Medical Dermatology – Page 3

Infectious Disease Update: Clinical Pearls

January 27, 2015

Stephen Tyring, MD, PhD, MBA

Dr Stephen Tyring provides us with key takeaway points from his presentation on Infectious Disease…

The recently approved HPV vaccine protects against 9 HPV types.
Helicase/primase inhibitors are safe and effective against HSV strains that have developed resistance to nucleoside inhibitors.
Therapeutic HSV vaccines are showing promise in clinical trials.
Coxsackievirus A6 is causing hand-foot-mouth disease in adults and producing more severe symptoms than in children.
Onychomadesis is a unique late sign of Coxsackievirus A6 infection.
Ebolavirus is a potentially lethal filovirus that produces mucocutaneous signs, e.g. ecchymoses and petechiae, late in the clinical course.
Ebolavirus is transmitted via infected body fluids.
Several new drugs and vaccines are being studied to manage ebola.
Chikungunya is a togavirus carried by mosquitoes that has spread rapidly throughout the Caribbean, southern United States and northern Latin America in the past year.
The most important symptoms of chikungunya are extreme joint pain and fever, and the most common cutaneous sign is erythematous macules.

Dermoscopy: Clinical Pearls

January 26, 2015

Ashfaq Marghoob, MD

Dermoscopy Clinical Pearls:

The presence of leaf-like and spoke wheel-like structures seen with dermoscopy is 100% specific for the diagnosis of basal cell carcinoma.
The presence of vessels arranged in a string of pearls pattern seen under dermoscopy is 100% specific for the diagnosis of clear cell acanthoma.
The presence of white blotches and strands within the same lesion seen with polarized dermoscopy is highly suggestive of basal cell carcinoma
Angulated lines forming a zigzag pattern or forming polygonal shapes is suggestive of pigmented actinic keratosis or lentigo maligna
The presence of any of the 10 melanoma specific structures in a melanocytic lesion should prompt consideration for a biopsy

Cutaneous Oncology: Clinical Pearls

January 26, 2015

George Martin, MD & Ted Rosen, MD

Why field therapy?

Data from Europe using a variety of techniques (including full face cross-polarized light examination, fluorescence photography, high definition optical coherence topography and reflectance confocal microscopy) clearly validate the concept of a “field” of abnormality in close spatial proximity to visible AK lesions.

Facial AKs:

Although we did not mention this in our talk, for those of you who use 5-FU, please remember that the Phase III data on 0.5% 5-FU demonstrated that 1 week of daily use of 0.5% 5-FU cleared nearly 75% of individual AKs. Try: 0.5% 5-FU QD x 1 week, wait 1 month, then follow with 2 -3 weeks QD application to “clean up” remaining AKs. This regiment has gained widespread acceptance by patients and physicians as a more tolerable field therapy. 5% 5-FU BID is equivalent to 0.5% 5-FU and can be used interchangeably.

Ingenol mebutate 0.015% applied nightly x 3 has been a remarkably effective therapy with great patient compliance. However, it’s FDA approval was for limited areas (25 cm²). As a full-face therapy, it appears very effective; however, controlled studies on “full face” clearance/efficacy is pending. Patients need to be counseled that they will experience a moderate to severe “sunburn-like” effect beginning 4 hours after application. This is likely due to its MOA, which includes a direct cytotoxic effect. Analgesia is generally required. Clinically, we have observed while treating full-face, ingenol mebutate is selective for AKs with mild/moderate erythema between AK lesions.

New data, both short term (11 weeks) and long term (one year), support the benefit of using ingenol mebutate in combination with standard liquid nitrogen cryotherapy. Cryotherapy is performed first, and then ingenol mebutate used per approved protocol three weeks late. At one year, the combination therapy has a higher complete clearance rate than cryotherapy followed by vehicle control. Off label, ingenol mebutate appears promising for the management of actinic cheilitis in the three day, FDA-approved regimen. More studies are needed to validate this idea.

If you perform PDT in your practice, and use 1 -> 3-hour ALA incubation periods, recent Phase II studies from DUSA show that 1, 2 or 3 hour incubation periods are roughly equally efficacious (35% – 50% clearance) but 2 treatments 8 weeks apart are required for most patients to achieve >70% individual lesion clearance. To maximize the efficacy of a 1-hour incubation, consider pre-treating with 5-FU for 1 week to the face or 10 days to the scalp then perform a 1 hr. ALA incubation. This combination will eliminate the need for a 2^nd PDT. For those patients with refractory facial AKs, consider pretreating for 7 days with 3.75% imiquimod followed by ALA PDT (1-3 hour incubation). Excellent long-term results (18 months) have been observed when destructive techniques such as PDT are combined with immune modulators.

Can ALA PDT be “painless”?? Try incubating for 15 mins with ALA and then place the patient under the blue light for 1 hour. Preliminary results (G.Martin MD) demonstrate that ALA PDT as monotherapy or in combination with 5-FU or 3.75% imiquimod, employing this technique is in fact “painless”. Individual AK clearance rates of 50% were demonstrated in a proof of concept small patient study. Large-scale studies are warranted to determine efficacy. Network meta-analysis (comparing different techniques against one-another) suggest that PDT is the optimal field therapy for AKs.

The focus of PDT has been aimed at treating AKs. Is there evidence that PDT may prevent BCCs? Data from studies on basal-cell nevus syndrome patients demonstrate long-term clearance and prevention of new BCC development compared to non-treated areas of the trunk following ALA PDT using red light.

The use of 3.75% imiquimod for diffuse facial AKs while effective, results in substantial “downtime” of nearly 6 weeks. Consider 3.75% imiquimod QD x 7 days, 2 weeks rest, followed by once weekly applications. There will be some initial unsightliness during the 1 week of continuous use. Individual AKs are seen to clear with continuous application with minimal irritation. Chronic immune stimulation (>1 year) appears to be helpful in limiting AK recurrences and may prove over time to inhibit the development of invasive SCC. Large-scale studies are warranted.

Systemic Agents

January 6, 2015

John Zone, MD

Dr Zone, an expert in systemic disease and Co-Director of the Immunopathology Lab at the University of Utah, discusses the medications that we use to treat these various conditions. Most of the therapies discussed in this presentation are off-label unless otherwise noted.

What does all of this cost? The table below depicts the numbers from the University of Utah pharmacy.

Dr Zone has said this before, if he gets pemphigus, he wants to take rituximab. He is convinced that rituximab is not only the best treatment, but it is the cheapest in the long run.

IgE

IgE is more under the purview of the Allergist, so it isn’t discussed much in dermatology. It is a monomer and is present in very low concentrations in the body. Its synthesis is 25 to 2000-fold less than other immunoglobulins making it difficult for us to measure. It lasts in the blood for 48 to 72 hours so it has a very short half-life. IgE doesn’t activate C’ and instead binds on mast cells for weeks to months. If you develop a sensitivity, once the IgE molecules bind to mast cells, they are going to be there for awhile no matter what you do.

The approach that we take to treat conditions like urticaria always astounds Dr Zone. We know that IgE binds to mast cells in our skin. When the mast cell becomes degranulated, it releases histamine, TNF, proteases, and heparin—the things that cause people to get symptoms of itching and swelling manifested as urticaria. We treat people with antihistamines– we give people something to block the effect of the histamine after it’s released. There are a number of papers studying the positive effects of TNF inhibitors in urticaria. At Dr Zone’s institution, they have treated about thirty people with fairly good results. If you have intractable urticaria, you are open to a lot of things. Over a longer period of time, there is release of prostaglandins and leukotrienes. There are prostaglandin inhibitors and montelukast that can be used as well for urticaria. Over the long run, we then see eosinophil recruitment and release of other cytokines.

Given this information on pathogenesis of urticaria, it is clearly better to block the effect of IgE and prevent the end results?

This graphic illustrates Omalizumab binding to an IgE molecule, which also takes place at the constant region of the IgE molecule. Note that IgE binds either to the FceRI receptor on the mast cell or to Omalizumab, but it cannot bind to both at the same time. Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor FceRI on the surface of mast cells and basophils. Reduction in surface-bound IgE on FceRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with omalizumab also reduces the number of FceRI receptors on basophils in atopic patients.

Omalizumab is approved for asthma at this time and has recently been approved for refractory urticarial. To read more about omalizumab, the following references may be helpful:

Pemphigoid
- G Ital Dermatol Venereol. 2012 Jun;147(3):251-7.
Urticaria
- Curr Opin Allergy Clin Immunol. 2012 Aug;12(4):406-11
Atopic dermatitis
- Clin Exp Dermatol. 2012 Oct 22

There are going to be a lot more studies on urticaria and atopic dermatitis with omalizumab. Dr Zone uses Omalizumab 150-375mg subcutaneously every two to four weeks. It costs anywhere from $500 to $2000 per month and he has been able to get insurance companies to cover it. Regarding side effects, anaphylaxis has been reported; however, omalizumab is rather well tolerated.

Intraveneous Immune Globulin in Autoimmune Diseases

IVIG is currently used for the following dermatologic disorders:

Pemphigus vulgaris
Pemphigus foliaceus
Bullous pemphigoid
Mucous membrane pemphigoid
Epidermolysis bullosa acquisita
Toxic epidermal necrolysis
Necrotizing fasciitis

There is mixed information suggesting that IVIG works; but because these diseases are very severe, there is likely to be approval.

IVIG comes from thousands of donors and there is no data to show that one brand is better than another. Somewhere around one percent of the population are IgA deficient. If you are IgA deficient, you can have an anaphylactic reaction when IgA-containing immunoglobin is administered. Dr Zone believes that everyone should have a total serum IgA done before receiving IVIG. If you cannot do this, then the patient should be given the IgA depleted therapy. IVIG is used in smaller doses for immunodeficiency.

The therapeutic effects of IVIG most likely reflect the function of natural antibodies in maintaining immune homeostasis in healthy people. We think that antibodies are just for killing bacteria and viruses, but it’s not just that. Antibodies regulate our immune system. When you get someone else’s IVIG, you have a great chance of changing the regulation of your immune system.

The debate on toxic epidermal necrolysis (TEN) and IVIG continues. Ten or so years ago, Dr Zone was convinced that IVIG was the best treatment for TEN; but now he’s not totally sure. Huang and colleagues conducted a systematic review and meta-analysis looking at the efficacy of IVIG on the treatment of TEN. Seventeen studies were included. (Huang, et al. BJD 2012:167:424-432) The studies reported that pediatric patients had lower mortality than adults and adults with high dose IVIG had lower mortality compared to low dose IVIG (18.9% vs 50%). However, logistic regression failed to show a significant correlation with mortality.

What would Dr Zone do if he had TEN? After studying the papers, he would take IVIG.

IVIG for SJS/TEN Overlap and TEN:

Start IVIG 1 gram per kg for 3 days or 0.75 gram per kg for 4 days
If there is any concern for IgA deficiency, start IgA depleted IVIG until IgA levels are confirmed
In cases of renal failure, obtain renal consult and consider 0.5 gram per kg for 4 days vs. short course, high dose steroids

Dr Zone believes that the survival is better if it is done carefully. He would also most likely take IVIG with progressive Stevens Johnson’s Syndrome. IVIG has been used for over thirty years for patients with primary or secondary antibody deficiency and has not been found to have long-term side effects. IVIG has been tested by PCR for hepatitis B and C and HIV. There have been no cases of HIV transmission and no recent cases of hepatitis transmission. Side effects of IVIG include:

Headache, migraine
Fatigue
Anaphylaxis
Aseptic meningitis
Congestive heart failure
Pulmonary edema
Acute renal failure
Leukopenia
Hemolytic anemia
Hepatitis
Venous thrombosis

There are a group of people who believe that cyclosporine works for SJS/TEN. A study of 29 patients was published in the British Journal of Dermatology suggesting a possible usefulness of cyclosporine in SJS and TEN that needs to be confirmed. (Valeyrie-Allanore L, et al. Br J Dermatol. 2010;163(4):847-853.)

Takeaway point—If Dr Zone had SJS/TEN, he would take IVIG. If you didn’t want to give IVIG, cyclosporine is an option. Otherwise, you are in for a disease with a thirty percent mortality rate.

Scleromyxedma

This is a very rare disease and as dermatologists, we will likely see one case in our lifetime. A case series from Johns Hopkins reported eight of out ten patients with either 100 percent complete or partial response rate with IVIG treatment 2G/kg/month in divided doses. In the old days, there was no good treatment for scleromyxedma. Once again, if Dr Zone had scleromyxedema, there is no doubt that he would take IVIG. You do end up taking it indefinitely, but we try to decrease the dose and frequency.

Oral Corticosteroids

Dr Zone feels that he sees a lot more side effects from oral corticosteroids than immunosuppressive therapy. Before starting a patient on oral corticosteroids, it is important that you check their blood pressure as well as glucose, electrolytes and creatinine. Dr Zone gives H2 blockers or proton pump inhibitors to most people who are on therapy for more than two or three weeks. Gastritis and upper GI bleeding is a common side effect. For more than two or three weeks, Dr Zone also uses osteoporosis prevention. It is also important to monitor side effects every two weeks.

How can we prevent osteoporosis?

Suggest Calcium carbonate plus D for short term (twice daily)
Bisphosphanates
- Alendronate 5 mg daily or 35 mg. weekly
- Beware of esophagitis
Calcitriol (Vitamin D3)
- .5-1.0 micrograms daily
- Beware of serum calcium
Estrogen or Testosterone

You can start prednisone at approximately 1mg/kg/day. The patient can take the entire dose in the morning or BID early in the day. Alternating day therapy prevents adrenal suppression, but not osteoporosis. It is extremely important that you try to control the disease then minimize the dose, not the reverse. The reason that you want to taper steroids is to avoid rebound in the short term and manage adrenal suppression in the long term. If you want to evaluate for adrenal suppression, you can do an 8am cortisol and ask the patient not to take their steroid.

Dapsone

Dr Zone uses a lot of dapsone in his practice because he treats a lot of patients with dermatitis herpetiformis (DH). Dapsone inhibits neutrophil chemotaxis and attachment. It has neither an effect on antibody or complement deposition nor an effect on the reaction to gluten in DH. Dapsone simply blocks the inflammation in the skin.

Every patient on dapsone gets hemolytic anemia. Dapsone is a sulfone, meaning it has a double-bond oxygen—an incredible oxidant stress. What does that do to red cells? Red cells older than 90 days don’t have much G-6-PD because it decreases as cells age. They don’t have the ability to withstand oxidant stress. When you give dapsone, you’re going to hemolyze cells that are over 90 days old. If the red cell lifespan is 120 days and you give dapsone, you might hemolyze one quarter of the red cell mass. What does this mean? If you’re a young person you might feel a little fatigued; however, if you’re 80 and have congestive heart failure (CHF), it might end up exacerbating the CHF. But remember that everyone is going to get hemolysis. What happens? Your bone marrow starts to produce reticulocytes so all of a sudden the mean cell volume (MCV) goes up. When you treat someone with dapsone, you will see macrocytosis (because of the big reticulocytes) and a slight fall in the hematocrit, or you may see a fairly big fall in the hematocrit. With time, most people will compensate enough so that they’ll have enough reticulocytosis that they’ll raise their hematocrits back to the normal level. They’ll still be constantly breaking apart the red cells that are more than 90 days old because they can’t withstand oxidant stress.

Before giving dapsone, you should perform a baseline CDC and chem profile as well as a G-6-PD in Asians, African Americans, or those of southern Mediterranean descent. Start dapsone at 25mg daily and increase by 25mg weekly until the symptoms are under control. A CBC should be done weekly for the first four weeks, then monthly for six months, then semiannually. A chem profile should be performed at six months and then annually.

Dr Zone has treated somewhere around 1000 people with dapsone. He’s had two people who have developed leukopenia within two weeks. You can get aplastic anemia that will occur within the first four to six weeks. This is why you want to check the blood counts frequently in the beginning.

Mycophenolate mofetil (MMF)

MMF was approved by the FDA in 1995 for the prophylaxis of acute rejection in renal transplant patients. It is an ester of mycophenolic acid (MPA) and is synthesized to increase the bioavailability of MPA. It works by inhibiting leukocyte recruitment and glycosylation of lymphocyte glycoproteins involved in endothelial and intercellular adhesion and lymphocyte trafficking.

When you think about what we do as dermatologists whether it’s eczema or severe dermatitis, we are treating lymphocytes. MMF is a fairly good to drug to use in these cases. It’s effective as a corticosteroid-sparing agent in corticosteroid responsive dermatoses. MMF takes six to eight weeks to have an effect. You should start patients at 500mg bid. The most effective dose is 1000mg bid and the maximum dose is 1500mg bid. You may want to monitor levels if you are concerned about toxicity.

Dr Zone has seen the following side effects in patients receiving more than 2 g/d:

GI disturbances (nausea, diarrhea, dyspepsia, abdominal pain)
Persistent cough
Reversible hematologic side effects

It is unknown as to whether or not MMF increases the risk of lymphoma and carcinogenicity. There is an increased risk of viral and bacterial infections.

Azathioprine

Dr Zone uses a lot of azathioprine and feels that it’s a great drug. Everyone should get a thiopurine methytransferase (TPMT) level before starting azathioprine as well as a CBC and comprehensive metabolic panel. Azathioprine is converted to 6 mercaptopurine within one hour. It works by inhibiting T lymphocyte function and Ig synthesis.

Dr Zone starts at 50mg/day and increases to 3mg/kg/day over one to two months. Some people get severe nausea and/or an acute febrile reaction. With severe nausea, most patients just can’t take the medication. With mild nausea, you can divvy up the dose to three times per day. It is important to monitor CBC for leukopenia and perform liver function tests for obstructive patterns and hepatocellular damage. You can taper steroids and continue the azathioprine.

Cyclosporine

Here’s the trick with this…the pharmacy may call you and ask if you want to use “modified” or “non-modified.” “Modified” cyclosporine (gengraf and neoral) has more consistent absorption than non-modified (sandimmune). They are NOT bioequivalent. It is important that you use one and stick with it. Before starting cyclosporine, you should perform a baseline CBC, metabolic profile and check magnesium.

Start cyclosporine at one to two mg/kg/day. Remember that hypertension and elevation of creatinine are limiting factors. Leukopenia may occur as well as hypomagnesemia. You should monitor CBC and metabolic profile monthly. Patients can also monitor their blood pressure at home.

Cyclophosphamide

This is used for ocular cicatricial pemphigoid and refractory bullous diseases as well as refractory vasculitis. If you haven’t used a lot of this drug, you should probably refer the patient to someone with experience. Cyclophosphamide can cause leukopenia as well as alopecia and gonadal damage. There is also a risk of leukemia and bladder cancer.

Applying Laboratory Breakthroughs to Treat Pediatric Skin Diseases: Part 2

December 12, 2014

Amy Paller, MD, MS

Biologics as Targeted Therapy

Genetic advances are teaching us more about psoriasis as a disease state. The discovery of pathways that influence psoriasis have led to treatments such as TNF alpha inhibitors, interleukin-23 inhibitors, and IL-17 and its receptors. We have also learned that CARD14 mutations are a cause of familial psoriasis/PRP. One of the ways that CARD14 works is through the activation of IL-23 signaling and Th-17 expression, leading to the use of ustekinumab, a commercially available agent that targets IL-12/-23 with success.

Through exome sequencing, we have learned more about generalized pustular psoriasis. There is a deficiency of the interleukin-36 receptor antagonist, DITRA, in hereditary pustular psoriasis (and some cases of “sporadic” generalized pustular psoriasis show mutations in the IL-36R antagonist). This discovery suggests that activated IL-36 (or its related compound, IL-1) may be an important target in pustular psoriasis.

What about alopecia areata? We have learned from some excellent genome-wide association studies (GWAS) that there are several loci that are increased in this disease, one is which is CTLA4. There are ongoing trials of abatacept (CTLA4-Ig initiated) and rixolitinib (JAK 1/2 inhibitor to suppress IL-15 activity), but an early report of JAK1/2 inhibition showed great promise.

Targeting Functional Pathways

We can use systemic administration of small molecule inhibitors to suppress signaling activation. This can be seen with the use of vismodegib in basal cell carcinoma and basal cell carcinoma syndrome (BCNS) (activation of hedgehog signaling) and oral rapamycin in tuberous sclerosis (activation of mTOR signaling). GNAQ mutations cause the majority of blue nevi and 90 percent of cases of Sturge-Weber syndrome and nonsyndromatic portwine stains. GNAQ mutations have now been shown to activate PKC and MAPK but not AKT or mTOR. This observation suggests that an inhibitor of PKC or MAPK signaling might be effective if applied topically. With epidermal nevi, activating mutations have been detected in the genes encoding RAS family members or affecting FGFR3/PI3K/AKT signaling. Differentiating the activated pathway could influence decision-making about the most appropriate inhibitor to apply topically in the future. G13R and Q61R or Q61L Hras mutations in melanocytes cause Spitz nevi and speckled lentiginous nevi, yet another situation in which a targeted inhibitor which blocks Ras signaling might be considered as therapy.

Protein Replacement Therapy

Intradermal or intravenous introduction of recombinant collagen VII into RDEB (recessive dystrophic epidermolysis bullosa) mice leads to the deposition of collagen VII at wound BMZ and decreased skin fragility. Recently, FDA approved a trial of injected collagen VII in patients with RDEB. Future investigations might involve topically applied recombinant collagen VII to wounds or even intravenous delivery to reach mucosal sites as well. Interestingly, studies in mice without epidermolysis bullosa suggest that even normal wounds heal more readily if collagen VII is administered, broadening the potential value of topically delivered collagen VII.

Replacement; however, may not be sufficient. In CHILD syndrome, the cholesterol biosynthetic pathway is blocked, leading to deficiency of cholesterol but also accumulation of toxic metabolites. Application of topical cholesterol to skin is not sufficient, but use of a statin to block both the accumulation of toxic metabolites, as well as replacement of cholesterol leads to dramatic improvement in affected skin using this “pathogenesis-based” therapy.

Summary

New technology has facilitated the advancement in our knowledge about gene function and the effects of gene alteration, including for some of the mosaic disorders. These discoveries have translated into new therapies for patients with genetic disorders and will help with innovative treatment in the future, whether personalized gene-based or pharmacologic therapy. While there are new discoveries to be made, one of the exciting new frontiers involves epigenetics—unraveling how and why genes are turned off with cell and tissue specificity – and then translation this information towards treating human disease.

Infectious Diseases: Update on the Management of Onychomycosis

December 12, 2014

Aditya K. Gupta, MD

Dr Gupta, an expert in the management of nail disorders, discusses clinical advances with regards to the management of onychomycosis.

Factors Affecting Diagnosis

It is very important that we correctly diagnose onychomycosis. For the first time in over twenty years, we are able to use techniques other than light microscopy and culture. Molecular biology can be used to accurately diagnose multiple organisms that may cause onychomycosis. Dr Gupta has learned, through his lab, that often we may have mixed infections of two dermatophytes, a dermatophyte and a non-dermatophyte, or two non-dermatophytes. PCR analysis is more sensitive than culture, so it has a greater ability to identify mixed infections.

Treatment

Oral Therapies

Onychomycosis can be managed with topical therapy, oral therapy, and/or devices, i.e., lasers. In terms of oral therapy, terbinafine is the gold standard. Itraconazole is also indicated for the treatment of onychomycosis and fluconazole can be used off-label.

There are two new oral drugs in development—posaconazole and albaconazole.

It is important to recognize that onychomycosis is a difficult disease to treat, so you should consider the fact that you may need booster therapy or extra treatment around six to nine months from the start of therapy. For example, with terbinafine, giving 250mg per day for four weeks and repeating that at nine months and twelve months.

Topical Therapies

Efinaconazole, a triazole, which was just approved in Canada, has a low MIC for dermatophytes, yeasts and non-dermatophyte molds and relatively low keratin binding to facilitate transungual penetration. With regards to mycological cure and complete cure, data for efinaconazole demonstrated 54 percent and 17 percent cure rates, respectively versus 32 percent and seven percent, respectively with ciclopirox.

Tavaborole, a broad-spectrum benzoxaborole antifungal, has a low molecular weight and low lipophilicity facilitating penetration into the nail plate. At week 52, tavaborole demonstrated a 34 percent mycological cure and an eight percent complete cure as compared to 32 percent and seven percent, respectively with ciclopirox.

We need to recognize that there are differences in the severity and population of participants between the studies looking at the efficacy of efinaconazole and tavaborole; therefore, precluding a head-to-head comparison.

Differences Between Efinaconazole and Tavaborole in Pivotal Phase III Studies

No upper age limit for tavaborole
Nail trim: tavaborole allowed no more than 1mm nail beyond hyponychium
Japan not included in tavaborole study
Efficacy of vehicle for efinaconazole 2x that of tavaborole

Luliconazole is a topical imidazole approved in the United States for the treatment of tinea pedis. There are phase II/III trials currently underway studying its efficacy for onychomycosis.

Device Therapy—Lasers

There is insufficient data to determine if lasers are fungicidal in onychomycosis, especially as the precise mechanism of action remains unclear. The most likely effect is a selective photothermal effect, although we cannot rule out a photoacoustic, photochemical, or photomechanical effect. Keep in mind that the fungus has to be heated to at least fifty degrees centigrade for at least ten to fifteen minutes or 60 degrees (or even 70 degrees) for shorter periods of time. The aim of selective photothermolysis is the create very high increases in temperature in the fungi while the water content in the dermis and the blood vessels surrounding the nail bed allows for the dissipation of heat to prevent pain and tissue necrosis. The pulse format of the laser is critical for ensuring that heat remains confined and elevated in the fungi, while providing sufficient time for the surrounding tissue to dissipate the heat,

In the United States, the division of the FDA that approves lasers is different from the division that approves anti-fungal treatments. Lasers are indicated for use for the temporary increase of clear nail in patients with onychomycosis—this is quite a different approval as it is a cosmetic approval that does not look for mycological or complete cure. These lasers have not been subject to the same stringent standards that we expect of topical and oral therapies. There have been a number of open, single assignment clinical trials conducted using laser systems; however, randomized, controlled studies are needed to determine if laser is an effective treatment

Prevention of Recurrence and Reinfection

Recurrence rates can be anywhere from 11 to 35 percent or even higher. Remember that fungi can be transmitted to uncontaminated clothing in the wash. It is important to remind patients to wash their clothes and shoes in hot water (greater than 60 degrees) for more than 45 minutes. Ozone can be used to sanitize shoes and sports equipment of dermatophytes, yeasts, and non-dermatophyte molds. Ultraviolet light can also be used to sanitize shoes and reduce fungal burden.

Factors Contributing to Recurrence and Reinfection

The fungus that causes onychomycosis is not just dermatophytes or non-dermatophytes, but mixed infections as well. We have also shown that T. rubrum is not just T. rubum; there are minute-based pair differences that produce different strain types. We have found that strain type switching may contribute to the failure of oral terbinafine.

In summary, terbinafine remains the gold standard for treating onychomycosis. Both continuous and pulsed regimens are beneficial with an optimal pulse regimen of four weeks on, four weeks off and four weeks on. We have found that using this strategy, taking into account the pharmacokinetics of the drug, we can achieve fairly high cure rates. Itraconazole 200mg melt extrusion tablet may lead to better compliance rates versus two 100mg capsules. Don’t forget about booster therapy!

Fluconazole, while off-label in the United States, can be used at 150mg/week for longer than six weeks is also effective. The efficacy for posanoazole and albaconazole is similar, but not superior, to that of terbinafine.

We also have new topicals for onychomycosis—efinaconazole and tavaborole. It remains to see whether or not they will be used as monotherapy or in combination. Perhaps they could be effectively used in patients who fail oral terbinafine. They may also be used to prevent early recurrence of onychomycosis. There are a lot of potentials for the topical therapy.

As dermatologists, we use lasers for many things. We still don’t know enough about the use of lasers for the therapeutic cure of onychomycosis.

Infectious Diseases Update: Part 1: Interesting ID Literature

November 23, 2014

Ted Rosen, MD

In this presentation, Dr Rosen provides us with new information on infectious diseases that has recently appeared in the literature.

MRSA

A study in the International Journal of Antimicrobial Agents states that minocycline is often forgotten but preferred to trimethoprim-sulfamethoxazole or doxycycline for the treatment of community-acquired methicillin-resistant Staphylococcus aureus skin (MRSA) and soft-tissue infections. (Cunha B. Int J Antimicrob Agents. 2013;42:497). They point out that there is about a thirty percent discrepancy in discordance between the in vitro antibacterial testing and actual clinical effectiveness when it comes to the tetracycline family, this is less so with minocycline.

When treating MRSA, remember that incision and drainage is the most important intervention, if possible. CA-MRSA can be either modestly or severely virulent depending upon the presence or absence of PVL (Panton-Valentine leukocidin).

Typically we have some choices in treatment. We tend to leave linezolid for the last resort and clindamycin often has inducible resistance so we’re left with doxycycline, TMP-SMX, and minocycline. Cunha and his colleagues point out that second only to TMP-SMX, minocycline is the best in tissue penetrability and is equivalent to linezolid in predictable efficacy. Nationwide, only one to two percent of MRSA are resistant to linezolid and minocycline; however, up to twelve percent are resistant to doxycycline.

Because there is a generic minocycline available, the cost issues are largely negated. There are other issues such as hypersensitivity reactions and rare autoimmune phenomena. The authors feel, from a microbiological standpoint, minocycline is a preferred drug.

Herpes

We now have some new therapies available for the treatment of herpes. Herpotherm utilizes thermotherapy for genital herpes. A prospective study conducted in Russia evaluated 32 women. Twenty-one patients received thermotherapy plus acyclovir and ten received thermotherapy alone. Treatment was initiated with the first objective sign of HSV-2. Within one day, symptoms were gone or almost gone, with or without acyclovir as concomitant therapy demonstrating that thermotherapy is beneficial for genital herpes. Although exposure id of short duration (seconds), patients should be warned to expect some discomfort.

Topical zinc sulfate in-vitro inhibits the growth of HSV. Mahajan and colleagues tried various concentrations of zinc sulfate on 100 clinical and Tzanck verified men with genital HSV over a six-month period. They had a very specific treatment protocol:

Q5d x 1 mo
Then Q10d x 2 mo
Then Q15d x 3 mo

Of note, all of the patients had nine or more recurrences per year, i.e., frequent outbreaks of genital HSV. Here’s what the authors found:

4% Zinc sulfate is a cheap, non-toxic therapy that is easy to use and may be a viable treatment for hard to manage HSV-2. The key is to apply this when there is an outbreak and as it heals, patients should continue to follow the protocol. (Mahajan BB. Indian J Sex Transm Dis. 2013;34:32-34.)

Flat Warts

A study by Li and colleagues, published in the Journal of the European Academy of Dermatology and Venereology evaluated photodynamic therapy with five percent, ten percent, and twenty percent aminolevulinic acid (ALA) in the treatment of generalized recalcitrant facial verruca plana. This was a prospective study of 55 adult patients with bilateral facial flat warts. The two sides of the patient’s faces were randomized to receive ALA 5 percent, 10 percent or 20 percent. There was no placebo control. Patients were irradiated with a 633-nm red light in two 7.5- minute sessions, separated by 30 minutes of non-exposure. This was repeated three times, every two weeks. This study demonstrated that ALA 10 and 20 percent were most efficacious for the treatment of generalized recalcitrant facial verruca plana. In the United States, we have Levulan Kerastick (20% ALA-d). (Li Q, et al. J Eur Acad Dermatol Venereol. 2013 Nov 25. [Epub ahead of print])

Onychomycosis in Psoriatic Patients

A systematic review by Klaassen and colleagues analyzed the literature with regards to the prevalence of onychomycosis in patients with nail psoriasis. They looked at over 700 studies out of which they chose ten based on their criteria. The authors found that an average of 18 percent of psoriasis patients with nail dystrophy have concurrent onychomycosis. There was no shift from dermatophytes to saprophytes or yeast in these studies. Because psoriasis is treated with immunosuppressive agents, this may aggravate any concurrent fungal infection. (Klaassen KMG, et al. J Eur Acad Dermatol Venereol. 2013 Aug 19)

Take Home Message: It is important that we check for fungal disease in patients with psoriasis nail dystrophy before instituting therapy.

Atypical Mycobacteria/Nontuberculous Mycobacteria

In a case series and epidemiologic study, Falsey and colleagues looked at cutaneous inoculation of nontuberculous mycobacteria during professional tattooing. How does this happen? One to four weeks after the tattoo is placed, it may itch or hurt and there are monomorphous crusted papules or postules that are confined to the tattoo area. At first blanche, we might look at this and think it’s bacterial, but it turns out that it is Mycobacterium either abcessus or chelonae. Clarithromycin, minocycline and ciprofloxacin are all viable treatment options; however, the authors strongly recommend that you send off one the papules for culture and sensitivity because the sensitivities vary widely. Why does this happen? Because the atypical mycobacteria are found as a contaminant in the tattoo ink or sometimes the non-sterile water used to dilute the ink (especially when outsourced from China). (Falsey R, et al. Clin Infect Dis. 2013;57(6):e143-147.)

Take Home Message: Think NTM in new tattoo lesions

Herpes Zoster

Wang and colleagues conducted a population-based retrospective cohort study looking at herpes zoster infection and acute coronary syndrome (ACS), i.e., any event that suddenly decreases blood flow to the heart muscle (heart attack, unstable angina). This study included 59,958 patients with herpes zoster compared to an age/sex- matched cohort of 231,832 non-zoster patients. The authors found that acute coronary syndrome was associated with herpes zoster 25 percent more commonly. This was statistically significant (p=.0001) at both three months and one year after the herpes zoster was resolved. (Wang CC, et al. Br J Dermatol. Dec 6, 2013. e-pub ahead of print)

Take Home Message: Warn zoster patients about the risk of ACS and review symptoms of ACS.

Flood-related Skin Diseases

Flood, one of the most common natural disasters, has contributed to many public health problems. A study conducted in Thailand identified the following flood-related dermatological disorders:

Irritant contact dermatitis
Webspace tinea pedis
Webspace mixed infection
Cellulitis (S. pyogenes, Aeromonas)
Gas gangrene (clostridium)
Fasciitis (Vibrio spp)
Traumatic wounds (check cuts for lacerations, punctures, serious digital injuries)
Insect bites and stings (mosquito, fire ant, centipede)
Animal bites (stray dogs/cats, snakes)
Aggravation of pre-existing skin disease due to psychic trauma (psoriasis, atopy/eczema, alopecia areata, urticaria, vitiligo)

Melanoma Clinic: Lunch, Lesions, and Lessons: Part 3

November 5, 2014

Hensin Tsao, MD, PhD

Ilona Frieden

Philip LeBoit, MD

Keith Flaherty, MD

Case Study

A forty year-old woman presents to her PCP with a lesion that she had removed near her left knee (cryotherapy) about one year ago. She thinks something is returning. “It is a tiny miniscule nodule that appears to be a scar.” This appears to be a dermatological issue and “she wants to see her old dermatologist to have it rechecked.” What is an appropriate next step for the physician?

Refer and document
Refer and follow-up with phone call in 1 m
Refer and call the local dermatologist
Refer and follow up with letters until lesion is removed

If you have a general concern, three certified letters can be a good approach. It is extremely important to follow-through and maintain good communication so that you are not held liable.

Seven months later, the patient returns to the PCP with her parents. She was diagnosed with an invasive melanoma. She didn’t see the dermatologist, whom she was supposed to see last spring, until just recently. The patient was referred to Massachusetts General Hospital.

Melanoma on the left knee showed NMM; 7.5mm thick, ulceration 0.4mm, 12 mits/mm²; no microsatellites. She underwent wide resection and sentinel lymph node biopsy (0/8). One year after the diagnosis, she returns for a follow-up and informs you that she wants to become pregnant. She is now 41 years old and she had a miscarriage several years ago. This scenario is not uncommon and Dr Tsao has had referrals regarding this situation.

What do you tell a 41 year-old woman with a stage IIc (life expectancy 30-50%) melanoma about pregnancy?

Fine to become pregnant
Wait at least 2 years
Wait at least 5 years
Wait at least 10 years

Dr Flaherty comments that the fundamental question that we don’t have a great answer to is whether or not every instance of microscopic metastatic disease would ultimately manifest as overt metastatic disease with time. Or, are there patients who can live chronically, i.e., forever with microscopic disease? We do know of late relapses with melanoma. Dr Flaherty tends to tell patients the suggestion that microscopic metastatic disease will convert to macroscopic metastatic disease and the worst that could happen, in the pregnancy setting, is that you could influence the conversion, in other words, it could happen sooner. It is also important to discuss where patients are on the risk curve. The risk of occurrence falls with time.

The risk of relapse after 10 years is actually not clear because high-risk lesions should have relapsed by then while thin relapses continue to emerge. There are differences in the kinetics of relapse between a thin melanoma and a thick melanoma. The bigger the tumor, the more aggressive it is. If the patient survives to year five or ten, it is less likely that something will happen. In fact, there might be a cross over point, probably around year 10, whereby if you had a thick tumor and you’re still alive, the likelihood of it recurring is quite low.

Pregnancy and Melanoma

There are many case control series of melanoma during pregnancy versus not during pregnancy. A 2008 study found no evidence that pregnancy worsens the prognosis. (Cancer Causes Control. 2008;5:437) Some studies suggest that melanoma during pregnancy may be slightly thicker but survival is not altered that much.

The patient visits with a high-risk obstetrician who clears her to become pregnant. Three months later, she finds out that she is pregnant. How do you follow a pregnant person with a history of melanoma?

Routine post-melanoma surveillance
Routine surveillance with total body photography
Increased surveillance every three months
Increased surveillance with total body photography

Total body photography could be a viable option. There is really no literature on dermoscopy in pregnancy. These patients should be followed very carefully. Regarding post-melanoma surveillance, you don’t need to necessarily change your practice because of pregnancy. There are no great studies that convincingly demonstrate a higher risk of relapse during pregnancy. This is highly anecdotal, yet it is very compelling and memorable when it happens.

At week 17 of her pregnancy, she noticed a small, firm nodule within her melanoma scar. Wedge biopsy showed recurrence of melanoma with neurotropism. Wide resection cleared recurrence and a skin graft was placed.

Management of Melanoma Recurrence During Pregnancy

There are treatment options; however, there are no data for metastatic disease during pregnancy. With regards to immunotherapy, high-dose IL-2, which is a physiologic stress, poses a theoretical risk of abruption (in the setting of hypotension). Ipilimumab is likely the first-line choice. Looking at targeted therapy, BRAF inhibitors showed no risk of teratogenicity in limited preclinical studies and MEK inhibitors are theoretically of greater concern; however, that may not be the case in combination with BRAF inhibitors. Chemotherapy is rarely an attractive first-line option in any case.

Package Inserts

Vemurafenib
- Pregnancy Category D
- Vemurafenib can cause fetal harm when administered to a pregnant woman based on its mechanism of action
Iplimumab
- Pregnancy Category C
- Use ipilimumab during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The patient received XRT to the left knee graft area with shielding of the fetus to prevent radiation crossover. At 36 weeks, she underwent a Caesarian section. A histological examination of the placenta did not reveal melanoma. (There have been reports of metastases to the placenta or fetus) One month after delivery she noticed two subcutaneous nodules in the mid-calf distal to the scar site. A biopsy showed metastatic melanoma consistent with in-transit disease. PET/CT showed multiple left lower leg FDG avid nodules, but no visceral metastases. Both radiologically and clinically, she’s beginning to develop at a faster pace.

What would you recommend now?

Isolated limb perfusion
Targeted removal of individual lesions
Genotyping with anti-BRAF agent if BRAF+
Systemic treatment with IL-2 or immune checkpoint antibody

In-Transit Metastases

We lack high-level evidence for the optimal approach in this case. According to the NCCN guidelines, enrollment in a clinical trial is the preferred approach. Options for local therapy include complete surgical excision, intralesional injection (BCG, IFN, IL-2), local ablation therapy, topical imiquimod for superficial dermal lesions, and consideration of palliative XRT for unresectable disease. Isolated limb infusions/perfusions with melphalan could be considered as a regional therapy option as well as the use of systemic therapy. Systemic used to be considered as bottom of the list; however, it is being utilized more and more.

The issue with regional therapy is that it has no impact on disease elsewhere. With regards to intralesional therapy, Weide and colleagues found a high response rate after intratumoral treatment with IL-2 in a phase two study of 51 patients with metastatic melanoma. The 2-year survival rate was 77 percent for patients with stage IIIB/IIIC disease. Efficacy and survival did not differ between patients who had greater than or equal to 20 lesions and patients who had less than 20 lesions. (Weide B, et al. Cancer. 2010;116(17):4139-4146.)

Alexander and colleagues analyzed factors that influenced the outcome in patients with in-transit malignant melanoma undergoing isolated limb perfusion using modern treatment parameters. Between May 1992 and February 2005, 91 patients underwent a 90-minute hyperthermic ILP. There were 62 complete responses (69%) and 23 partial responses (26%) in 90 assessable patients.

The patient underwent isolated limb perfusion with melphalan but unfortunately continued to progress. She continued to progress through multiple experimental treatments over the ensuing year and she expired six years after her initial diagnosis.

Pregnancy and Melanoma-Take Home Points

Pregnancy does not appear to compromise survival
- “Wait time” considerations include:
  - Potential treatment complications during pregnancy
  - Age of patient and desire for children
  - Personal outlook (e.g. religion, “abandoning” children)
  - Availability of oocyte cryopreservation
- Risk extinction is more obvious for thicker tumors
Bottom line (not scientifically based)
- For patients with multiple DN- watch q3m’s during pregnancy
- For MIS and thin melanomas- OK to start (need discussion)
- For melanomas >1mm- wait 2 yrs unless age is major concern
Discussion (Push/pull model)
Push information-
- There is the chance of relapse and death (estimate prognosis)
- Come to an agreement on a course of action
- There is a tiny chance of transplacental metastasis
- Pregnancy per se does not appear to influence outcome- gestation cannot be an instrument of guilt or regret
- Need partnership with high-risk OB and possibly early consult with medical oncology
- Patients should probably be monitored more frequently
- Inform patient about possibility of additional biopsies during pregnancy
- Inform patient about oocyte cryopreservation
Pull information (warning: takes time and may be difficult emotionally)-
- Does the patient understand the implications of relapse during pregnancy (including the possibility of termination)?
- What are the plans should baby survive but mother does not?
  - Discussion becomes more concrete and intense as relapse risk increases
  - Wait time is meant to clarify this risk a bit
  - May need social work to help through these conversations

MauiDerm News Editor-Judy Seraphine

Pediatric Dermatology: When to Suspect a Genetic Disease and How to Make a Diagnosis

November 5, 2014

James Treat, MD

In this presentation, Dr James Treat, an expert in pediatric dermatology, discusses genetic diseases in dermatology and provides us with information on how to make an accurate diagnosis.

Dr Treat reminds us that it is impossible to memorize all of the genetic diseases. As dermatologists, we can identify unusual cutaneous findings, i.e., describe the skin, as this can be helpful in making a genetic diagnosis. Remember that pathways can help you understand the disease(s). If you wonder about a genetic diagnosis, always ask yourself these four important questions:

Does your patient have two or more unusual findings?
Is there is a family history of similar findings?
Is the child developing normally?
Does the child have dysmorphic features?

Case Study Example

A child presents to your office with congenital red patches. What are they? What should we do about them?

Does your patient have two or more unusual findings?—Yes, headaches
Is there is a family history of similar findings?—Two uncles and his father have similar findings and he has an uncle with anyeurism
Is the child developing normally?—He is having some difficulty in school
Does the child have dysmorphic features?—No

If you have a patient who has multiple unusual findings OR multiple family members with one unusual finding, use your resources!

Online Mendelian Inheritance in Man (OMIM)- http://www.ncbi.nlm.nih.gov/omim

Google scholar- http://scholar.google.com /

Genetests.org- www.ncbi.nlm.nih.gov/sites/GeneTests/

Technology provides us with an abundance of resources. When we have no idea or no specific search terms, we can use Google; however, we must be cautious in its use. In order to weed out non-scientific website answers, use Google Scholar. Does hand, foot, and mouth affect the buttocks? We can use Google images to search; yet, be aware that many images are mislabeled. OMIM can help when your patient has at least two unusual diagnoses and Genetests.org can aid if you’re wondering if a genetic test is available.

Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM)

Dr Treat feels that this is something that is probably under-recognized. It’s a RASA-1 mutation that is associated with multiple capillary malformations that are inherited autosomal dominantly. There is usually a family history of multiple people with these red patches.

Clinical Pearls:

They look like café-AU-laits, but they are red-purple
They may all be nascent AVMS, so be careful using a laser

Remember that some patients have AVMs internally; they can be anywhere in the central nervous system and early screening for AVMs can be lifesaving. Given the association with CNS/spinal AVMs, the potential recommended work-up would be to consider an MRI/MRA.

Case Study Example

A patient presents with congenital red patches. He has a very large head with hydrocephalus. There is no other family history and he is developing normally. Does the child have dysmorphic features? Yes, he has a very large head and his 2nd and 3^rd toes are fused (syndactyly). If we use our resources (Google Scholar or Google), we will find the name Macrocephaly-Capillary Malformation (and in small writing macrocephaly-cutis marmorata telangiectatica congenital CMTC).. M-CMTC was the name of this disease for a very long time, and went under-recognized because the skin finding is NOT CMTC it is a more recently described entity called a retiulated port wine stain. As dermatologists, we need to be able to tell the difference between the vascular formations.

Associations:

Macrocephaly
CM which tends to fade over time and tend to be more evanescent
2^nd-3^rd toe syndactyly
Developmental delays

How do we diagnosis M-CM?

This disease was recently linked to disruption of the PI3k-AKT signaling. Findings indicative of M-CM are macrocephaly plus capillary malformations and two of the following:

Asymmetry of overgrowth
Developmental delay
Midline facial capillary malformations
Neonatal hypotonia
Syndactyly/polydactyly
Frontal bossing
Joint hypermobility
Hyperelastic skin, and hydrocephalus

This patient was diagnosed with hemangioma with arrested growth. How do we make the clinical diagnosis to differentiate hemangioma from capillary malformations and other vascular malformations? Look for red papules, ulceration (commonly seen in hemangiomas in this area), and large telangiectatic blood vessels as well as a peripheral rim of vasocontriction.

Case Study Example

Your patient presents with exuberant warts on the hands. With widespread, severe warts, we ask ourselves if there could be genetic immunodeficiency. Does your patient have other unusual findings? Yes, he has severe atopic dermatitis and always seems to be sick. There is no family history of similar findings, no dysmorphic features, and the child is developing normally.

Combined Immunodeficiency Associated with DOCK8 Mutations

DOCK8 was recently described as a cause of immunodeficiency that leads to severe viral infections, including the infections that we see as dermatologists, as well as upper respiratory tract infections and severe atopic dermatitis.

Most patients with severe atopic dermatitis and a few warts do not have anything wrong with their immune system; however, if you see a patient with terrible warts and terrible atopic dermatitis, you should think about having that patient see an immunologist.

Case Study Example

You notice congenital tan patches on your patient. What are they? Does your patient have other medical problems? No, and it’s only one tan patch. Is there a family history of similar findings? No. Is the child developing normally? Yes. Does the child have dysmorphic features? Yes, a large head.

This patient has neurofibromatosis Type 1 (NF1-). How do we diagnose this? We need two or more of the following: (Note that several of these findings are dermatologic)

Six or more café-AU-lait spots 1.5cm or larger in post-pubertal individuals, 0.5cm or larger in pre-puberatal individuals
Two or more neurofibromas of any type or one or more plexiform neurofibroma
Freckling in the axilla or groin
Optic glioma (tumor optic pathway)
Two or more Lisch nodules (benign iris hamartomas)
A distinctive bony lesion: dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex
A first-degree relative with NF-1

What if you are sure that your patient has NF-1 and the testing is negative? You can also test for SPRED1.

SPRED1 is a novel mutation in the same pathway regulated by Neurofibromin, It is part of the SPRED/SPROUTY family which regulates MAP kinase activity (as does Neurofibromin). Most patients reported were adults and did not have other sequalae of NF-1. These patients have some increased risk of cognitive and developmental behavior abnormalities.

What is your workup in a healthy ten year-old with an isolated congenital flat tan patch?

Send blood to evaluate for GNAS1 mutation
Reassure
Send blood to evaluate for NF-1 mutation
Send blood to evaluate for SPRED1 mutation

These consults can be frustrating because we don’t always know what else can be doing on. Segmental pigmentary disorders (block-like, midline cutoff, isolated) have clinical characteristics that are reassuring as there is normally nothing else going on. Other diagnoses to be considered:

McCune Albright (typically multiple darker patches along thick lines of blaschko)
Neurofibromatosis (typically >6 oval smaller patches)
SPRED1 (same clinical café au lait macules as NF1)
Speckled Lentiginous nevi (by early childhood can often see the speckling within the larger tan patch)

Conclusions

You, as the dermatologist, have the power of accurate skin description. Look for capillary malformations, warts that are a bit too exuberant and café-AU-lait macules versus other pigmentary disorders. If you suggest a genetic disease, ask the important questions and utilize the resources that technology has provided us.

MauiDerm News Editor-Judy Seraphine

Update in Cutaneous T-cell Lymphoma (CTCL)

October 26, 2014

Alain H. Rook, MD

At MauiDerm 2014, Dr Rook provided the audience with an update on CTCL, a challenging disease in the field of dermatology. Dr Rook, one of the world’s leading authorities on CTCL, is a professor at the Perelman School of Medicine at the University of Pennsylvania.

There is one scenario that unfortunately occurs all too often with patients who present with erythroderma—you must be absolutely sure of the diagnosis before you administer therapies (anti-TNF agents, ustekinumab, cyclosporine, etc) that will blunt the immune response. This is extremely important because you do not want to administer these agents in patients with CTCL as they can lead to rapid disease progression.

Diagnosis of Erythroderma

In an erythrodermic patient, dermatologists should be aware that a single biopsy is inadequate in up to fifty percent of cases due to the absence of critical diagnostic features.

What do we look for in a biopsy?

When looking at a biopsy, we look for well-known epidermotropic morphology. We also look for clusters of cells. Another critical finding is the lining up of some large lymphocytes at the dermal/epidermal junction. The malignant T-cells are being recruited towards the epidermis by chemokines, with the “sentinel sign” a characteristic that is more often found in erythroderma than is epidermotropism. We also need to look for large atypical cells in the dermis occasionally in association with eosiniphils. Eosiniphilia, together with erythroderma, should not equal pityriasis rubra pilaris or psoriasis, but is more characteristic of erythroderma associated with either atopic dermatitis or cutaneous T-cell lymphoma (CTCL).

In up to fifty percent of cases, there is a high frequency of non-diagnostic histology in Sezary syndrome, the leukemic variant of CTCL. Published studies have observed chronic dermatitis in 33 percent of biopsies from Sezary syndrome and no evidence of CTCL in 25 percent of biopsies from these patients. “Non-specific cutaneous histopathologic findings are common in Sezary syndrome.” (Trotter MJ. J Cut Pathol. 1997)

In addition, we like to study both the skin and the blood and determine if there is a dominant T-cell clone. In particular, if you see matching clones in the skin and blood, that’s usually typical of CTCL, but not always. Autoimmunity can be associated with dominant clones; however, you typically do not see the identical clone in the skin and blood in a patient with autoimmune disease. This is much more characteristic of CTCL or a T-cell lymphoma.

Flow cytometry is absolutely critical to perform on an erythrodermic patient in whom you would like to rule out CTCL. Prior to about ten years ago, the gold standard was looking for the loss of CD7 on CD4 T-cells that is known to occur in about 50 percent of leukemic patients. Now, we typically look for loss of CD26, occurring in greater than 90 percent of leukemic patients in our experience. This is important because in more than 80 percent of active erythrodermic CTCL cases, you will see active peripheral blood involvement or leukemia. This is a critical test to perform in a highly skilled laboratory. Many of the public laboratories that are not associated with academic programs do not monitor for loss of CD26.

Flow Cytometry

More useful than Sezary prep
Confirms presence of blood disease
CD4+/CD7- or CD4+/CD26-
False positive increase in CD4+/CD26- T-cells in atopic dermatitis
> 20% circulating lymphocytes that are CD4+/CD26- highly suggestive of Sezary syndrome

Don’t forget about physical examination, i.e., palpate lymph nodes.

It’s important to remember that when you’re treating Sezary syndrome, you should NOT use:

Cyclosporine
Azathioprine
Mycophenylate mofetil
Anti-tumor necrosis factor agents
Anti-IL-12/23

The reason that we cannot use the therapies mentioned above is because the cellular immune response is absolutely critical for these patients. Combined immune potentiators for advanced CTCL have been shown to produce high response rates. These include combinations of interferons, bexarotene (or an RAR specific retinoid), GM-CSF, and photopheresis. We also attempt to debulk the skin with PUVA or total skin electron beam.

It is noteworthy that a 2011 paper demonstrated that psoralen plus UVA light can be associated with the clearing of peripheral blood disease in advanced CTCL. (Raphael BA, et al. JAAD.2011;65(1):212-214.) In fact, three out of the five patients presented in this series cleared their blood when PUVA was added to their regimen. And we certainly can accomplish the same in the majority of patients who receive full dose total skin electron beam.

Why is the skin involved in T-cell lymphoma?

Malignant T-cells are very high expressors of cutaneous lymphoid antigen (CLA). When the cutaneous endothelium is activated by interferon gamma or tumor necrosis factor, you observe upregulation of E-Selectin. The cells then begin to adhere and roll very slowly. The malignant cells are also very high expressers of CCR4; this is important because CCR4 is the chemokine receptor for CCL17 (TARC) which is manufactured in the epidermis and which is responsible for attracting the cells into the skin.

Phase I trial data demonstrate that KW-0761, an anti-CCR4 monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) currently in phase III trials for leukemic forms of CTCL, is both efficacious and safe.

Treatment of CTCL

Alemtuzumab, which is particularly useful for leukemic CTCL in the absence of bulky nodal disease, targets CD52 on T-cells, B-cells, and monocytes, which at high dose, causes patients to become severly immunodepressed. In 2007, Maria Bernengo published a clinical protocol for the use of low-dose alemtuzumab.

3 mg days 1 and 3
10 mg days 5 and 7
Continue 10 mg every other day until Sezary count < 1000/ mm³
Monitor Sezary count Q2 weeks for one month then Q month
If Sezary count exceeds 2000/ mm³ resume treatment
High response rates of non-transformed disease
Low infection rates

Alemtuzumab is extremely effective at this dose and Dr Rook has never seen a serious or life-threatening infection at his institution. But, nevertheless, patients still require prophylaxis against PCP, fungal infection, and against reactivation of Herpes and varicella zoster.

Histone deacetylase inhibitors are very effective for advanced disease, particularly romidepsin. Romidepsin is a parenteral agent that produces responses in advanced disease in about fifty percent for both tumor stage disease and refractory Sezary syndrome. It is generally pretty well tolerated unless the patient has serious cardiovascular disease. While vorinostat is easier to administer because it is oral, patients don’t tend to like it because of unpleasant side effects including diarrhea and fatigue.

Brentuximab vedotin is an agent that is likely to be useful for large-cell transformation and is under investigation. It is currently FDA-approved for CD30-positive lymphomas, ALCL, and relapsed Hodgkin’s disease. This drug is a fusion protein that contains an antibody directed at CD30. This is important because CD30 gets upregulated in large-cell transformation. Appended to it is monomethyl auristatin, a tubulin toxin. In view of its affinity for CD30, brentuximab can be administered to patients with refractory large-cell transformation. Adverse effects can include peripheral neuropathy.

Early Disease

This is the typical arciform distribution of early disease. The fact that we can see clearing in the center is highly suggestive that the host immune response is playing a role in keeping this somewhat under control. The survival rate of patients with stage 1a disease when treated is similar to that of the general population. It is important to note that patients who present with plaques have a worse prognosis than patients who present with patches, these patients need to be treated vigorously and immediately.

Treatment of Stage T1 (patches or plaques on less than 10 percent of the skin surface area)

Potent Topical Steroids
Nitrogen Mustard (0.01-0.04% ointment)
Carmustine (0.03-0.04% ointment)
Narrowband UVB
PUVA
Topical Retinoids (Bexarotene, Tazarotene)
Imiquimod

A novel mechlorethamine 0.016% gel (Valchlor) was FDA-approved in 2013 for the treatment of CTCL. Dr Rook advises that this compound be used with caution because it can be irritating. When using a topical chemotherapeutic, Dr Rook prefers to use it nightly in an effort to avoid drug resistance. However, because Valchlor is irritating, the recommendations are to use it every other night and perhaps in conjunction with topical steroids to prevent/reduce irritation.

Interferon Alpha and Antitumor Effects

Interferon activates anti-tumor cytolytic cells and inhibits the growth of malignant T-cells. It also inhibits the production of Th2 cytokines. We have also found that response rates are greater when used in combination with PUVA, retinoids, photopheresis, and/or interferon gamma. In order to minimize the side effects of interferon, Dr Rook utilizes a low-dose interferon. Nevertheless, there is a dose related effect with higher doses being more efficacious but are less well tolerated.

Treatment Protocol

Initial Dose 5-2.5 million Units SQ 3 x per week
Increase to: 5-7.5 million Units SQ 4-5 x per week
Typical Dose: 5-5 million Units SQ every other day

Bexarotene

Bexarotene induces apoptosis of malignant T-cells. Keep in mind that not all patients will respond; there is only about a forty percent response rate due to the likely reason that the critical RXR receptors may not be expressed at the cell surface of the malignant population in all patients. Dr Rook recommends using bexarotene in combination with interferon, PUVA, and/or photopheresis in an effort to prevent resistance. If you are treating patients using bexarotene, they will require intensive control of hyperlipidemia, i.e, use of a statin and/or other lipid-lowering drugs. Bexartone also produces central hypothyroidism by suppressing TSH so thyroid function should be measured with free T4 (not TSH). Bexarotene may be more difficult to use in diabetics and patients with hyperlipidemia.

Imidazoquinolines

These particular drugs are powerful Toll-like receptor agonists and are therapeutically active for CTCL. Many patients may not respond to imiquimod. Dr Rook prefers to use the Zyclara Pump (3.75% Imiquimod) as it is easier to control the amount dispensed as well as easy to spread.

Resiquimod, a combined TLR 7 and 8 agonist, is at the first stages of the pipeline. It has a bioavailability ten times greater than imiquimod and potency up to 100 times greater than imiquimod. A one-gram application induces a systemic interferon alpha response. Dr Rook is conducting a phase 1 trial with resiquimod and has found that patients get systemic absorption, activation of circulating antigen-presenting cells, and widespread clinical responses. This appears to be a very exciting drug that clears treated lesions and induces the resolution of distant lesions.

MauiDerm News Editor-Judy Seraphine