United States, have recognized that these are different products, and there is no interchangeability among botulinum toxin neuromodulators.

Xeomin

Sattler, et al published a non-inferiority trial comparing Xeomin to Botox in the treatment of glabellar frown lines. The independent rater and patient assessment between both products were very similar at weeks four and 12. Because this was a non-inferiority study with two time-points, you can miss the “duration of efficacy” and the “waning effect.” The authors concluded that Xeomin is equally as effective as Botox and both preparations were well tolerated.

Other Considerations

When we look at the FDA studies for the available neuromodulators, they dose the medial corrugator exactly the same as the lateral corrugator and for the convenience of an FDA study. For Botox and Xeomin, it was four units in five injection points and for Dysport it was ten units in five injection points. The reality of our practice is that patients typically have a much more prominent medial corrugator than a lateral corrugator, and when you inject the lateral corrugator with a large dose you risk unwanted spread to the frontalis, which can knock-out the lateral frontalis function of keeping the brow up. So consider lower doses in the lateral corrugator when appropriate, and consider orienting the needle tip more medially to avoid lateral spread to the frontalis.

Combination Delivery

Combining fillers and neuromodulators in the same syringe is not something I would recommend and is considered controversial. It is ok to consider combination therapy, as there is good data on this, but not in the same syringe. In 2013, Drs Cohen and Mariwalla wrote a letter to the editor of Journal of Drugs in Dermatology referencing an article whereby these products were mixed in the same syringe, cautioning practitioners about the potential pitfalls of this sort of approach. Keep in mind that combination same-syringe delivery (e.g. botulinum toxin-A and hyaluronic acid filler ”mixed together”) can be imprecise on many levels, from not uniformly mixed to potential unintended spread of one of the agents. I personally think it would take more time to mix the neuromodulator in the filler syringe, then to simply draw up and inject the Botox on its own—and on its own seems much more precise.

Another important consideration is that of combination neuromodulators and chemical peels on the same day. Swelling can potentially carry a neuromodulator, even a centimeter or two. Use caution on the same day and in same region as procedures that may cause significant swelling with regards to migration, such as non-ablative fractional, ablative fractional, higher concentration chemical peels, and even tightening devices.

Dosing

Remember that dosing, dilution, and reconstitution are different concepts. Dr Cohen reconstitutes his neuromodulators differently by region, using 1cc dilution per 100 units (Botox/Xeomin) in most areas (glabellar, lateral canthus, DAO, and mentalis); however, he uses 5cc for the perioral lines, forehead, platysmal bands, and hyperhidrosis.

When looking specifically at dosing, aesthetic physicians have historically used high-dosages in the forehead, which often caused them to look completely “flat”. “Many patients prefer simply softening the musculature in the forehead without totally knocking it out — achieving a relaxed and natural look. Over the years, Dr Cohen and colleagues have found that they can basically cut the forehead dose in half. This helps in achieving a natural look, softens the musculature and maintains brow shape and positioning–many patients prefer. There are published consensus statements and recommendations on how much product to use and how best to use it for each of the products available. As dermatologists, we also need to consider the anatomic differences between men and women and how we approach the use of neuromodulators in the forehead.

Summary

Remember that all three products have demonstrated positive efficacy and safety profiles. As clinicians, it is important to understand how to use each product, their differences and most importantly, how to individualize treatment and set realistic expectations for our patients. Utilizing the Merz scales or other scales can help with achieving aesthetic treatment goals, by explaining to patients their point on a scale now versus where you are striving to get them to after treatment.

It is critical to understand the changes and differences in the FDA requirements in the studies for neuromodulators. When Botox was approved, studies were designed differently—and improvement was scored differently with follow-up evaluations looking at persistence of some degree of improvement (but not 2-grade improvement necessarily). With Xeomin, a two-grade improvement was required, which was a much higher standard. This is an important concept to keep in mind when looking at responder rates over various studies. With the recent approval of Botox for Crow’s feet, Allergan similarly was held to the 2-grade improvement scale as well.