For decades, limited understanding and a lack of available treatment options made neuromyelitis optica spectrum disorder (NMOSD) an especially difficult diagnosis for neurologists to make and deliver. A rare and lifelong autoimmune disease that impacts the optic nerve(s) and spinal cord,

 NMOSD affects up to 15,000 people in the U.S.,

 and can cause lasting damage to the nervous system, including blindness, muscle weakness and even paralysis.

 Due to its overlapping characteristics with multiple sclerosis (MS), NMOSD is often misdiagnosed and can worsen if treated improperly with MS medication or if left untreated.

The importance of proper diagnosis and treatment for NMOSD cannot be underestimated. Without treatment, in just five years from diagnosis, up to half of people with NMOSD will likely require a wheelchair, and more than 60 percent may become functionally blind.

 Until recently, there were no medicines specifically evaluated and approved to treat NMOSD, leaving healthcare professionals with limited options for treatment. Given the progressive nature of this debilitating condition, the medical community was in need of targeted treatments.

Fortunately, the understanding of NMOSD has improved substantially, thanks to continued investment in neuroscience research and development, and collaboration between biotechnology companies, healthcare providers and patient advocacy organizations. These advancements have paved the way for Genentech, a member of the Roche Group, to better understand NMOSD and advance treatment.

Meaningful Advancements in Understanding the Science of NMOSD

Although it’s not clear what causes NMOSD, there is strong scientific evidence that interleukin-6 (IL-6), a protein made by immune cells, may play a key role in the inflammation associated with the condition. IL-6 helps regulate the body’s immune response to inflammation, including the production of aquaporin-4 (AQP4) antibodies, which target and damage cells found in the optic nerves, brain and spinal cord. In response, these cells produce even more IL-6. In fact, IL-6 has been found in excess in the blood and brain of people diagnosed with NMOSD. Increased IL-6 can lead to more inflammation, which can lead to relapses, one of the clinical hallmarks of the condition. These unpredictable, severe relapses may cause cumulative, irreversible, neurological damage and disability for those living with NMOSD.

Ashish Pradhan, M.D., Executive Director of Neuroimmunology at Genentech, explained that this improved understanding of the connection between IL-6 and NMOSD inspired researchers at Chugai, another member of the Roche Group, to explore what happened when IL-6 receptor activity was blocked. “They hypothesized that by blocking IL-6 signaling pathways, it could reduce the inflammation commonly seen in people with NMOSD. A novel recycling antibody technology was used so that after binding to the IL-6 receptor, the treatment being designed could be released back into circulation, allowing it to bind to other IL-6 receptors. This continued investment in research and development paved the way for our team at Genentech to better understand the condition and help deliver a new, innovative treatment.”

It has been a little over one year since EnspryngTM (satralizumab-mwge) was approved by the U.S. Food and Drug Administration in August 2020 as the first and only subcutaneous treatment option for adults with AQP4 antibody-positive NMOSD, which is detectable in approximately 80 percent of those living with the NMOSD.

 It is also the only approved NMOSD therapy designed to target and inhibit the IL-6 receptor.

Enspryng was studied in one of the largest pivotal clinical trial programs undertaken for this rare neurological disease. The two studies -- SAkuraSky and SAkuraStar -- found that Enspryng significantly reduced the risk of relapse in AQP4 positive patients at 96 weeks compared to treatment with a placebo by 74% and 78% respectively [HR = 0.26, 0.22; CI = (0.11, 0.63), (0.06, 0.82); p = 0.0014, 0.0143].

 Enspryng is contraindicated in patients with a known hypersensitivity to satralizumab or any of the inactive ingredients, an active hepatitis B infection, or active or untreated latent tuberculosis. The warnings and precautions for Enspryng are infections, including hepatitis B virus reactivation and tuberculosis, elevated liver enzymes, decreased neutrophil counts, and hypersensitivity reactions. Appropriate precautions should be taken by the healthcare provider when considering vaccinations.

“For decades, we relied on unproven or off-label therapies in a sort of ‘blunt force’ approach to treat NMOSD,” said Geoffrey Eubank, M.D., System Medical Chief, General Neurology at OhioHealth Neurological Physicians and one of the Enspryng clinical trial investigators. “Exploring the role of IL-6 in NMOSD and discovering a treatment to block those chemical messengers and reduce attacks has filled a significant gap in how NMOSD is treated and provided much-needed hope for patients and those of us who treat them.”

In addition to its IL-6 inhibition, Enspryng was designed using novel recycling antibody technology that allows for longer duration of antibody circulation and subcutaneous dosing every four weeks.

 Instead of needing to go to a healthcare facility for infusion therapies, Enspryng can be self-administered by a person living with NMOSD or a caregiver at home, after an initial loading dose and following training from a healthcare provider, if deemed appropriate by a physician.

Continuing to Advance the Science of NMOSD

While Genentech has made a tremendous advancement in NMOSD, its work isn’t over yet. The discovery of the role of IL-6 role in NMOSD has redefined the company’s understanding of the condition and it remains committed to advancing NMOSD clinical research, including ongoing safety and efficacy studies with Enspryng. Genentech is also conducting research to gain a deeper scientific understanding of NMOSD in diverse patient populations that could help provide better care for those living with the condition.

Dr. Pradhan added, “We are proud of the progress we have made in addressing many key challenges that have long eluded the neuroscience community, including NMOSD and other neurological conditions that limit human potential. To sustain this forward trajectory, we must continue to follow the science, push the boundaries of scientific understanding, monitor the safety and efficacy of our treatments and keep patients where they belong -- at the heart of our research. We can then look to the future of neuroscience with more confidence, knowing that we will continue to focus on areas with the highest unmet needs and provide patients with the support and care needed to live their best lives beyond their disease.”

For more information on Enspryng, please visit 

Important Safety Information & Indication

ENSPRYNG is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

ENSPRYNG is contraindicated in patients with a known hypersensitivity to satralizumab or any of the inactive ingredients, an active hepatitis B infection, or active or untreated latent tuberculosis.

An increased risk of infections, including serious and potentially fatal infections, has been observed in patients treated with IL-6 receptor antagonists, including ENSPRYNG. The most common infections reported in a randomized clinical trial of patients treated with ENSPRYNG who were not on other chronic immunosuppressant therapies and that occurred more often than in patients receiving placebo, were nasopharyngitis (12%) and cellulitis (10%). The most common infections in patients who were on an additional concurrent immunosuppressant, and that occurred more often than in patients receiving placebo, were nasopharyngitis (31%), upper respiratory infection (19%), and pharyngitis (12%). Delay ENSPRYNG administration in patients with an active infection, including localized infections, until the infection is resolved.

Risk of HBV reactivation has been observed with other immunosuppressant therapies. Patients with chronic HBV infection were excluded from clinical trials. Perform HBV screening in all patients before initiation of treatment with ENSPRYNG. Do not administer ENSPRYNG to patients with active hepatitis. For patients who are chronic carriers of HBV [HBsAg+] or are negative for HBsAg and positive for HB core antibody [HBcAb+], consult liver disease experts before starting and during treatment with ENSPRYNG.

Tuberculosis has occurred in patients treated with other IL-6 receptor antagonists. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating ENSPRYNG. Consider anti-tuberculosis therapy prior to initiation of ENSPRYNG in patients with a history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consult infectious disease experts regarding whether initiating anti-tuberculosis therapy is appropriate before starting treatment. Patients should be monitored for the development of signs and symptoms of tuberculosis with ENSPRYNG, even if initial tuberculosis testing is negative.

Live or live-attenuated vaccines should not be given concurrently with ENSPRYNG because clinical safety has not been established. Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ENSPRYNG for non-live vaccines.



Mild and moderate elevations of liver enzymes have been observed in patients treated with ENSPRYNG at a higher incidence than in patients receiving placebo. ALT and AST levels should be monitored every 4 weeks for the first 3 months of treatment, followed by every 3 months for one year, and thereafter, as clinically indicated.

Decreases in neutrophil counts were observed in patients treated with ENSPRYNG at a higher incidence than placebo. Neutrophil counts should be monitored 4 to 8 weeks after initiation of therapy, and thereafter at regular clinically determined intervals.

Hypersensitivity reactions, including rash, urticaria, and fatal anaphylaxis, have occurred with other IL-6 receptor antagonists.

There are no adequate data on the developmental risk associated with the use of ENSPRYNG in pregnant women. In an animal reproduction study, no adverse effects on maternal animals or fetal development were observed in pregnant monkeys and their offspring, with administration of ENSPRYNG at doses up to 50 mg/kg/week. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

No information is available on the presence of ENSPRYNG in human milk, the effects of ENSPRYNG on the breastfed infant, or the effects of ENSPRYNG on milk production. ENSPRYNG was excreted in the milk of lactating monkeys administered ENSPRYNG throughout pregnancy. Human IgG is excreted in human milk and the potential for absorption in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENSPRYNG and any potential adverse effects on the breastfed infant from ENSPRYNG or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of ENSPRYNG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, population pharmacokinetic analyses in patients with NMOSD did not show that age affected the pharmacokinetics of ENSPRYNG. In general, caution should be used when dosing the elderly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

The most common adverse reactions (≥15% in either trial) were nasopharyngitis (31%), headache (27%), upper respiratory tract infection (19%), rash (17%), arthralgia (17%), extremity pain (15%), gastritis (15%), fatigue (15%), and nausea (15%).

For additional safety information, please see the full 

REFERENCES
1. Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. Lancet Neurol 2007;6:805-815.
2. Guthy Jackson Foundation. NMO FAQs. https://guthyjacksonfoundation.org/nmo-faqs.
3. Kessler RA, et al. Neurol Neuroimmunol Neuroinflamm 2016;3:e269.
4. Williamson_Poster_2018_ ICPE_Epidemiologic Temporal Trends of NMOSD
5. Chihara N, Aranami T, Sato W, Miyazaki Y, Miyake S, Okamoto T, et al. Interleukin 6 signaling promotes anti‐aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad Sci USA. 2011;108:3701–6.
6. Bradshaw M, Kimbrough D. Neuromyelitis Optica Spectrum Disorders. Practical Neurology. February 2019;76-84.
7. Traboulsee A et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, palcebo-controlled phase 3 trial. Lancet Neurology. 2020;19:402-412.
8. Yamamura T et al. Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder. N Eng J Med. 2019;381:2114-2124.
9. Our Proprietary Technologies: About Chugai.” Chugai Pharmaceutical Co, Ltd. www.chugai-pharm.co.jp/english/profile/rd/technologies.html.
10. Igawa T. Nat Biotechnol. 2010; 28:1203 -07.

Articles

Breakthroughs in NMOSD: Better Understanding the Science and Treatment

Atopic dermatitis (AD) is one of the most common skin conditions managed by primary care clinicians.

 For doctors who care for infants and children, early education in skin care management is vital for the long-term success of patients who struggle with AD and sensitive skin. Eczema Awareness Month is a prime opportunity to equip our patient care teams with evidence-based skin care advice and tips for AD prevention.

Nearly all pediatricians can identify the red, itching rash of AD. Despite this intimate clinical familiarity, the exact cause of AD is unknown. Research has clearly shown a strong association with family history and over 45 genes are implicated in AD.

 However, the heritability of the disease is largely unexplained. Research has also suggested structural deficits and a disordered immune response as causes of AD, but these have never been proven.

 Regardless of the primary cause, patients with AD share the consequences of a complex interaction between internal and external factors that result in a poorly functioning outer skin layer.

The abnormality in patients with AD is a dysfunctional epidermis. Abnormal skin structure and function result in increased water loss, chronic inflammation, increased skin pH, and microbial colonization. In addition, cytokines and other immune modulators interact with neural fibers resulting in chronic itch.

 These changes result in patients with AD experiencing cycles of itching rash with intermittent flares requiring medical care.

Most patients with AD begin to have flares by the age of five years.

 Trouble spots in infancy are the cheeks, scalp, and extensor surfaces of the arms and legs. As kids age, the commonly affected areas are the flexor surfaces of the elbows and knees, ankles, wrists, and neck. Acute flares involve the development of intensely itchy, dry, red papules, and vesicles. Chronic lesions present as thickened skin with altered pigmentation.

 Affected areas change over time due to the natural changes in skin architecture as a person ages.

Infant skin is fully functional at birth but carries some significant differences from mature skin. The transport and distribution of water are notably different in infant versus adult skin, with newborn skin being initially drier and of neutral pH. Over 2-3 months, newborn skin becomes slightly acidic as the acid mantle forms.

 Water-binding factors and free fatty acids increase on the surface of the skin, improving the function of the outermost skin layer as the pH drops. The acid mantle is necessary for proper epidermal function and is influenced by products used on the skin.

Beginning in the labor and delivery suite, care decisions can promote the development of healthy infant skin. At delivery, term infants are covered in a thick substance called vernix. Vernix is thought to be critical to the development of the outmost skin layer while in utero, as well as protective against the unavoidable insults to newborn skin. Although vernix is primarily water, it also contains enzymes and proteins with antimicrobial and water-binding properties. Due to these protective factors, it's recommended that vernix stays on infant skin for at least six hours after birth. Gentle dry wiping after birth allows some vernix to remain in place,

 and delaying the first infant bath until 24 hours of life is preferred.

Use the right products and timing for infant bathing. Routine bathing can begin after the first week of life without disrupting the skin barrier.

 Infant cleansing products should contain a low amount of surfactants and have a neutral to slightly acidic pH. Most research suggests using a liquid-based, mild synthetic detergent, followed by a thorough rinse.

 Immersion bathing is preferred, but typically avoided until the umbilical stump is gone. However, there is little to no evidence of increased umbilical infection with immersion bathing.

 A quick, warm water bath (less than 10 minutes), 2-3 times per week is typically enough for most babies.

After the bath, maintaining and replacing skin moisture is key to routine care, especially for infants at risk of developing AD. Beginning daily, full-body emollient treatments at three weeks of life is one of the few evidence-based AD prevention strategies.

 Emollients should be fragrance-free and contain few preservatives. Additives like ceramides or colloidal oatmeal may be increasingly helpful to hydrate infant skin and are typically well-tolerated.

 After the bath is the best time to apply emollients, trapping water in the skin while preventing water loss.

Although AD classically spares the warm and humid diaper environment, the presence of debris on sensitive infant skin can lead to breakdown and diaper rash. In addition, friction caused by excessive wiping, or the diaper itself, can damage the skin surface and make the area prone to inflammation and infection. For children with sensitive skin, commercially available disposable diapers are preferred to cloth diapers. Disposable diapers do a superior job removing wetness and maintaining proper skin pH during wear.

In addition to disposable diapers, parents should be encouraged to use effective diaper wipes and creams. Diaper wipes with minimal ingredients, like WaterWipes, are preferred to diaper wipes containing surfactants or other unnecessary ingredients. In a large clinical trial, babies cleansed with wipes with the fewest ingredients had less incidence of diaper rash and shorter duration of the rash.

 In turn, WaterWipes was awarded the National Eczema Association seal of acceptance. Finally, applying a barrier ointment or zinc-based diaper cream will protect infant skin from the chemicals in the urine and feces that begin skin breakdown, preventing skin damage that makes babies prone to diaper rash.

Above all else, one of the most powerful care tools for patients with AD is education. At every well visit, reinforcing the message to parents about routine skin care will help families maintain skin integrity and limit AD flares. Providing a written plan for families augments the office conversation and solidifies verbal instruction. Free AD plans to use with patients and their families are available online from reputable organizations, such as the American Academy of Allergy, Asthma & Immunology

 and the American Academy of Dermatology.

Education is not just for the exam room. Our patients need support from all members of our care teams, including the nurses who help with in-office or phone advice. Keeping the medical team up-to-date with current recommendations helps all patients receive a consistent and accurate skin care message. A free, one-hour course on infant skin care is available online from the 

. The course features evidence-based infant skin care recommendations and information on the most common infant rashes seen in the primary pediatric office. This CE-accredited course is ideal for clinical nursing teams, care providers, and interested parents.

Healthy skin care is important for all infants, especially those at risk for AD. Providing evidence-based education to families and caregivers about care for this chronic condition, including best practices and products for bathing and diapering. Additionally, every office visit is an opportunity to remind families about the importance of limiting irritants and replacing skin moisture to prevent AD flares. The efforts of every member of the health care team will ensure each patient has the tools needed for a lifetime of healthy skin.

Dr. Natasha Burgert is a board-certified pediatrician who practices at Pediatric Associates in Overland Park, KS. She is also a spokesperson for the American Academy of Pediatrics and routine contributor to Forbes Health. She also serves as a medical advisor for WaterWipes.

1.Fishbein AB, Silverberg JI, Wilson EJ, Ong PY. Update on Atopic Dermatitis: Diagnosis, Severity Assessment, and Treatment Selection. J Allergy Clin Immunol Pract. 2020;8:91-101.

2.Waldman AR, Ahluwalia J, Udkoff J, Borok JF, Eichenfield LF. Atopic Dermatitis. Pediatr Rev. 2018;39:180-193.

3.Oetjen LK, Mack MR, Feng J et al. Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell. 2017;171:217-228.e13.

4.Gerner T, Haugaard JH, Vestergaard C et al. Disease severity and trigger factors in Danish children with atopic dermatitis: a nationwide study. J Eur Acad Dermatol Venereol. 2021;35:948-957.

5.Blume-Peytavi U, Hauser M, Stamatas GN, Pathirana D, Garcia Bartels N. Skin care practices for newborns and infants: review of the clinical evidence for best practices. Pediatr Dermatol. 2012;29:1-14.

6.Visscher MO, Adam R, Brink S, Odio M. Newborn infant skin: physiology, development, and care. Clin Dermatol. 2015;33:271-280.

7.Johnson E, Hunt R. Infant skin care: updates and recommendations. Curr Opin Pediatr. 2019;31:476-481.

8.Blume-Peytavi U, Cork MJ, Faergemann J, Szczapa J, Vanaclocha F, Gelmetti C. Bathing and cleansing in newborns from day 1 to first year of life: recommendations from a European round table meeting. J Eur Acad Dermatol Venereol. 2009;23:751-759.

9.Silverberg NB. Atopic dermatitis prevention and treatment. Cutis. 2017;100:173;177;192.

10.Price AD, Lythgoe J, Ackers-Johnson J, Cook PA, Clarke-Cornwell AM, MacVane Phipps F. The BaSICS (Baby Skin Integrity Comparison Survey) study: A prospective experimental study using maternal observations to report the effect of baby wipes on the incidence of irritant diaper dermatitis in infants, from birth to eight weeks of age. Pediatr Neonatol. 2021;62:138-145.

11. Aaaai.org. 2021. [online] Available at: <https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Libraries/AtopicDerm-English.pdf> [Accessed 4 October 2021].

12.aad.org. 2021. [online] Available at: <https://assets.ctfassets.net/1ny4yoiyrqia/ZPT1WHhZHcxlpbDgq3hZX/3973a527e55d064306e40509d5004bb7/eczema-action-plan.pdf> [Accessed 4 October 2021].

Atopic Dermatitis Prevention: Evidence-Based Infant Skin Care for the Primary Care Office

Join Linda Stein Gold, MD and Larry Eichenfield, MD for an informative presentation about recent developments in atopic dermatitis (AD). They will review the evolving understanding of AD, diagnosis, management, the patient journey, and new novel treatment option.

To learn more, watch the live broadcast on Tuesday, October 19, 2021, 6:00 pm EDT and 8:30 pm EDT. To register for the event, visit  

https://studio.mjhassoc.com/reach/incyte-broadcast

The Burden of Atopic Dermatitis and a Novel Topical Pathway

The complexity and heterogeneity of asthma reflects its wide range of potential triggers, clinical manifestations, and underlying drivers. Various disease pathways – spanning both innate and adaptive immunity – can serve as tributaries to the chronic inflammatory state at the core of the disease.

In many individuals with severe, uncontrolled asthma, pathogenic processes can overlap dynamically in ways that can change over time.

 This can makes it difficult to base clinical management decisions the apparent predominance of a specific inflammatory pathway and its constituent mediators.

 As a result, the estimated 1 million people in the U.S. contending with severe, uncontrolled asthma face ongoing challenges that can evolve into exacerbations, hospitalizations and consequent use of health care resources.

In recent years, new insights into the role of the airway epithelium in asthma have provided a framework for understanding how diverse and changeable inflammatory signals can converge to promote severe clinical disease. The significance of airway epithelium in asthma derives not only from the well-known structural damage it undergoes but from the proinflammatory signals it initiates.

As the first point of contact between potential asthma triggers and the lungs, the epithelium sits at the headwaters of multiple distinct inflammatory cascades. Whether the immediate trigger is a pathogen, allergen, or irritant, the epithelium can respond by releasing proinflammatory cytokines including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP).

 First identified as a growth factor in the early 1990s, TSLP has more recently attracted considerable scientific interest because of its capacity to drive multiple downstream innate and adaptive immune responses.

TSLP Action Across Major Inflammatory Categories

Despite its vast phenotypic diversity, asthma can be categorized at a high level based on major patterns of inflammation. About two-thirds of individuals with severe asthma exhibit type 2 (T2) inflammatory patterns.

 T2 inflammation includes classic allergy, where antigen presentation to type 2 helper T (Th2) cells promotes the production of allergen-specific IgE antibodies, mast cell degranulation, and release of proinflammatory mediators.

T2 inflammation also encompasses nonallergic pathways that share key features with allergic inflammation. In lieu of antigen presentation and clonal selection of IgE-producing B cells, type 2 innate lymphoid cells (ILC2s) directly provide cytokine signals promoting recruitment and activation of eosinophils.

While a significant proportion of patients with severe asthma exhibit T2 inflammation, there remains a substantial portion of patients with severe asthma who exhibit a non-T2 inflammatory pattern, where target-tissue inflammation is primarily mediated by IL-17A, produced by Th17 cells. Eosinophils do not play a major role in non-T2 inflammation, although neutrophil proliferation may occur. Non-T2 inflammation is commonly associated with late-onset asthma.

, each of these broad inflammatory pathways can ladder back to the epithelial release of TSLP. A broad array of innate and adaptive immune cells – including dendritic cells, naïve and differentiated T cells, ILC2 cells, and mast cells – respond to TSLP via TSLP receptors. TSLP thus is capable of activating diverse downstream inflammatory cascades.

Regardless of the underlying inflammatory processes at play, airway narrowing through progressive tissue remodeling poses major challenges to asthma management that increase in urgency with disease severity.

Early research demonstrates a potential role of TSLP in airway remodeling. Fibroblasts and airway smooth muscle cells (ASMCs) both express TSLP receptors. TSLP has been shown in vitro to stimulate collagen production by fibroblasts and promote ASMC proliferation. ASMCs produce TSLP as well as respond to it; airway remodeling may be mediated in part through TSLP cross-talk between ASMCs and mast cells.

Multiple lines of evidence suggest a central role of TSLP in the pathogenesis of severe asthma, largely independent of inflammatory phenotype and biomarker patterns:

Airway TSLP is overexpressed in patients with asthma and increases with disease severity.

 Airway TSLP expression has been found to be higher in patients with asthma compared with healthy controls, and the elevated levels correlated significantly with asthma severity.

Airway TSLP expression correlates with reduced lung function.

 A study of 70 patients with asthma of varying severity found that airway TSLP concentrations were inversely correlated with FEV

TSLP may drive reduced corticosteroid responses.

 ILC2s obtained by bronchoalveolar lavage from patients with severe asthma showed a reduced in vitro response to dexamethasone after exposure to TSLP. Further, the reduced response to dexamethasone was greater in patients with higher airway TSLP expression.

Our increased understanding of the role of TSLP in asthma underscores the importance of the airway epithelium as the first point of contact with environmental stimuli. TSLP, a key epithelial cytokine produced in response to environmental triggers, can drive multiple downstream inflammatory pathways that may contribute to severe, uncontrolled asthma. Because TSLP sits at the top of these disparate inflammatory cascades, there is evidence that it plays a central role in the pathogenesis of severe asthma.

Global initiative for Asthma. Global strategy for asthma management and prevention, 2020. Available from: 

Roan F, Obata-Ninomiya K, Ziegler SF. Epithelial cell-derived cytokines: more than just signaling the alarm. 

Kupczyk M, Dahlen B, Sterk PJ et.al. Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma. 

Busse WW. Biological treatments for severe asthma: a major advance in asthma care. 

Price D, Canonica GW. Biomarker relatability in the International Severe Asthma Network. 

Centers for Disease Control and Prevention. https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm. 2021.

Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. 

Wang E, Wechsler ME, Tran TN, et al. Characterization of severe asthma worldwide: data from the International Severe Asthma Registry. 

Gauvreau GM, Sehmi R, Ambrose CS, Griffiths JM. 

Rochman Y, Leonard WJ. Thymic stromal lymphopoietin: a new cytokine in asthma. 

Peters MC, Mekonnen ZK, Yuan S, et al. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. 

Bartemes KR, Kita H. Dynamic role of epithelial-derived cytokines in asthma. 

Li Y, Wang W, Lu Z et.al. Elevated expression of IL-33 and TSLP in the airways of human asthmatics In vivo: a potential biomarker of severe refractory disease. 

Liu S, Verma M, Michalec L, et al. Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin. 

Cao L, Liu F, Liu Y, et al. TSLP promotes asthmatic airway remodeling via p38-STAT3 signaling pathway in human lung fibroblast. 

Ko HK, Cheng SL, Lin CH, et al. Blood tryptase and thymic stromal lymphopoietin levels predict the risk of exacerbation in severe asthma. 

Ying S, O'Connor B, Ratoff J, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. 

The Proinflammatory Role of Epithelial TSLP in Severe Asthma 

Total knee arthroplasty (TKA) procedures are one of the most common surgeries in the United States and the demand for TKA procedures continues to increase every year. Annually, 

approximately 790,000 knee replacement surgeries

 are performed, and that number is projected to be 

. While recovery protocols have evolved over the years, surgeons are taking a closer look at how they can improve different aspects of the recovery process with new technology, research, and medications, including non-opioids.

Dr. Vinod Dasa, Professor of Clinical Orthopaedics and Director of Research at LSU Health in New Orleans, is sharing a new analysis about rapid recovery protocols (RRPs) that can enhance and improve patient outcomes following TKA procedures. His goal is to educate clinicians about innovative approaches and medical advancements related to multimodal pain management protocols including using NSAIDs, acetaminophen, local anesthetics, cryotherapy, physical therapy and more.

Like many surgeons, Dr. Dasa and his team were using standard recovery protocols (SRP) to treat patients after total knee replacement surgeries. The SRP included using a femoral nerve block, spinal anesthesia, multimodal analgesia and limited patient education prior to surgery. After considering new advancements in the field, Dr. Dasa and his team set out to revamp the TKA recovery process and develop a protocol that would allow their patients to get back to their day-to-day activities sooner.

A vital component to the new RRP was implementing a coordinated effort from every person involved in the surgical and recovery journey including surgeons, physical therapists, operating room staff, and nurses. Further, the new process included engaging and educating patients about the procedure, technology, and pain management options used throughout the perioperative period. Communication from all of these people throughout the surgical journey was a crucial component of the process.

The team also needed to determine how to measure success for patients following TKA. Two main factors that were evaluated as part of the RRP were range of motion (ROM) of the knee and length of stay (LOS) in the hospital. ROM is measured both before and after surgery using a goniometer, or a compass used by surgeons to calculate precise angles. LOS is determined by the number of calendar days a patient remains in the hospital after the completion of their surgery.

Advances in Pain Management Techniques Prior to Surgery

While Dr. Dasa and his team implemented basic changes (e.g., team approach, improved communication) they also incorporated more technical ones. Recently, attention has turned to the use of presurgical techniques to reduce pain and opioid use associated with knee arthroplasty. Novel platforms, such as cryoneurolysis also known as 

°, have been applied to prospective TKA patients to reduce pain and opioid use. One-to-two weeks before surgery, Dr. Dasa’s team uses this cryotherapy treatment to treat peripheral nerves and immediately reduce pain by using the body’s natural response to cold. This step freezes the sensory nerves prior to surgery and helps patients feel more confident about pain management throughout the surgical process.

Techniques to Manage Pain Intraoperatively

Local infiltration anesthesia (LIA) has become a standard practice for a number of joint procedures over the years. Dr. Dasa and his team use 

® (bupivacaine liposome injectable suspension), a long-acting local anesthetic injected near the surgical site, which slowly releases a numbing medication to provide pain relief for the first couple days after surgery. LIA like EXPAREL have improved enhanced recovery pathways for Dr. Dasa’s patients. After surgery, he encourages clinicians to quickly enroll patients in postoperative physical therapy. Additionally, he reassesses the multimodal pain management strategy by limiting or eliminating the use of opioids to manage pain after surgery.

When using a multimodal approach, including the use of cryoneurolysis, NSAIDs, acetaminophen, local anesthetics, and physical therapy to manage postsurgical pain, Dr. Dasa and his team found that patients’ overall LOS in the hospital decreased. Historically, patients undergoing knee replacements with a standard recovery protocol would stay in the hospital for a few days; however, with the RRP group the LOS decreased to less than one day for most patients. In addition, Dr. Dasa noted the RRP was associated with a higher flexion, or range of motion, in the 12 weeks after the procedure. Dr. Dasa has also seen many patients in the last year reduce their opioid consumption, only taking mild pain relievers following TKA using this novel, multimodal, team-based approach.

The findings from this latest research are encouraging as it points to a multimodal pain management approach enhancing recovery for patients after TKA procedures. Dr. Dasa is dedicated to continuing sharing information about the latest medical advancements, including the use of non-opioid options, with his peers to continue to provide optimal results for his patients.

The iovera° system is used to destroy tissue during surgical procedures by applying freezing cold. It can also be used to produce lesions in peripheral nervous tissue by the application of cold to the selected site for the blocking of pain. It is also indicated for the relief of pain and symptoms associated with osteoarthritis of the knee for up to 90 days. The iovera° system is not indicated for treatment of central nervous system tissue. The iovera° system’s “1x90” Smart Tip configuration (indicating one needle which is 90 mm long) can also facilitate target nerve location by conducting electrical nerve stimulation from a separate nerve stimulator.

The iovera° system is contraindicated for use in patients with the following:

Cryoglobulinemia, paroxysmal cold hemoglobinuria, cold urticaria, Raynaud’s disease, and open and/or infected wounds at or near the treatment site

As with any surgical treatment that uses needle-based therapy and local anesthesia, there is a potential for site-specific reactions, including, but not limited to:

Ecchymosis, edema, erythema, local pain and/or tenderness, and localized dysesthesia

Proper use of the device as described in the User Guide can help reduce or prevent the following complications:

At the treatment site(s): injury to the skin related to application of cold or heat, hyper- or hypopigmentation, and skin dimpling

Outside the treatment site(s): loss of motor function

EXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local analgesia and as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia. Safety and efficacy have not been established in other nerve blocks.

EXPAREL is contraindicated in obstetrical paracervical block anesthesia

Adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via infiltration were nausea, constipation, and vomiting; adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via interscalene brachial plexus nerve block were nausea, pyrexia, and constipation

If EXPAREL and other non-bupivacaine local anesthetics, including lidocaine, are administered at the same site, there may be an immediate release of bupivacaine from EXPAREL. Therefore, EXPAREL may be administered to the same site 20 minutes after injecting lidocaine

EXPAREL is not recommended to be used in the following patient population: patients <18 years old and/or pregnant patients

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease

Warnings and Precautions Specific to EXPAREL

Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL

EXPAREL is not recommended for the following types or routes of administration: epidural, intrathecal, regional nerve blocks 

other than interscalene brachial plexus nerve block

, or intravascular or intra-articular use

The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dosage administered and may last for up to 5 days, as seen in clinical trials

Warnings and Precautions for Bupivacaine-Containing Products

 There have been reports of adverse neurologic reactions with the use of local anesthetics. These include persistent anesthesia and paresthesia. CNS reactions are characterized by excitation and/or depression

 Toxic blood concentrations depress cardiac conductivity and excitability which may lead to dysrhythmias, sometimes leading to death

 Allergic-type reactions (eg, anaphylaxis and angioedema) are rare and may occur as a result of hypersensitivity to the local anesthetic or to other formulation ingredients

 There have been reports of chondrolysis (mostly in the shoulder joint) following intra-articular infusion of local anesthetics, which is an unapproved use

 Cases of methemoglobinemia have been reported with local anesthetic use

How Novel Technologies and Opioid Alternatives Can Improve Patient Outcomes

Revamping Recovery Protocols with Non-Opioid for TKA Procedures

Uncovering the unseen and unspoken signs of eosinophilic esophagitis

“I don’t know what’s going on, but it’s been really hard for me to swallow and it feels like I’m ‘choking’ on my food when I eat.” A 35-year-old male visits your office telling you what brings him in today. When you ask how long this has been happening, he says 15 years, since college. As your conversation continues, you learn he also has heartburn in addition to his dysphagia.

When you ask what prompted him to see you after all this time, he explained the impact on his day-to-day life: the anxiety of having a choking episode at a work dinner or a date. “I’m 35 years old,” he says. “I should’ve been able to figure out how to eat without any issues by now.”

For many patients, the road to an Eosinophilic Esophagitis (EoE) diagnosis can be a long, difficult journey.

 As a disease that is growing in prevalence

, EoE is a chronic, immune-mediated inflammatory disease localized in the esophagus.

 While the exact cause of EoE is unknown, researchers believe several variables play a role, including genetics, environmental factors, immune system dysfunction

EoE impacts an estimated one in 2,000 people

 of all ages and races in the U.S. While both men and women may be affected, men are approximately twice as likely to develop EoE.

The chronic, persistent inflammation of the esophagus can lead to a range

 of symptoms that manifest differently from patient to patient. Younger children including toddlers may exhibit feeding avoidance or intolerance, regurgitation, and vomiting. Older children may have similar symptoms and may also have chest or abdominal pain, and adolescents more often also have dysphagia as well as food impactions in some cases. While adults can experience all of these symptoms, dysphagia is the most frequently reported symptom. Adults with unrecognized, long-standing inflammation and potential esophageal scarring can also experience episodes of food impaction.

Patients with EoE may also present with psychiatric comorbidities.

 One retrospective study found that one-third of adults and one in seven children with EoE have received a diagnosis of a psychiatric condition, like anxiety or depression.*

People with EoE can develop adaptive behaviors to cope with everyday life, especially to manage their symptoms when eating.

Substituting solids with blended or pureed foods

Earlier detection is important as it can help reduce a patient’s potential risk of disease complications.

However, identifying EoE can be complex and delayed diagnosis is common among patients, up to eight years on average for adults according to one systematic review.

Several factors can contribute to these delays. EoE can be under-recognized among specialists.

 Symptoms may also be under-reported by patients — around 50 percent of dysphagia cases may not be discussed with a physician,

** yet it’s the most common symptom of EoE.

Additionally, EoE symptoms can mimic other more common diseases such as gastroesophageal reflux disease (GERD)

 and patients can also present with one or more atopic disorders, such as asthma, rhinitis, atopic dermatitis and food allergies, making it challenging to assess and diagnose.

An EoE diagnosis first begins with a look at the patient experience. Patients should present with esophageal symptoms; however, physicians must be astute to adaptive behaviors and the potential for these behaviors to mask physical symptoms.

Endoscopic and histopathologic results are other critical factors to consider.

 An endoscopy can help assess severity of EoE based on specific features, including edema, rings, exudates, furrows, and strictures.

 Of those with EoE, up to approximately 25 percent have normal endoscopic findings.

*** Current guidelines stipulate that esophageal biopsy results demonstrate an eosinophil count of ≥15/hpf (high-power field) for a diagnosis of EoE with biopsy samples taken from multiple levels of the esophagus.

The diagnosis of EoE is made by this confirmation of esophageal eosinophilia on biopsies in patients who have signs and symptoms of esophageal dysfunction that are not explained by another underlying condition.

In combination with the presence of esophageal eosinophilia, the assessment of symptoms and endoscopic findings are important in the evaluation for and diagnosis of EoE.

Sponsored