Highlights from Today’s CME Presentations:
Atopic Dermatitis (AD) Research Updates with Brad Glick
Dr. Brad Glick shared some exciting research on Atopic Dermatitis. He began by discussing where we’re headed: to a place with a better understanding of the presentation, co-morbidities, and therapeutic treatment options for this chronic, inflammatory disease. He briefly discussed how the science has shifted from the 1960’s to present day. He shared challenges to treating this complex condition in a 20-minute office visit while sharing evidence that the burden of disease in terms of affected individuals is expected to rise significantly based upon past and current trends. There is a chilling reality to the significant impact of AD on Quality of Life—not just for the patient, for the caregivers and significant others as well. When you combine these realities with the vast differences in racial and ethnic morphology, one could wish to choose another medical specialty! Don’t lose sight, the future is in the science!
We have a wealth of topical and systemic therapies for AD. We have targeted therapy options for pruritus, barrier repair, and lichenification. AD is a Th2 mediated disease with current treatment targets including IL-5, PDE4, IL-4, IL-13, and Janus Kinase inhibition. Dr. Glick shared pivotal trial data for oral and topical JAK Inhibitors in detail. He also discussed biologic therapies approved to treat AD including IL-4/IL-13 blockade and IL-13 binding. It’s always exciting to have head-to-head data! Dr. Glick revealed research findings of two, head-to-head randomized control trials for abrocitinib vs. dupilumab and upadacitinib vs. dupilumab demonstrating superiority for abrocitinib 200 mg daily dosing for itch response and upadacitinib 30 mg daily for EASI-75 at week 16.
Dr. Glick briefly discussed the next shift in AD research focus: skin microbiome, comorbidities, and pruritus. It’s not surprising learning disability may be associated with AD in children. Skin hygiene is the foundation of therapy in AD. For this reason, focus is shifting to barrier repair and the skin microbiome as consideration for stopping the AD March. The National Eczema Association has funded research looking at psychological burden of disease in AD patients. IL-31 shows promise with itch reduction. According to Dr. Glick, we must focus on the microbiome to reduce overall risks of infection. We have foundational evidence indicating skin microbiota transplantation may have efficacy in this disorder. Finally, itch remains the greatest unmet need in AD treatment.
AD Patients and Contact Dermatitis: Impact of Flares and Systemic Medications with David Cohen
Dr. David Cohen gave us an update on contact dermatitis. Based on new data, we should consider concomitant ACD in patients with recalcitrant AD. Our chief ACD subjects include wool alcohols, cocamidopropyl betaine (and dimethylaminopropylamine), chromate, and fragrance mix 1. To adequately care for the AD patient, we should be familiar with patch testing. Consider some allergens can polarize and cross-sensitize. For instance, nickel can skew results to fragrance allergy due to baseline inflammation. Dr. Cohen shared data indicating Methotrexate may not affect patch test results and may be safe to use while patch testing. However, this may not be true for azathioprine, cyclosporine, and oral prednisone which seem to show a high degree of lost reactions. Duplilumab treatment may not equate with complete clearance of rash in patients with AD who have co-morbid ACD. For this reason, we should be comfortable distinguishing between AD and ACD. The hallmark of therapy for ACD remains avoidance of the offending allergen. Dr. Cohen reminded us to beware of “natural” therapies which can be sensitizing agents. In conclusion, patch testing during acute flare of AD may not yield useable data because patch testing on affected skin may alter the results.
Psoriasis Therapy and Infection: Realities and Myths with Ted Rosen
In true Dr. Rosen fashion, he began his discussion with a question: Does psoriasis cause infection or does infection cause psoriasis? Well, the short answer: BOTH! The most known infections which can trigger psoriasis are b-hemolytic strep and HIV. Interestingly enough—just to taunt us with his wisdom, Dr. Rosen showed a study indicating patients with PSO who had a tonsillectomy showed PASI 30-90 responses from surgical therapy alone compared with those who PSO and no tonsillectomy. We recognize that PSO has a slightly higher prevalence amount HIV+ individuals compared with the general population. Did you know some therapies (Highly Active Antiretroviral Therapy) in HIV may resolve PSO? Well, it’s true! What muddies the water is the reality that patients with PSO are at an increased risk of non-serious and serious infections—even though the risk is low. It is helpful to have a good understanding of what infection vs. serious infection represents. Infection includes nasopharyngitis, upper respiratory infection, HS< and impetigo. Whereas serious infections include cellulitis, sepsis, osteomyelitis, meningitis, pneumonia, zoster, necrotizing fasciitis, active TB, and COVID infection.
Dr. Rosen shared data sets of commonly used systemic therapies for psoriasis with rates of serious infections. In addition, he reminded us about acitretin, a second-generation retinoid, with an infection rate less than half of methotrexate, even when used chronically. Dr. Rosen detailed methotrexate to be less risky for infection than some biologic agents and cyclosporine, except with latent tuberculosis and HIV which may be increased risk. Apremilast gets “two green stars” from Dr. Rosen indicating low risk of infection and serious infection. Patients treated with cyclosporine are at greater infection risk while on therapy. TNF-alpha can reactivate both TB and HBV with the highest risk being for infliximab. The IL-23 and IL12/23 class gets very minor associations with infection. The IL-17 Class has known risks for mucocutaneous candida infections. COVID-19 has altered our thinking in terms of therapy for psoriatic patients.
Dr. Rosen suggests shared decision-making is important with this serious infection. Further, current best evidence suggests most therapies for PSO and PSA do not meaningfully alter risk of COVID-19 acquisition or prognosis. COVD-19 immunizations are not contraindicated in patients receiving biologic therapy. However, patients on infliximab and other systemic therapies may not develop adequate immune response from vaccination for COVID-19.
Cutaneous Signs of Systemic Disease with Brad Glick
Dr. Glick gave a fascinating talk this morning on cutaneous manifestations of systemic disease. He began by reminding us that the skin often mirrors systemic manifestations. We can see disorders of the endocrine, rheumatologic, paraneoplastic, cardiovascular, ad other organ systems within the skin. In patients with Diabetes Mellitus, autoimmune skin lesions are common in type 1 whereas cutaneous infections are common in type 2. Necrobiosis Lipoidica (NL) is a necrotizing skin disorder commonly involving the pre-tibial legs of women with DM. NL can also present as bullous. Acanthosis Nigricans (AN) presents as velvety-smooth, hyperpigmented patches in folds of skin (posterior neck, axilla, groin, umbilicus, areola) and is associated with insulin resistance. However, AN is also associated with gastric carcinoma, medications such as corticosteroids and hormonal therapies, pineal tumors, endocrine disorders such as Cushing’s and PCOS, and obesity.
Dr. Glick reminded us to be alert for infections in patients with DM—including candida and bacterial. Thyroid disease commonly affects the skin coloring, thickness, and can cause changes to the eye orbits. As is the case with most comprehensive differential diagnoses, malignancy and paraneoplastic conditions should always be included. Dr. Glick shared several cases from his archive included Bazex’s Paraneoplastic Syndrome, Alopecia Neoplastica, Ductal Breast Cancer, Lesser Trelat Syndrome, Necrolytic Migratory Erythema, and Schnitzer Syndrome. Lipid infiltrations of the eyelids and extremities can occur in coronary artery disease.
If you’ve ever felt challenged to catch cutaneous lupus erythematosus, Dr. Glick shared some keys including malar rash, rash with sun exposure, non-pruritic psoriasiform dermatitis on the back/chest/arms, and a symmetric distribution. Pyoderma gangrenosum is a cutaneous manifestation of Crohn’s Disease. Sweet’s Syndrome manifests as “juicy” red papules on the head/neck, and upper extremities. Sweet’s Syndrome is common after URI and can be associated with AML and polycythemia vera. Seborrheic Dermatitis can be associated with Parkinson’s Disease, HIV infection, and Cerebrovascular Accident. We also looked at common nail manifestations of systemic disease.
Tough Day at the Office: Lupus, Sarcoidosis, and a Side of Morphea with Adam Friedman
Dr. Adam Friedman began his talk today with chilling images from his clinic of patients with lupus erythematosus, sarcoidosis, and morphea. He began with a “Choose Your Own Adventure” feel. Did you choose correctly or were you fooled? He introduced Discoid Lupus Erythematosus (DLE) and helped us understand some key features including prevalence in women and black Americans. According to Dr. Friedman, Cutaneous Lupus Erythematosus is more impactful and disabling than DLE. Alopecia is associated with all forms of cutaneous lupus. We looked at a simple treatment algorithm for using hydroxychloroquine in practice to treat LE. Saphnelo (Anifrolumab) was recently FDA-approved to treat LE and is a Type 1 IFN receptor antagonist. Saphnelo is administered via infusion. There are many other therapies in the pipeline to treat LE so stay tuned! Dr. Friedman also shared some great wisdom about Sarcoidosis. This disorder is most common in females, black Americans, and peaks in the fourth decade. Don’t miss syphilis! It can mimic other infections and skin disorders so don’t be fooled! Dr. Friedman ended his talk looking at morphea and scleroderma. He shared some recommendations for treatment and briefly discussed what to do with recalcitrant disease.
Off-Label Pearls with Ted Rosen
Have you ever wondered how off-label medications began to be considered for treatment in other disorders? Dr. Ted Rosen’s lecture on off-label medications began by discussing neuroleptics, doxycycline, carvediolol, topical timolol, and indomethacin for burning red scrotum syndrome. The next time you see generalized Granuloma Annulare in the office, don’t fear! Consider steroids, the Excimer laser, Humira (adalimumab), Stelara (ustekinumab), Otezla (apremilast), Dupixent (dupilumab), or methotrexate. In a small study from China, hyperthermia of molluscum contagiosum was therapeutically helpful for reduction of pox.
When you become frustrated with the wart that won’t go away, consider encouraging HPV vaccination per Dr. Rosen. There is some data suggesting HPV vaccination may be helpful for wart clearance. Citrus Bioflavonoid (go ahead, add it to your shopping cart) may be helpful in senile purpura. Try a nitroglycerin patch on condradermatitis nodularis helicis! When appropriate, oral, low dose minoxidil may be used in chronic telogen effluvium. Consider hydroxychloroquine and finasteride combo-therapy for frontal fibrosing alopecia. Dupixent (dupilumab) may be helpful to treat widespread Grover’s Disease. Olumiant (baricitinib) can treat lichen planus onychodystrophy.
Dr. Rosen suggested combination therapies for scabies infestations such as oral ivermectin and permethrin or Spinosad for optimal outcomes. He also described a “painless PDT” using natural sunlight for incubation and pre-treating with oral Vitamin D3 supplementation prior to Levulan (aminolevulinic acid) application. In recalcitrant Hidradenitis Suppurativa, consider combination biologic agent and surgery. Finally, oral cimetidine may be helpful as adjuvant therapy in the treatment of acute atopic dermatitis and 5% Cysteamine (which can be purchased for around $50 from Walmart) can be useful in Melasma/Chloasma patients.
Handling Hidradenitis with Hefty Immunomodulators with Adam Friedman
Dr. Adam Friedman began his talk entitled, “Handling Hidradenitis with Hefty Immunomodulators” by reminding us of the many unique presentations of HS. He insisted we view the whole patient with HS understanding this systemic, inflammatory disease state has many comorbidities. Further, don’t miss Squamous Cell Carcinoma arising with an HS plaque! If something isn’t responding to treatment consider a biopsy for confirmation of diagnosis. Our North American HS Treatment Guidelines remind us to screen for metabolic syndrome, depression, anxiety, diabetes, PCOS, inflammatory arthropathy, and tobacco abuse. We should consider a referral to other specialists in some patients.
Dr. Friedman reminded us of a staggering reality! It takes an average of 7-10 years to get a HS diagnosis. Missed, ignored, and undertreated HS is commonality. Our HS patients require education on disease-state, nutrition support (minimal dairy, low-carbohydrate with the current best evidence), and a thorough discussion about minimizing friction/trauma to areas of disease activity for best outcomes. He reminded us of factors that can worsen HS such as medications (lithium, androgenic medications, progestins like hormonal IUD’s and Depo-Provera injections), Smoking, Stress, Friction/Trauma, and Obesity.
Did you know—there is some evidence for zinc and Vitamin C supplementation for patients with HS? To control inflammation in HS, we use oral antibiotics (Clindamycin, Rifampin, Tetracycline antibiotics), corticosteroids, retinoids, anti-hormonal therapies, and biologic agents. Dr. Friedman insists combination therapy is imperative. When patients are progressing, he recommended considering other therapeutic treatment options. When “problem areas” remain despite aggressive treatment, consider surgical treatments. Dr. Friedman shared evidence Dapsone can be used to treat HS. Remicade (infliximab), Stelara (ustekinumab) and Humira (adalimumab) are widely used therapies for HS. However, methotrexate can be used in combination with these therapies. Surgical outcomes can offer wonderful control but patients should stay on systemic therapy for best results. Cosentyx (secukinumab) may be approved for HS soon. However, some case reports reveal Cosentyx (secukinumab)-paradoxical HS. Dr. Friedman shared case report data of Siliq (brodalumab) use in HS with strong results. Bimzelx (bimikizumab) is currently in Phase 2 testing for HS and other therapeutic targets include IL-23, IL-36, JAK inhibition, and Complement Proteins. Stay tuned for future options for patients with HS!
Scientific Poster of the Day
POSTER NUMBER: 16
TITLE: Comparison of the Affinity and in vitro Activity of Lebrikizumab, Tralokinumab, and Cendakimab
AUTHORS & AFFILIATIONS:
Angela Okragly1, Aya Ryuzoji2, Montanea Daniels1, Chetan Patel2, Robert Benschop1
1Immunology Research and 2BioTechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285
ABSTRACT:
Background: Interleukin 13 (IL-13) is the primary upregulated cytokine in atopic dermatitis skin biopsy samples and is a central pathogenic mediator driving multiple features of atopic dermatitis pathophysiology. Lebrikizumab is a novel, monoclonal antibody that selectively targets IL-13 and prevents formation of the IL-13 receptor alpha 1 (IL-13Rα1)/IL-4 receptor alpha (IL-4Rα) heterodimer receptor-signaling complex. Tralokinumab and cendakimab are other antibodies to IL-13 that inhibit signaling by preventing IL-13 from binding to both IL-13Rα1 and IL-13Rα2. We undertook studies to compare the in vitro binding affinities and functional activities of lebrikizumab, tralokinumab, and cendakimab.
Methods: The binding kinetics and affinity were studied using surface plasmon resonance. Antibodies were captured on the surface of a CM4 chip with immobilized Protein A followed by the injection of different concentrations of IL-13 to assess the binding kinetics on a Biacore T200 (Cytiva, Marlborough, MA) at 37oC. IL-13 reagents were expressed in HEK293 and purified by standard methods. STAT6 reporter assay was performed in human HEK293 cells (transfected with STAT6 reporter construct, Invivogen, San Diego, CA) were incubated with compounds and 3 ng/mL glycosylated human IL-13 at 37°C at 5% CO2. STAT6-reporter activation was measured after overnight incubation using QuantiBlue reagent (Invivogen). Primary cell assays were performed in primary human dermal and lung fibroblasts incubated with compounds and 200 ng/mL glycosylated human IL-13 at 37°C with 5% CO2. After 48-hour incubation, cell culture supernatants were collected and periostin secretion was measured by ELISA (R&D Systems Inc., Minneapolis, MN).
Results: The binding affinity of lebrikizumab to aglycosylated human IL-13 was <5.9 pM (n=1) at 37°C, which is similar to previously published values. Lebrikizumab binds the more physiological relevant glycosylated form of human IL-13 with a binding affinity of 187±7.9 pM (n=3, SD) at 37°C. In comparison, the binding affinity to glycosylated IL-13 was 1804±154 pM for tralokinumab and 1132±67 pM for cendakimab. The IC50 of lebrikizumab was 13.3±1.0 pM (n=3, SD) while the IC50 was 97±19.8 pM for tralokinumab and 37±19.5 pM for cendakimab, demonstrating that lebrikizumab was significantly more potent in preventing IL 13Rα1/IL-4Rα signaling. Similar potency differences were observed in primary fibroblast assays. Our data show that, across these monoclonal antibodies, lebrikizumab has the highest affinity and in vitro potency, followed by cendakimab, and then tralokinumab.
Conclusion: Overall, lebrikizumab binds human IL-13 with high affinity and neutralizes its functional activity with high potency, providing insight to the clinical efficacy seen by lebrikizumab in Phases 2b and 3 atopic dermatitis studies.
SPONSOR: Eli Lilly and Company